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class="user-info-component-wrapper"><div class="user-summary-cta-container"><div class="user-summary-container"><div class="social-profile-avatar-container"><img class="profile-avatar u-positionAbsolute" alt="Miguel Cavadas" border="0" onerror="if (this.src != '//a.academia-assets.com/images/s200_no_pic.png') this.src = '//a.academia-assets.com/images/s200_no_pic.png';" width="200" height="200" src="https://0.academia-photos.com/32999621/23944764/22943710/s200_miguel.cavadas.jpg" /></div><div class="title-container"><h1 class="ds2-5-heading-sans-serif-sm">Miguel Cavadas</h1><div class="affiliations-container fake-truncate js-profile-affiliations"><div><a class="u-tcGrayDarker" href="https://gulbenkian.academia.edu/">Instituto Gulbenkian de Ciência</a>, <a class="u-tcGrayDarker" href="https://gulbenkian.academia.edu/Departments/Membrane_Traffic/Documents">Membrane Traffic</a>, <span class="u-tcGrayDarker">Post-Doc</span></div></div></div></div><div class="sidebar-cta-container"><button 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href="https://www.academia.edu/31739576/Hypercapnia_Suppresses_the_HIF_dependent_Adaptive_Response_to_Hypoxia"><img alt="Research paper thumbnail of Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia" class="work-thumbnail" src="https://attachments.academia-assets.com/52048562/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31739576/Hypercapnia_Suppresses_the_HIF_dependent_Adaptive_Response_to_Hypoxia">Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/PeterSporn">Peter Sporn</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/EoinCummins">Eoin Cummins</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative me...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-􏰀 protein stabil- ity and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The sup- pressive effects of hypercapnia on HIF-􏰀 protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H􏰺 -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-􏰀 protein. Based on these results, we hypothesize that hypercapnia counter-reg- ulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-􏰀 subunits. Therefore, hypercapnia may play a key role in the pathophysiol- ogy of diseases where HIF is implicated.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="2fdc57b842e1edf38ad5667f611dc395" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52048562,"asset_id":31739576,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52048562/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31739576"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31739576"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31739576; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31739576]").text(description); $(".js-view-count[data-work-id=31739576]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31739576; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31739576']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31739576, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "2fdc57b842e1edf38ad5667f611dc395" } } $('.js-work-strip[data-work-id=31739576]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31739576,"title":"Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia","translated_title":"","metadata":{"abstract":"Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-􏰀 protein stabil- ity and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The sup- pressive effects of hypercapnia on HIF-􏰀 protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="31739493"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor"><img alt="Research paper thumbnail of REST is a hypoxia-responsive transcriptional repressor" class="work-thumbnail" src="https://attachments.academia-assets.com/52048513/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor">REST is a hypoxia-responsive transcriptional repressor</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://ucd.academia.edu/CiaraKeogh">Ciara Keogh</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/ZsoltFabian1">Zsolt Fabian</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AnitaWdowicz">Anita Wdowicz</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/EoinCummins">Eoin Cummins</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AlexCheong1">Alex Cheong</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pat...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up-or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5402e0b2c062eef5d20dbcda96beb948" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52048513,"asset_id":31739493,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52048513/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31739493"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31739493"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31739493; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31739493]").text(description); $(".js-view-count[data-work-id=31739493]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31739493; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31739493']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31739493, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5402e0b2c062eef5d20dbcda96beb948" } } $('.js-work-strip[data-work-id=31739493]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31739493,"title":"REST is a hypoxia-responsive transcriptional repressor","translated_title":"","metadata":{"abstract":"Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up-or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia. "},"translated_abstract":"Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up-or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="31738805"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31738805/Cavadas_et_al_2017_The_regulation_of_transcriptional_repression_in_hypoxia"><img alt="Research paper thumbnail of Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia" class="work-thumbnail" src="https://attachments.academia-assets.com/52047843/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31738805/Cavadas_et_al_2017_The_regulation_of_transcriptional_repression_in_hypoxia">Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia</a></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism a...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. However, much less is known about the mechanism(s) responsible for gene repression, an essential part of the adaptive transcriptional response. Hypoxia-induced gene repression leads to a reduction in energy demanding processes and the redirection of limited energetic resources to essential housekeeping functions. Recent developments have underscored the importance of transcriptional repressors in cellular adaptation to hypoxia. To date, at least ten distinct transcriptional repressors have been reported to demonstrate sensitivity to hypoxia. Central among these is the Repressor Element- 1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="509d44e5de4f5638f87fbe86c660c118" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52047843,"asset_id":31738805,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52047843/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31738805"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31738805"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31738805; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31738805]").text(description); $(".js-view-count[data-work-id=31738805]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31738805; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31738805']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31738805, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "509d44e5de4f5638f87fbe86c660c118" } } $('.js-work-strip[data-work-id=31738805]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31738805,"title":"Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia","translated_title":"","metadata":{"abstract":"A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. 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Central among these is the Repressor Element- 1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.\n"},"translated_abstract":"A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24984333"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24984333/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia"><img alt="Research paper thumbnail of REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24984333/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia">REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a> and <a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a></span></div><div class="wp-workCard_item"><span>Scientific reports</span><span>, 2015</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which p...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1...</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24984333"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24984333"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24984333; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24984333]").text(description); $(".js-view-count[data-work-id=24984333]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24984333; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24984333']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24984333, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=24984333]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24984333,"title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia","translated_title":"","metadata":{"abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1...","publication_date":{"day":null,"month":null,"year":2015,"errors":{}},"publication_name":"Scientific reports"},"translated_abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1...","internal_url":"https://www.academia.edu/24984333/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia","translated_internal_url":"","created_at":"2016-05-03T06:57:21.199-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":48001460,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":19798095,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":42651569,"co_author_invite_id":null,"email":"e***s@ucd.ie","display_order":0,"name":"Eoin Cummins","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798096,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":32999621,"co_author_invite_id":null,"email":"m***s@igc.gulbenkian.pt","affiliation":"Instituto Gulbenkian de Ciência","display_order":4194304,"name":"Miguel Cavadas","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798097,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":47811246,"co_author_invite_id":null,"email":"m***s@gmail.com","affiliation":"Kuleuven","display_order":6291456,"name":"Marion Mesnieres","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798098,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":47951587,"co_author_invite_id":null,"email":"m***a@ucdconnect.ie","display_order":7340032,"name":"M. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744977"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744977/Hypercapnia_suppresses_the_HIF_dependent_adaptive_response_to_hypoxia"><img alt="Research paper thumbnail of Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia." class="work-thumbnail" src="https://attachments.academia-assets.com/45073714/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744977/Hypercapnia_suppresses_the_HIF_dependent_adaptive_response_to_hypoxia">Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia.</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/PeterSporn">Peter Sporn</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://northwestern.academia.edu/LynnWelch">Lynn Welch</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states including acute and chronic respiratory diseases. The hypoxia inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia, however little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and in cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at constant pCO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="bd4855ec3d61823e94e88f76b5c6ed01" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073714,"asset_id":24744977,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073714/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744977"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744977"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744977; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744977]").text(description); $(".js-view-count[data-work-id=24744977]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744977; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744977']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744977, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "bd4855ec3d61823e94e88f76b5c6ed01" } } $('.js-work-strip[data-work-id=24744977]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744977,"title":"Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia.","translated_title":"","metadata":{"abstract":"Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism, respectively. 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Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated."},"translated_abstract":"Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states including acute and chronic respiratory diseases. The hypoxia inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia, however little is known about the impact of hypercapnia on gene transcription. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744909"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744909/Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation"><img alt="Research paper thumbnail of Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation" class="work-thumbnail" src="https://attachments.academia-assets.com/45073701/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744909/Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation">Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a> and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/TimErrington">Tim Errington</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibili...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from " COT drives resistance to RAF inhibition through MAPK pathway reactivation " by Johannessen and colleagues, published in Nature in 2010 (Johannessen et al., 2010). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/ TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="39f9a2e1d66ee9a9ec5162be7477920a" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073701,"asset_id":24744909,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073701/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744909"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744909"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744909; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744909]").text(description); $(".js-view-count[data-work-id=24744909]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744909; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744909']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744909, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "39f9a2e1d66ee9a9ec5162be7477920a" } } $('.js-work-strip[data-work-id=24744909]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744909,"title":"Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation","translated_title":"","metadata":{"abstract":"The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from \" COT drives resistance to RAF inhibition through MAPK pathway reactivation \" by Johannessen and colleagues, published in Nature in 2010 (Johannessen et al., 2010). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/ TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife."},"translated_abstract":"The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from \" COT drives resistance to RAF inhibition through MAPK pathway reactivation \" by Johannessen and colleagues, published in Nature in 2010 (Johannessen et al., 2010). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/ TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.","internal_url":"https://www.academia.edu/24744909/Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation","translated_internal_url":"","created_at":"2016-04-25T09:28:45.035-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":19530832,"work_id":24744909,"tagging_user_id":32999621,"tagged_user_id":47836026,"co_author_invite_id":4430145,"email":"t***m@cos.io","display_order":0,"name":"Tim Errington","title":"Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation"}],"downloadable_attachments":[{"id":45073701,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/45073701/thumbnails/1.jpg","file_name":"elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation.pdf","download_url":"https://www.academia.edu/attachments/45073701/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Registered_Report_COT_drives_resistance.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/45073701/elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation-libre.pdf?1461601865=\u0026response-content-disposition=attachment%3B+filename%3DRegistered_Report_COT_drives_resistance.pdf\u0026Expires=1733011563\u0026Signature=KyC1010yOL5AlLJLbLFFtpJ6xxXOE~8MfeCQzqt4SR9Uz3AY5lyzSIYbR-WAAr6EpGIkUv3US43OyQOoAbXcRSgk3ajvbAwGJ9xdHf-ViY~B~FiDbkL-XipURsrgkipz082MkzEtPNSEDWf7UjhoMd1scfCTpdXAsAeUgGnagWTSaZESn7HbB3fZUV4XRiUaOIErbitpd53XZ41sKl~-4FEB~24IKWPvTVw9oO54h0Bf~XnxAgg37Bwqf~9jDpi1WF~bMtxCTQUQu2WC0k3IS3NfSqJXXhqiTlJIhoUXB2pFgXSKfFP9VVlJ1J92Szt0uOeAwrOkEgLMrmRdR8jA2Q__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation","translated_slug":"","page_count":32,"language":"en","content_type":"Work","owner":{"id":32999621,"first_name":"Miguel","middle_initials":"","last_name":"Cavadas","page_name":"MiguelCavadas","domain_name":"gulbenkian","created_at":"2015-07-12T03:59:24.369-07:00","display_name":"Miguel Cavadas","url":"https://gulbenkian.academia.edu/MiguelCavadas"},"attachments":[{"id":45073701,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/45073701/thumbnails/1.jpg","file_name":"elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation.pdf","download_url":"https://www.academia.edu/attachments/45073701/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Registered_Report_COT_drives_resistance.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/45073701/elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation-libre.pdf?1461601865=\u0026response-content-disposition=attachment%3B+filename%3DRegistered_Report_COT_drives_resistance.pdf\u0026Expires=1733011563\u0026Signature=KyC1010yOL5AlLJLbLFFtpJ6xxXOE~8MfeCQzqt4SR9Uz3AY5lyzSIYbR-WAAr6EpGIkUv3US43OyQOoAbXcRSgk3ajvbAwGJ9xdHf-ViY~B~FiDbkL-XipURsrgkipz082MkzEtPNSEDWf7UjhoMd1scfCTpdXAsAeUgGnagWTSaZESn7HbB3fZUV4XRiUaOIErbitpd53XZ41sKl~-4FEB~24IKWPvTVw9oO54h0Bf~XnxAgg37Bwqf~9jDpi1WF~bMtxCTQUQu2WC0k3IS3NfSqJXXhqiTlJIhoUXB2pFgXSKfFP9VVlJ1J92Szt0uOeAwrOkEgLMrmRdR8jA2Q__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":6021,"name":"Cancer","url":"https://www.academia.edu/Documents/in/Cancer"},{"id":13828,"name":"Cancer Cell Biology","url":"https://www.academia.edu/Documents/in/Cancer_Cell_Biology"},{"id":14195,"name":"Cancer Biology","url":"https://www.academia.edu/Documents/in/Cancer_Biology"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744900"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744900/FIH_Regulates_Cellular_Metabolism_through_Hydroxylation_of_the_Deubiquitinase_OTUB1"><img alt="Research paper thumbnail of FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1" class="work-thumbnail" src="https://attachments.academia-assets.com/45073685/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744900/FIH_Regulates_Cellular_Metabolism_through_Hydroxylation_of_the_Deubiquitinase_OTUB1">FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/DougHalligan">Doug Halligan</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AlexKriegsheim">Alex Kriegsheim</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://adelaide1.academia.edu/DanielPeet">Daniel Peet</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypox...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. Hypoxia is a commonly encountered physiologic and pathophysiologic stress to which mammalian cells have evolved an effective adaptive response. This response is governed by a transcription factor termed the hypoxia-inducible factor (HIF). The mechanisms linking the cellular sensing of oxygen levels to HIF activation have been elucidated and involve oxygen-dependent hydroxylation of HIF on proline and asparagine residues by a family of hydroxylases. A key question that remains unclear is the extent to which oxygen-dependent hydroxylation occurs as a functional post-translational modification outside of the HIF pathway. This is key to developing our understanding of whether hydroxylation is a general regulatory modification or one which has specifically evolved for the regulation of</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="fa97a324a63e2b45b1e3d5137e564aa6" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073685,"asset_id":24744900,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073685/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744900"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744900"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744900; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744900]").text(description); $(".js-view-count[data-work-id=24744900]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744900; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744900']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744900, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "fa97a324a63e2b45b1e3d5137e564aa6" } } $('.js-work-strip[data-work-id=24744900]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744900,"title":"FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1","translated_title":"","metadata":{"abstract":"The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. Hypoxia is a commonly encountered physiologic and pathophysiologic stress to which mammalian cells have evolved an effective adaptive response. This response is governed by a transcription factor termed the hypoxia-inducible factor (HIF). The mechanisms linking the cellular sensing of oxygen levels to HIF activation have been elucidated and involve oxygen-dependent hydroxylation of HIF on proline and asparagine residues by a family of hydroxylases. A key question that remains unclear is the extent to which oxygen-dependent hydroxylation occurs as a functional post-translational modification outside of the HIF pathway. This is key to developing our understanding of whether hydroxylation is a general regulatory modification or one which has specifically evolved for the regulation of"},"translated_abstract":"The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. Hypoxia is a commonly encountered physiologic and pathophysiologic stress to which mammalian cells have evolved an effective adaptive response. This response is governed by a transcription factor termed the hypoxia-inducible factor (HIF). The mechanisms linking the cellular sensing of oxygen levels to HIF activation have been elucidated and involve oxygen-dependent hydroxylation of HIF on proline and asparagine residues by a family of hydroxylases. 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dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744858"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN"><img alt="Research paper thumbnail of REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN" class="work-thumbnail" src="https://attachments.academia-assets.com/45073645/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN">REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/MManresa">M. Manresa</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which p...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α-(but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 .</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="acb327469b8e3627688d02df2b6a2522" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073645,"asset_id":24744858,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073645/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744858"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744858"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744858; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744858]").text(description); $(".js-view-count[data-work-id=24744858]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744858; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744858']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744858, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "acb327469b8e3627688d02df2b6a2522" } } $('.js-work-strip[data-work-id=24744858]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744858,"title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN","translated_title":"","metadata":{"abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α-(but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 ."},"translated_abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α-(but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 .","internal_url":"https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN","translated_internal_url":"","created_at":"2016-04-25T09:24:20.036-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":19530826,"work_id":24744858,"tagging_user_id":32999621,"tagged_user_id":47811246,"co_author_invite_id":4430141,"email":"m***s@gmail.com","affiliation":"Kuleuven","display_order":0,"name":"Marion Mesnieres","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN"},{"id":19530827,"work_id":24744858,"tagging_user_id":32999621,"tagged_user_id":47951587,"co_author_invite_id":751138,"email":"m***a@ucdconnect.ie","display_order":4194304,"name":"M. Manresa","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN"},{"id":19530836,"work_id":24744858,"tagging_user_id":32999621,"tagged_user_id":47819262,"co_author_invite_id":4430146,"email":"a***g@aston.ac.uk","display_order":6291456,"name":"Alex Cheong","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN"},{"id":19530853,"work_id":24744858,"tagging_user_id":32999621,"tagged_user_id":48001460,"co_author_invite_id":4430150,"email":"b***o@hotmail.it","display_order":7340032,"name":"Bianca Crifo","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN"},{"id":19530855,"work_id":24744858,"tagging_user_id":32999621,"tagged_user_id":69924116,"co_author_invite_id":4430151,"email":"a***e@ucdconnect.ie","display_order":7864320,"name":"Andrew Selfridge","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN"},{"id":19530861,"work_id":24744858,"tagging_user_id":32999621,"tagged_user_id":null,"co_author_invite_id":443608,"email":"c***r@ucd.ie","display_order":8126464,"name":"Cormac Taylor","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN"}],"downloadable_attachments":[{"id":45073645,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/45073645/thumbnails/1.jpg","file_name":"Cavadas_et_al._2015_Sci_Rep_srep17851_FINAL_REST_resolution_of_HIF_responses.pdf","download_url":"https://www.academia.edu/attachments/45073645/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"REST_mediates_resolution_of_HIF_dependen.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/45073645/Cavadas_et_al._2015_Sci_Rep_srep17851_FINAL_REST_resolution_of_HIF_responses-libre.pdf?1461601568=\u0026response-content-disposition=attachment%3B+filename%3DREST_mediates_resolution_of_HIF_dependen.pdf\u0026Expires=1732938994\u0026Signature=DqsTy1DcDXaKWiTw-yYbX1et0jCBpFKYk0gUCTw5ldWI~juHYAv2Y2Li~5pyZHvpO~HTV68N69W5BIyPauVDLDDh1uMpvGBzq1WxCFHCqYagUvRTzib834o9ZuJA7RuG2T46a178Ksv15OPTSsdAM7ik6F1ojPUCN0ruY0Hm8zr9uAhrqK1Nqcxs7jh2ftvtL-cyMcJ1-1YDbFN8oadE-Pwmm-MxSi4vOSbReWOmAcTkt8um9gmk97vQ2HNNX067zQresL89gppdpZk1G9LnqeQ9G5wT5aF1N7FI01AaCgXnOD~9C7T66Bo1PW1YlLOyuwXB1Yf6OseK-frx5Y32lw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN","translated_slug":"","page_count":12,"language":"en","content_type":"Work","owner":{"id":32999621,"first_name":"Miguel","middle_initials":"","last_name":"Cavadas","page_name":"MiguelCavadas","domain_name":"gulbenkian","created_at":"2015-07-12T03:59:24.369-07:00","display_name":"Miguel Cavadas","url":"https://gulbenkian.academia.edu/MiguelCavadas"},"attachments":[{"id":45073645,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/45073645/thumbnails/1.jpg","file_name":"Cavadas_et_al._2015_Sci_Rep_srep17851_FINAL_REST_resolution_of_HIF_responses.pdf","download_url":"https://www.academia.edu/attachments/45073645/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"REST_mediates_resolution_of_HIF_dependen.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/45073645/Cavadas_et_al._2015_Sci_Rep_srep17851_FINAL_REST_resolution_of_HIF_responses-libre.pdf?1461601568=\u0026response-content-disposition=attachment%3B+filename%3DREST_mediates_resolution_of_HIF_dependen.pdf\u0026Expires=1732938994\u0026Signature=DqsTy1DcDXaKWiTw-yYbX1et0jCBpFKYk0gUCTw5ldWI~juHYAv2Y2Li~5pyZHvpO~HTV68N69W5BIyPauVDLDDh1uMpvGBzq1WxCFHCqYagUvRTzib834o9ZuJA7RuG2T46a178Ksv15OPTSsdAM7ik6F1ojPUCN0ruY0Hm8zr9uAhrqK1Nqcxs7jh2ftvtL-cyMcJ1-1YDbFN8oadE-Pwmm-MxSi4vOSbReWOmAcTkt8um9gmk97vQ2HNNX067zQresL89gppdpZk1G9LnqeQ9G5wT5aF1N7FI01AaCgXnOD~9C7T66Bo1PW1YlLOyuwXB1Yf6OseK-frx5Y32lw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":10990,"name":"Hypoxia","url":"https://www.academia.edu/Documents/in/Hypoxia"},{"id":23323,"name":"Transcription Factors","url":"https://www.academia.edu/Documents/in/Transcription_Factors"},{"id":147607,"name":"Transcriptional regulation","url":"https://www.academia.edu/Documents/in/Transcriptional_regulation"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="13940629"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940629/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility"><img alt="Research paper thumbnail of Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility" class="work-thumbnail" src="https://attachments.academia-assets.com/44783453/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940629/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility">Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility</a></div><div class="wp-workCard_item"><span>Nanomedicine : nanotechnology, biology, and medicine</span><span>, 2011</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery s...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples...</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="ec5f9344514e1de53067efedc56e2579" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783453,"asset_id":13940629,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783453/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940629"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940629"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940629; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13940629]").text(description); $(".js-view-count[data-work-id=13940629]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13940629; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='13940629']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 13940629, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "ec5f9344514e1de53067efedc56e2579" } } $('.js-work-strip[data-work-id=13940629]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":13940629,"title":"Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility","translated_title":"","metadata":{"abstract":"The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples...","publication_date":{"day":null,"month":null,"year":2011,"errors":{}},"publication_name":"Nanomedicine : nanotechnology, biology, and medicine"},"translated_abstract":"The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples...","internal_url":"https://www.academia.edu/13940629/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility","translated_internal_url":"","created_at":"2015-07-12T04:00:50.974-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":2923024,"work_id":13940629,"tagging_user_id":32999621,"tagged_user_id":null,"co_author_invite_id":751136,"email":"r***o@dq.fct.unl.pt","display_order":0,"name":"Ricardo Franco","title":"Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility"},{"id":19530848,"work_id":13940629,"tagging_user_id":32999621,"tagged_user_id":39286425,"co_author_invite_id":null,"email":"g***a@gmail.com","display_order":4194304,"name":"África González-fernández","title":"Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility"}],"downloadable_attachments":[{"id":44783453,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/44783453/thumbnails/1.jpg","file_name":"Pathogen-mimetic_stealth_nanocarriers_fo20160416-28548-116t2aj.pdf","download_url":"https://www.academia.edu/attachments/44783453/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Pathogen_mimetic_stealth_nanocarriers_fo.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/44783453/Pathogen-mimetic_stealth_nanocarriers_fo20160416-28548-116t2aj-libre.pdf?1460790401=\u0026response-content-disposition=attachment%3B+filename%3DPathogen_mimetic_stealth_nanocarriers_fo.pdf\u0026Expires=1733011563\u0026Signature=AX~5lL8Jzx67VAECF6wD16Ugyi~cSMLGMVQcHfDI-uvK1-jxEtpuCZdiW3pCFkA~-g37D42TRnrwZGyrxq-CqtWImoC8Jd1rTv5SKJTBCLhCoL5aeTVZDcRfemgAe~UrFvVzyGsquUkPoAG7FbeYjokthfr~K-5DnUNhxUmvvVjckDQTbfInQRdvutKolMPzQJfjDGR5Jv2uefWf~Zt8mBaji2juTvyAcRqRYBj4RAM1FNmxJ3KNguC9lvkGt~smcdMntTaJ6tgmxUhPmJVOIf80JYA16RPWcXY~lqbI~bl5KBLMW-eKr1Q9ME8P~yLW8BKLd~9jRMPuonVN0CR-Ew__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility","translated_slug":"","page_count":14,"language":"en","content_type":"Work","owner":{"id":32999621,"first_name":"Miguel","middle_initials":"","last_name":"Cavadas","page_name":"MiguelCavadas","domain_name":"gulbenkian","created_at":"2015-07-12T03:59:24.369-07:00","display_name":"Miguel Cavadas","url":"https://gulbenkian.academia.edu/MiguelCavadas"},"attachments":[{"id":44783453,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/44783453/thumbnails/1.jpg","file_name":"Pathogen-mimetic_stealth_nanocarriers_fo20160416-28548-116t2aj.pdf","download_url":"https://www.academia.edu/attachments/44783453/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Pathogen_mimetic_stealth_nanocarriers_fo.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/44783453/Pathogen-mimetic_stealth_nanocarriers_fo20160416-28548-116t2aj-libre.pdf?1460790401=\u0026response-content-disposition=attachment%3B+filename%3DPathogen_mimetic_stealth_nanocarriers_fo.pdf\u0026Expires=1733011563\u0026Signature=AX~5lL8Jzx67VAECF6wD16Ugyi~cSMLGMVQcHfDI-uvK1-jxEtpuCZdiW3pCFkA~-g37D42TRnrwZGyrxq-CqtWImoC8Jd1rTv5SKJTBCLhCoL5aeTVZDcRfemgAe~UrFvVzyGsquUkPoAG7FbeYjokthfr~K-5DnUNhxUmvvVjckDQTbfInQRdvutKolMPzQJfjDGR5Jv2uefWf~Zt8mBaji2juTvyAcRqRYBj4RAM1FNmxJ3KNguC9lvkGt~smcdMntTaJ6tgmxUhPmJVOIf80JYA16RPWcXY~lqbI~bl5KBLMW-eKr1Q9ME8P~yLW8BKLd~9jRMPuonVN0CR-Ew__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":923,"name":"Technology","url":"https://www.academia.edu/Documents/in/Technology"},{"id":13621,"name":"Nanoparticles","url":"https://www.academia.edu/Documents/in/Nanoparticles"},{"id":21466,"name":"Polymers","url":"https://www.academia.edu/Documents/in/Polymers"},{"id":47884,"name":"Biological Sciences","url":"https://www.academia.edu/Documents/in/Biological_Sciences"},{"id":159187,"name":"Drug Delivery Systems","url":"https://www.academia.edu/Documents/in/Drug_Delivery_Systems"},{"id":260118,"name":"CHEMICAL SCIENCES","url":"https://www.academia.edu/Documents/in/CHEMICAL_SCIENCES"},{"id":376644,"name":"Phagocytosis","url":"https://www.academia.edu/Documents/in/Phagocytosis"},{"id":496063,"name":"Thrombosis","url":"https://www.academia.edu/Documents/in/Thrombosis"},{"id":923659,"name":"Virulence Factors","url":"https://www.academia.edu/Documents/in/Virulence_Factors"},{"id":1894220,"name":"Nanocarriers","url":"https://www.academia.edu/Documents/in/Nanocarriers"},{"id":1900203,"name":"Hemolysis","url":"https://www.academia.edu/Documents/in/Hemolysis"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="13940627"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940627/Gold_nanoparticle_based_fluorescence_immunoassay_for_malaria_antigen_detection"><img alt="Research paper thumbnail of Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection" class="work-thumbnail" src="https://attachments.academia-assets.com/44783444/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940627/Gold_nanoparticle_based_fluorescence_immunoassay_for_malaria_antigen_detection">Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://unl-pt.academia.edu/IsabelSilva">Isabel Silva</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://unl-pt.academia.edu/In%C3%AAsGomes">Inês Gomes</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://unl-pt.academia.edu/PedroBaptista">Pedro Baptista</a></span></div><div class="wp-workCard_item"><span>Analytical and bioanalytical chemistry</span><span>, 2012</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The development of rapid detection assays for malaria diagnostics is an area of intensive researc...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The development of rapid detection assays for malaria diagnostics is an area of intensive research, as the traditional microscopic analysis of blood smears is cumbersome and requires skilled personnel. Here, we describe a simple and sensitive immunoassay that successfully detects malaria antigens in infected blood cultures. This homogeneous assay is based on the fluorescence quenching of cyanine 3B (Cy3B)-labeled recombinant Plasmodium falciparum heat shock protein 70 (PfHsp70) upon binding to gold nanoparticles (AuNPs) functionalized with an anti-Hsp70 monoclonal antibody. Upon competition with the free antigen, the Cy3B-labeled recombinant PfHsp70 is released to solution resulting in an increase of fluorescence intensity. Two types of AuNP-antibody conjugates were used as probes, one obtained by electrostatic adsorption of the antibody on AuNPs surface and the other by covalent bonding using protein cross-linking agents. In comparison with cross-linked antibodies, electrostatic ad...</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="d09d1929bcef57147ab57186f0126d41" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783444,"asset_id":13940627,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783444/download_file?st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940627"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940627"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940627; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13940627]").text(description); $(".js-view-count[data-work-id=13940627]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13940627; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='13940627']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 13940627, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "d09d1929bcef57147ab57186f0126d41" } } $('.js-work-strip[data-work-id=13940627]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":13940627,"title":"Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection","translated_title":"","metadata":{"abstract":"The development of rapid detection assays for malaria diagnostics is an area of intensive research, as the traditional microscopic analysis of blood smears is cumbersome and requires skilled personnel. 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thumbnail of Regulation of IL-1 -induced NF- B by hydroxylases links key hypoxic and inflammatory signaling pathways" class="work-thumbnail" src="https://attachments.academia-assets.com/44783493/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940616/Regulation_of_IL_1_induced_NF_B_by_hydroxylases_links_key_hypoxic_and_inflammatory_signaling_pathways">Regulation of IL-1 -induced NF- B by hydroxylases links key hypoxic and inflammatory signaling pathways</a></div><div class="wp-workCard_item"><span>Proceedings of the National Academy of Sciences</span><span>, 2013</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="bcec1135b7827543332f90cdfeb75448" class="wp-workCard--action" rel="nofollow" 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inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor κB (NF-κB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1β, a major proinflammatory cytokine that regulates NF-κB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1β-induced NF-κB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1β-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. 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/></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940615/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility">Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility</a></div><div class="wp-workCard_item"><span>Nanomedicine: Nanotechnology, Biology and Medicine</span><span>, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="231438d9cb53b22b57c9c1116d2affe2" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783456,"asset_id":13940615,"asset_type":"Work","button_location":"profile"}" 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Current approaches rely on the protein-and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples of alternatives to PEGylation. We present a novel conceptual approach that includes virulence factors for the engineering of bioactive, immune system-evasive stealth nanocarriers.","publication_date":{"day":null,"month":null,"year":2011,"errors":{}},"publication_name":"Nanomedicine: Nanotechnology, Biology and Medicine","grobid_abstract_attachment_id":44783456},"translated_abstract":null,"internal_url":"https://www.academia.edu/13940615/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility","translated_internal_url":"","created_at":"2015-07-12T04:00:50.198-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":2923020,"work_id":13940615,"tagging_user_id":32999621,"tagged_user_id":null,"co_author_invite_id":751136,"email":"r***o@dq.fct.unl.pt","display_order":0,"name":"Ricardo Franco","title":"Pathogen-mimetic stealth nanocarriers for drug delivery: a future 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data-work-id="13940614"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940614/A_dynamic_model_of_the_hypoxia_inducible_factor_1_HIF_1_network"><img alt="Research paper thumbnail of A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network" class="work-thumbnail" src="https://attachments.academia-assets.com/44783429/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940614/A_dynamic_model_of_the_hypoxia_inducible_factor_1_HIF_1_network">A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a> and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/MManresa">M. Manresa</a></span></div><div class="wp-workCard_item"><span>Journal of Cell Science</span><span>, 2013</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="25dc81634af1896200c3ecd333d86ffb" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783429,"asset_id":13940614,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783429/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940614"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940614"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940614; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13940614]").text(description); $(".js-view-count[data-work-id=13940614]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13940614; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='13940614']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 13940614, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "25dc81634af1896200c3ecd333d86ffb" } } $('.js-work-strip[data-work-id=13940614]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":13940614,"title":"A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network","translated_title":"","metadata":{"publication_date":{"day":null,"month":null,"year":2013,"errors":{}},"publication_name":"Journal of Cell Science"},"translated_abstract":null,"internal_url":"https://www.academia.edu/13940614/A_dynamic_model_of_the_hypoxia_inducible_factor_1_HIF_1_network","translated_internal_url":"","created_at":"2015-07-12T04:00:50.102-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":2922987,"work_id":13940614,"tagging_user_id":32999621,"tagged_user_id":3667510,"co_author_invite_id":null,"email":"l***n@ucd.ie","display_order":0,"name":"Lan K. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="13940613"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940613/Hypoxia_inducible_factor_HIF_network_insights_from_mathematical_models"><img alt="Research paper thumbnail of Hypoxia-inducible factor (HIF) network: insights from mathematical models" class="work-thumbnail" src="https://attachments.academia-assets.com/44783439/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940613/Hypoxia_inducible_factor_HIF_network_insights_from_mathematical_models">Hypoxia-inducible factor (HIF) network: insights from mathematical models</a></div><div class="wp-workCard_item"><span>Cell Communication and Signaling</span><span>, 2013</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="7344531f9648a9645bde56008d9c625b" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783439,"asset_id":13940613,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783439/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940613"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940613"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940613; 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When oxygen demand exceeds supply, the oxygen sensing pathway centred on the hypoxia inducible factor (HIF) is switched on and promotes adaptation to hypoxia by upregulating genes involved in angiogenesis, erythropoiesis and glycolysis. The regulation of HIF is tightly modulated through intricate regulatory mechanisms. Notably, its protein stability is controlled by the oxygen sensing prolyl hydroxylase domain (PHD) enzymes and its transcriptional activity is controlled by the asparaginyl hydroxylase FIH (factor inhibiting HIF-1). To probe the complexity of hypoxia-induced HIF signalling, efforts in mathematical modelling of the pathway have been underway for around a decade. In this paper, we review the existing mathematical models developed to describe and explain specific behaviours of the HIF pathway and how they have contributed new insights into our understanding of the network. Topics for modelling included the switch-like response to decreased oxygen gradient, the role of micro environmental factors, the regulation by FIH and the temporal dynamics of the HIF response. We will also discuss the technical aspects, extent and limitations of these models. Recently, HIF pathway has been implicated in other disease contexts such as hypoxic inflammation and cancer through crosstalking with pathways like NFκB and mTOR. We will examine how future mathematical modelling and simulation of interlinked networks can aid in understanding HIF behaviour in complex pathophysiological situations. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> </div><div class="profile--tab_content_container js-tab-pane tab-pane" data-section-id="3202573" id="papers"><div class="js-work-strip profile--work_container" data-work-id="31739576"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31739576/Hypercapnia_Suppresses_the_HIF_dependent_Adaptive_Response_to_Hypoxia"><img alt="Research paper thumbnail of Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia" class="work-thumbnail" src="https://attachments.academia-assets.com/52048562/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31739576/Hypercapnia_Suppresses_the_HIF_dependent_Adaptive_Response_to_Hypoxia">Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/PeterSporn">Peter Sporn</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/EoinCummins">Eoin Cummins</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative me...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-􏰀 protein stabil- ity and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The sup- pressive effects of hypercapnia on HIF-􏰀 protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H􏰺 -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-􏰀 protein. Based on these results, we hypothesize that hypercapnia counter-reg- ulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-􏰀 subunits. Therefore, hypercapnia may play a key role in the pathophysiol- ogy of diseases where HIF is implicated.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="2fdc57b842e1edf38ad5667f611dc395" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52048562,"asset_id":31739576,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52048562/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31739576"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31739576"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31739576; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31739576]").text(description); $(".js-view-count[data-work-id=31739576]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31739576; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31739576']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31739576, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "2fdc57b842e1edf38ad5667f611dc395" } } $('.js-work-strip[data-work-id=31739576]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31739576,"title":"Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia","translated_title":"","metadata":{"abstract":"Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-􏰀 protein stabil- ity and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The sup- pressive effects of hypercapnia on HIF-􏰀 protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H􏰺 -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-􏰀 protein. Based on these results, we hypothesize that hypercapnia counter-reg- ulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-􏰀 subunits. Therefore, hypercapnia may play a key role in the pathophysiol- ogy of diseases where HIF is implicated."},"translated_abstract":"Molecular oxygen and carbon dioxide are the primary gaseous substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states, including acute and chronic respiratory diseases. The hypoxia-inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia; however, little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-􏰀 protein stabil- ity and HIF target gene expression both in mice and cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The sup- pressive effects of hypercapnia on HIF-􏰀 protein stability could be mimicked by reducing intracellular pH at a constant level of partial pressure of CO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H􏰺 -ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-􏰀 protein. Based on these results, we hypothesize that hypercapnia counter-reg- ulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-􏰀 subunits. Therefore, hypercapnia may play a key role in the pathophysiol- ogy of diseases where HIF is implicated.","internal_url":"https://www.academia.edu/31739576/Hypercapnia_Suppresses_the_HIF_dependent_Adaptive_Response_to_Hypoxia","translated_internal_url":"","created_at":"2017-03-06T11:56:24.285-08:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":27910987,"work_id":31739576,"tagging_user_id":32999621,"tagged_user_id":69924116,"co_author_invite_id":4430151,"email":"a***e@ucdconnect.ie","display_order":1,"name":"Andrew Selfridge","title":"Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia"},{"id":27910988,"work_id":31739576,"tagging_user_id":32999621,"tagged_user_id":54151829,"co_author_invite_id":null,"email":"c***z@gmail.com","display_order":3,"name":"Carsten C. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="31739493"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor"><img alt="Research paper thumbnail of REST is a hypoxia-responsive transcriptional repressor" class="work-thumbnail" src="https://attachments.academia-assets.com/52048513/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31739493/REST_is_a_hypoxia_responsive_transcriptional_repressor">REST is a hypoxia-responsive transcriptional repressor</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://ucd.academia.edu/CiaraKeogh">Ciara Keogh</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/ZsoltFabian1">Zsolt Fabian</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AnitaWdowicz">Anita Wdowicz</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/EoinCummins">Eoin Cummins</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AlexCheong1">Alex Cheong</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pat...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up-or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5402e0b2c062eef5d20dbcda96beb948" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52048513,"asset_id":31739493,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52048513/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31739493"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31739493"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31739493; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31739493]").text(description); $(".js-view-count[data-work-id=31739493]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31739493; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31739493']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31739493, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "5402e0b2c062eef5d20dbcda96beb948" } } $('.js-work-strip[data-work-id=31739493]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31739493,"title":"REST is a hypoxia-responsive transcriptional repressor","translated_title":"","metadata":{"abstract":"Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up-or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. Based on these data, we propose that REST is a key mediator of gene repression in hypoxia. "},"translated_abstract":"Cellular exposure to hypoxia results in altered gene expression in a range of physiologic and pathophysiologic states. Discrete cohorts of genes can be either up-or down-regulated in response to hypoxia. While the Hypoxia-Inducible Factor (HIF) is the primary driver of hypoxia-induced adaptive gene expression, less is known about the signalling mechanisms regulating hypoxia-dependent gene repression. Using RNA-seq, we demonstrate that equivalent numbers of genes are induced and repressed in human embryonic kidney (HEK293) cells. We demonstrate that nuclear localization of the Repressor Element 1-Silencing Transcription factor (REST) is induced in hypoxia and that REST is responsible for regulating approximately 20% of the hypoxia-repressed genes. Using chromatin immunoprecipitation assays we demonstrate that REST-dependent gene repression is at least in part mediated by direct binding to the promoters of target genes. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="31738805"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/31738805/Cavadas_et_al_2017_The_regulation_of_transcriptional_repression_in_hypoxia"><img alt="Research paper thumbnail of Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia" class="work-thumbnail" src="https://attachments.academia-assets.com/52047843/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/31738805/Cavadas_et_al_2017_The_regulation_of_transcriptional_repression_in_hypoxia">Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia</a></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism a...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. However, much less is known about the mechanism(s) responsible for gene repression, an essential part of the adaptive transcriptional response. Hypoxia-induced gene repression leads to a reduction in energy demanding processes and the redirection of limited energetic resources to essential housekeeping functions. Recent developments have underscored the importance of transcriptional repressors in cellular adaptation to hypoxia. To date, at least ten distinct transcriptional repressors have been reported to demonstrate sensitivity to hypoxia. Central among these is the Repressor Element- 1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="509d44e5de4f5638f87fbe86c660c118" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52047843,"asset_id":31738805,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52047843/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31738805"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31738805"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31738805; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31738805]").text(description); $(".js-view-count[data-work-id=31738805]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31738805; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31738805']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31738805, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "509d44e5de4f5638f87fbe86c660c118" } } $('.js-work-strip[data-work-id=31738805]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31738805,"title":"Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia","translated_title":"","metadata":{"abstract":"A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. However, much less is known about the mechanism(s) responsible for gene repression, an essential part of the adaptive transcriptional response. Hypoxia-induced gene repression leads to a reduction in energy demanding processes and the redirection of limited energetic resources to essential housekeeping functions. Recent developments have underscored the importance of transcriptional repressors in cellular adaptation to hypoxia. To date, at least ten distinct transcriptional repressors have been reported to demonstrate sensitivity to hypoxia. Central among these is the Repressor Element- 1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.\n"},"translated_abstract":"A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia. However, much less is known about the mechanism(s) responsible for gene repression, an essential part of the adaptive transcriptional response. Hypoxia-induced gene repression leads to a reduction in energy demanding processes and the redirection of limited energetic resources to essential housekeeping functions. Recent developments have underscored the importance of transcriptional repressors in cellular adaptation to hypoxia. To date, at least ten distinct transcriptional repressors have been reported to demonstrate sensitivity to hypoxia. Central among these is the Repressor Element- 1 Silencing Transcription factor (REST), which regulates over 200 genes. In this review, written to honor the memory and outstanding scientific legacy of Lorenz Poellinger, we provide an overview of our existing knowledge with respect to transcriptional repressors and their target genes in hypoxia.\n","internal_url":"https://www.academia.edu/31738805/Cavadas_et_al_2017_The_regulation_of_transcriptional_repression_in_hypoxia","translated_internal_url":"","created_at":"2017-03-06T10:34:52.867-08:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":27910240,"work_id":31738805,"tagging_user_id":32999621,"tagged_user_id":null,"co_author_invite_id":443608,"email":"c***r@ucd.ie","display_order":1,"name":"Cormac Taylor","title":"Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia"},{"id":27910241,"work_id":31738805,"tagging_user_id":32999621,"tagged_user_id":47819262,"co_author_invite_id":null,"email":"a***g@aston.ac.uk","display_order":2,"name":"Alex Cheong","title":"Cavadas et al. 2017 The regulation of transcriptional repression in hypoxia"}],"downloadable_attachments":[{"id":52047843,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/52047843/thumbnails/1.jpg","file_name":"Cavadas_et_al._2017_Exp_Cell_Research_Trancriptional_Repressors_in_Hypoxia_Accep_Manuscript.pdf","download_url":"https://www.academia.edu/attachments/52047843/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Cavadas_et_al_2017_The_regulation_of_tra.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/52047843/Cavadas_et_al._2017_Exp_Cell_Research_Trancriptional_Repressors_in_Hypoxia_Accep_Manuscript-libre.pdf?1488825835=\u0026response-content-disposition=attachment%3B+filename%3DCavadas_et_al_2017_The_regulation_of_tra.pdf\u0026Expires=1733011563\u0026Signature=SHZGQejNkANUbinB5dCvFIkWcloLNMFPGuG25NXFHoheO1sJKv88QuJpETtd1P-a~x7WPKkwRCPEGTbOE~MdNO3oygKJHnyZwb3P4e3CVUrJ-zabLyQReH-gV284P~T~r1ZeZCwPan-RPzaK0cGmAQvXdxorPzJ9SmoNsu8EZPDZTRkg3dZvAMT4On7T2aT9ObenTZ3~a50R7BUFc7ZPt2XakTUf2XdrSWsy8avWvcNNOP2aWUvxgYFLnJ3CbfrnAzHfftRrK3yGsC5KDUnnPCwH5h1eNIp53HOTQseQ19grZ6zmh-I8Tk1w3QQQmcX9U~aJCvVrwNHmqqlNgC06Bw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Cavadas_et_al_2017_The_regulation_of_transcriptional_repression_in_hypoxia","translated_slug":"","page_count":28,"language":"en","content_type":"Work","owner":{"id":32999621,"first_name":"Miguel","middle_initials":"","last_name":"Cavadas","page_name":"MiguelCavadas","domain_name":"gulbenkian","created_at":"2015-07-12T03:59:24.369-07:00","display_name":"Miguel Cavadas","url":"https://gulbenkian.academia.edu/MiguelCavadas"},"attachments":[{"id":52047843,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/52047843/thumbnails/1.jpg","file_name":"Cavadas_et_al._2017_Exp_Cell_Research_Trancriptional_Repressors_in_Hypoxia_Accep_Manuscript.pdf","download_url":"https://www.academia.edu/attachments/52047843/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Cavadas_et_al_2017_The_regulation_of_tra.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/52047843/Cavadas_et_al._2017_Exp_Cell_Research_Trancriptional_Repressors_in_Hypoxia_Accep_Manuscript-libre.pdf?1488825835=\u0026response-content-disposition=attachment%3B+filename%3DCavadas_et_al_2017_The_regulation_of_tra.pdf\u0026Expires=1733011563\u0026Signature=SHZGQejNkANUbinB5dCvFIkWcloLNMFPGuG25NXFHoheO1sJKv88QuJpETtd1P-a~x7WPKkwRCPEGTbOE~MdNO3oygKJHnyZwb3P4e3CVUrJ-zabLyQReH-gV284P~T~r1ZeZCwPan-RPzaK0cGmAQvXdxorPzJ9SmoNsu8EZPDZTRkg3dZvAMT4On7T2aT9ObenTZ3~a50R7BUFc7ZPt2XakTUf2XdrSWsy8avWvcNNOP2aWUvxgYFLnJ3CbfrnAzHfftRrK3yGsC5KDUnnPCwH5h1eNIp53HOTQseQ19grZ6zmh-I8Tk1w3QQQmcX9U~aJCvVrwNHmqqlNgC06Bw__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":10990,"name":"Hypoxia","url":"https://www.academia.edu/Documents/in/Hypoxia"},{"id":147607,"name":"Transcriptional regulation","url":"https://www.academia.edu/Documents/in/Transcriptional_regulation"},{"id":931948,"name":"Gene expression and regulation","url":"https://www.academia.edu/Documents/in/Gene_expression_and_regulation"},{"id":2653107,"name":"Transcriptional Repressors","url":"https://www.academia.edu/Documents/in/Transcriptional_Repressors"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24984333"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24984333/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia"><img alt="Research paper thumbnail of REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia" class="work-thumbnail" src="https://a.academia-assets.com/images/blank-paper.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24984333/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia">REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a> and <a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a></span></div><div class="wp-workCard_item"><span>Scientific reports</span><span>, 2015</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which p...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1...</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24984333"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24984333"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24984333; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24984333]").text(description); $(".js-view-count[data-work-id=24984333]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24984333; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24984333']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24984333, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (false){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "-1" } } $('.js-work-strip[data-work-id=24984333]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24984333,"title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia","translated_title":"","metadata":{"abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1...","publication_date":{"day":null,"month":null,"year":2015,"errors":{}},"publication_name":"Scientific reports"},"translated_abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1...","internal_url":"https://www.academia.edu/24984333/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia","translated_internal_url":"","created_at":"2016-05-03T06:57:21.199-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":48001460,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":19798095,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":42651569,"co_author_invite_id":null,"email":"e***s@ucd.ie","display_order":0,"name":"Eoin Cummins","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798096,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":32999621,"co_author_invite_id":null,"email":"m***s@igc.gulbenkian.pt","affiliation":"Instituto Gulbenkian de Ciência","display_order":4194304,"name":"Miguel Cavadas","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798097,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":47811246,"co_author_invite_id":null,"email":"m***s@gmail.com","affiliation":"Kuleuven","display_order":6291456,"name":"Marion Mesnieres","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798098,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":47951587,"co_author_invite_id":null,"email":"m***a@ucdconnect.ie","display_order":7340032,"name":"M. Manresa","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798099,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":69924116,"co_author_invite_id":4430151,"email":"a***e@ucdconnect.ie","display_order":7864320,"name":"Andrew Selfridge","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"},{"id":19798100,"work_id":24984333,"tagging_user_id":48001460,"tagged_user_id":null,"co_author_invite_id":443608,"email":"c***r@ucd.ie","display_order":8126464,"name":"Cormac Taylor","title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia"}],"downloadable_attachments":[],"slug":"REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia","translated_slug":"","page_count":null,"language":"en","content_type":"Work","owner":{"id":48001460,"first_name":"Bianca","middle_initials":null,"last_name":"Crifo","page_name":"BiancaCrifo","domain_name":"independent","created_at":"2016-04-30T08:29:45.224-07:00","display_name":"Bianca Crifo","url":"https://independent.academia.edu/BiancaCrifo"},"attachments":[],"research_interests":[{"id":10990,"name":"Hypoxia","url":"https://www.academia.edu/Documents/in/Hypoxia"},{"id":23323,"name":"Transcription Factors","url":"https://www.academia.edu/Documents/in/Transcription_Factors"},{"id":147607,"name":"Transcriptional regulation","url":"https://www.academia.edu/Documents/in/Transcriptional_regulation"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24787432"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24787432/Ngyun_and_Cavadas_2012_HIF_model_JCS"><img alt="Research paper thumbnail of Ngyun and Cavadas 2012 HIF model JCS" class="work-thumbnail" src="https://attachments.academia-assets.com/45115015/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24787432/Ngyun_and_Cavadas_2012_HIF_model_JCS">Ngyun and Cavadas 2012 HIF model JCS</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/CrystalK4">Crystal K</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/CabreroManresa">Cabrero Manresa</a></span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="5654da675ba7710725e23ea3cd8fe503" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45115015,"asset_id":24787432,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45115015/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24787432"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24787432"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24787432; 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Although many of the key proteins involved have been characterised, the dynamics of their interactions in generating this response remain unclear. In the present study, we have generated a comprehensive mathematical model of the HIF-1a pathway based on core validated components and dynamic experimental data, and confirm the previously described connections within the predicted network topology. Our model confirms previous work demonstrating that the steps leading to optimal HIF-1a transcriptional activity require sequential inhibition of both prolyl-and asparaginyl-hydroxylases. We predict from our model (and confirm experimentally) that there is residual activity of the asparaginyl-hydroxylase FIH (factor inhibiting HIF) at low oxygen tension. Furthermore, silencing FIH under conditions where prolylhydroxylases are inhibited results in increased HIF-1a transcriptional activity, but paradoxically decreases HIF-1a stability. Using a core module of the HIF network and mathematical proof supported by experimental data, we propose that asparaginyl hydroxylation confers a degree of resistance upon HIF-1a to proteosomal degradation. Thus, through in vitro experimental data and in silico predictions, we provide a comprehensive model of the dynamic regulation of HIF-1a transcriptional activity by hydroxylases and use its predictive and adaptive properties to explain counter-intuitive biological observations.","publication_date":{"day":18,"month":3,"year":2014,"errors":{}},"grobid_abstract_attachment_id":45115015},"translated_abstract":null,"internal_url":"https://www.academia.edu/24787432/Ngyun_and_Cavadas_2012_HIF_model_JCS","translated_internal_url":"","created_at":"2016-04-26T16:29:26.909-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":19838119,"work_id":24787432,"tagging_user_id":32999621,"tagged_user_id":3667510,"co_author_invite_id":null,"email":"l***n@ucd.ie","display_order":0,"name":"Lan K. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744977"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744977/Hypercapnia_suppresses_the_HIF_dependent_adaptive_response_to_hypoxia"><img alt="Research paper thumbnail of Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia." class="work-thumbnail" src="https://attachments.academia-assets.com/45073714/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744977/Hypercapnia_suppresses_the_HIF_dependent_adaptive_response_to_hypoxia">Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia.</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/PeterSporn">Peter Sporn</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://northwestern.academia.edu/LynnWelch">Lynn Welch</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states including acute and chronic respiratory diseases. The hypoxia inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia, however little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and in cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at constant pCO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="bd4855ec3d61823e94e88f76b5c6ed01" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073714,"asset_id":24744977,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073714/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744977"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744977"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744977; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744977]").text(description); $(".js-view-count[data-work-id=24744977]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744977; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744977']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744977, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "bd4855ec3d61823e94e88f76b5c6ed01" } } $('.js-work-strip[data-work-id=24744977]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744977,"title":"Hypercapnia suppresses the HIF-dependent adaptive response to hypoxia.","translated_title":"","metadata":{"abstract":"Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states including acute and chronic respiratory diseases. The hypoxia inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia, however little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and in cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at constant pCO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. Therefore, hypercapnia may play a key role in the pathophysiology of diseases where HIF is implicated."},"translated_abstract":"Molecular oxygen and carbon dioxide are the primary substrate and product of oxidative metabolism, respectively. Hypoxia (low oxygen) and hypercapnia (high carbon dioxide) are co-incidental features of the tissue microenvironment in a range of pathophysiologic states including acute and chronic respiratory diseases. The hypoxia inducible factor (HIF) is the master regulator of the transcriptional response to hypoxia, however little is known about the impact of hypercapnia on gene transcription. Because of the relationship between hypoxia and hypercapnia, we investigated the effect of hypercapnia on the HIF pathway. Hypercapnia suppressed HIF-α protein stability and HIF target gene expression both in mice and in cultured cells in a manner that was at least in part independent of the canonical O2-dependent HIF degradation pathway. The suppressive effects of hypercapnia on HIF-α protein stability could be mimicked by reducing intracellular pH at constant pCO2. Bafilomycin A1, a specific inhibitor of vacuolar-type H+-ATPase that blocks lysosomal degradation, prevented the hypercapnic suppression of HIF-α protein. Based on these results, we hypothesize that hypercapnia counter-regulates activation of the HIF pathway by reducing intracellular pH and promoting lysosomal degradation of HIF-α subunits. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744909"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744909/Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation"><img alt="Research paper thumbnail of Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation" class="work-thumbnail" src="https://attachments.academia-assets.com/45073701/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744909/Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation">Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a> and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/TimErrington">Tim Errington</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibili...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from " COT drives resistance to RAF inhibition through MAPK pathway reactivation " by Johannessen and colleagues, published in Nature in 2010 (Johannessen et al., 2010). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/ TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="39f9a2e1d66ee9a9ec5162be7477920a" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073701,"asset_id":24744909,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073701/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744909"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744909"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744909; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744909]").text(description); $(".js-view-count[data-work-id=24744909]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744909; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744909']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744909, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "39f9a2e1d66ee9a9ec5162be7477920a" } } $('.js-work-strip[data-work-id=24744909]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744909,"title":"Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation","translated_title":"","metadata":{"abstract":"The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from \" COT drives resistance to RAF inhibition through MAPK pathway reactivation \" by Johannessen and colleagues, published in Nature in 2010 (Johannessen et al., 2010). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/ TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife."},"translated_abstract":"The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from \" COT drives resistance to RAF inhibition through MAPK pathway reactivation \" by Johannessen and colleagues, published in Nature in 2010 (Johannessen et al., 2010). The key experiments to be replicated are those reported in Figures 3B, 3D-E, 3I, and 4E-F. In Figures 3B, D-E, RPMI-7951 and OUMS023 cells were reported to exhibit robust ERK/MEK activity concomitant with reduced growth sensitivity in the presence of the BRAF inhibitor PLX4720. MAP3K8 (COT/ TPL2) directly regulated MEK/ERK phosphorylation, as the treatment of RPMI-7951 cells with a MAP3K8 kinase inhibitor resulted in a dose-dependent suppression of MEK/ERK activity (Figure 3I). In contrast, MAP3K8-deficient A375 cells remained sensitive to BRAF inhibition, exhibiting reduced growth and MEK/ERK activity during inhibitor treatment. To determine if RAF and MEK inhibitors together can overcome single-agent resistance, MAP3K8-expressing A375 cells treated with PLX4720 along with MEK inhibitors significantly inhibited both cell viability and ERK activation compared to treatment with PLX4720 alone, as reported in Figures 4E-F. The Reproducibility Project: Cancer Biology is collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.","internal_url":"https://www.academia.edu/24744909/Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation","translated_internal_url":"","created_at":"2016-04-25T09:28:45.035-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":19530832,"work_id":24744909,"tagging_user_id":32999621,"tagged_user_id":47836026,"co_author_invite_id":4430145,"email":"t***m@cos.io","display_order":0,"name":"Tim Errington","title":"Registered Report: COT drives resistance to RAF inhibition through MAP kinase pathway reactivation"}],"downloadable_attachments":[{"id":45073701,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/45073701/thumbnails/1.jpg","file_name":"elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation.pdf","download_url":"https://www.academia.edu/attachments/45073701/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Registered_Report_COT_drives_resistance.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/45073701/elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation-libre.pdf?1461601865=\u0026response-content-disposition=attachment%3B+filename%3DRegistered_Report_COT_drives_resistance.pdf\u0026Expires=1733011563\u0026Signature=KyC1010yOL5AlLJLbLFFtpJ6xxXOE~8MfeCQzqt4SR9Uz3AY5lyzSIYbR-WAAr6EpGIkUv3US43OyQOoAbXcRSgk3ajvbAwGJ9xdHf-ViY~B~FiDbkL-XipURsrgkipz082MkzEtPNSEDWf7UjhoMd1scfCTpdXAsAeUgGnagWTSaZESn7HbB3fZUV4XRiUaOIErbitpd53XZ41sKl~-4FEB~24IKWPvTVw9oO54h0Bf~XnxAgg37Bwqf~9jDpi1WF~bMtxCTQUQu2WC0k3IS3NfSqJXXhqiTlJIhoUXB2pFgXSKfFP9VVlJ1J92Szt0uOeAwrOkEgLMrmRdR8jA2Q__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"slug":"Registered_Report_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation","translated_slug":"","page_count":32,"language":"en","content_type":"Work","owner":{"id":32999621,"first_name":"Miguel","middle_initials":"","last_name":"Cavadas","page_name":"MiguelCavadas","domain_name":"gulbenkian","created_at":"2015-07-12T03:59:24.369-07:00","display_name":"Miguel Cavadas","url":"https://gulbenkian.academia.edu/MiguelCavadas"},"attachments":[{"id":45073701,"title":"","file_type":"pdf","scribd_thumbnail_url":"https://attachments.academia-assets.com/45073701/thumbnails/1.jpg","file_name":"elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation.pdf","download_url":"https://www.academia.edu/attachments/45073701/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&","bulk_download_file_name":"Registered_Report_COT_drives_resistance.pdf","bulk_download_url":"https://d1wqtxts1xzle7.cloudfront.net/45073701/elife-11414-v1_Registered_Report-_COT_drives_resistance_to_RAF_inhibition_through_MAP_kinase_pathway_reactivation-libre.pdf?1461601865=\u0026response-content-disposition=attachment%3B+filename%3DRegistered_Report_COT_drives_resistance.pdf\u0026Expires=1733011563\u0026Signature=KyC1010yOL5AlLJLbLFFtpJ6xxXOE~8MfeCQzqt4SR9Uz3AY5lyzSIYbR-WAAr6EpGIkUv3US43OyQOoAbXcRSgk3ajvbAwGJ9xdHf-ViY~B~FiDbkL-XipURsrgkipz082MkzEtPNSEDWf7UjhoMd1scfCTpdXAsAeUgGnagWTSaZESn7HbB3fZUV4XRiUaOIErbitpd53XZ41sKl~-4FEB~24IKWPvTVw9oO54h0Bf~XnxAgg37Bwqf~9jDpi1WF~bMtxCTQUQu2WC0k3IS3NfSqJXXhqiTlJIhoUXB2pFgXSKfFP9VVlJ1J92Szt0uOeAwrOkEgLMrmRdR8jA2Q__\u0026Key-Pair-Id=APKAJLOHF5GGSLRBV4ZA"}],"research_interests":[{"id":6021,"name":"Cancer","url":"https://www.academia.edu/Documents/in/Cancer"},{"id":13828,"name":"Cancer Cell Biology","url":"https://www.academia.edu/Documents/in/Cancer_Cell_Biology"},{"id":14195,"name":"Cancer Biology","url":"https://www.academia.edu/Documents/in/Cancer_Biology"}],"urls":[]}, dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744900"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744900/FIH_Regulates_Cellular_Metabolism_through_Hydroxylation_of_the_Deubiquitinase_OTUB1"><img alt="Research paper thumbnail of FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1" class="work-thumbnail" src="https://attachments.academia-assets.com/45073685/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744900/FIH_Regulates_Cellular_Metabolism_through_Hydroxylation_of_the_Deubiquitinase_OTUB1">FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/DougHalligan">Doug Halligan</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/AlexKriegsheim">Alex Kriegsheim</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/BiancaCrifo">Bianca Crifo</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://adelaide1.academia.edu/DanielPeet">Daniel Peet</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypox...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. Hypoxia is a commonly encountered physiologic and pathophysiologic stress to which mammalian cells have evolved an effective adaptive response. This response is governed by a transcription factor termed the hypoxia-inducible factor (HIF). The mechanisms linking the cellular sensing of oxygen levels to HIF activation have been elucidated and involve oxygen-dependent hydroxylation of HIF on proline and asparagine residues by a family of hydroxylases. A key question that remains unclear is the extent to which oxygen-dependent hydroxylation occurs as a functional post-translational modification outside of the HIF pathway. This is key to developing our understanding of whether hydroxylation is a general regulatory modification or one which has specifically evolved for the regulation of</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="fa97a324a63e2b45b1e3d5137e564aa6" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073685,"asset_id":24744900,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073685/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744900"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744900"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744900; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744900]").text(description); $(".js-view-count[data-work-id=24744900]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744900; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744900']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744900, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "fa97a324a63e2b45b1e3d5137e564aa6" } } $('.js-work-strip[data-work-id=24744900]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744900,"title":"FIH Regulates Cellular Metabolism through Hydroxylation of the Deubiquitinase OTUB1","translated_title":"","metadata":{"abstract":"The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. Hypoxia is a commonly encountered physiologic and pathophysiologic stress to which mammalian cells have evolved an effective adaptive response. This response is governed by a transcription factor termed the hypoxia-inducible factor (HIF). The mechanisms linking the cellular sensing of oxygen levels to HIF activation have been elucidated and involve oxygen-dependent hydroxylation of HIF on proline and asparagine residues by a family of hydroxylases. A key question that remains unclear is the extent to which oxygen-dependent hydroxylation occurs as a functional post-translational modification outside of the HIF pathway. This is key to developing our understanding of whether hydroxylation is a general regulatory modification or one which has specifically evolved for the regulation of"},"translated_abstract":"The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22. Mutation of N22 leads to a profound change in the interaction of OTUB1 with proteins important in cellular metabolism. Furthermore, in cultured cells, overexpression of N22A mutant OTUB1 impairs cellular metabolic processes when compared to wild type. Based on these data, we hypothesize that OTUB1 is a target for functional hydroxylation by FIH. Additionally, we propose that our results provide new insight into the regulation of cellular energy metabolism during hypoxic stress and the potential for targeting hydroxylases for therapeutic benefit. Hypoxia is a commonly encountered physiologic and pathophysiologic stress to which mammalian cells have evolved an effective adaptive response. This response is governed by a transcription factor termed the hypoxia-inducible factor (HIF). The mechanisms linking the cellular sensing of oxygen levels to HIF activation have been elucidated and involve oxygen-dependent hydroxylation of HIF on proline and asparagine residues by a family of hydroxylases. 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dispatcherData: dispatcherData }); $(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="24744858"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN"><img alt="Research paper thumbnail of REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN" class="work-thumbnail" src="https://attachments.academia-assets.com/45073645/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/24744858/REST_mediates_resolution_of_HIF_dependent_gene_expression_in_prolonged_hypoxia_OPEN">REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://kernkracht.academia.edu/MarionMesnieres">Marion Mesnieres</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/MManresa">M. Manresa</a></span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which p...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. However, the degree and duration of HIF-1α expression in hypoxia must be carefully balanced within cells in order to avoid unwanted side effects associated with excessive activity. The expression of HIF-1α mRNA is suppressed in prolonged hypoxia, suggesting that the control of HIF1A gene transcription is tightly regulated by negative feedback mechanisms. Little is known about the resolution of the HIF-1α protein response and the suppression of HIF-1α mRNA in prolonged hypoxia. Here, we demonstrate that the Repressor Element 1-Silencing Transcription factor (REST) binds to the HIF-1α promoter in a hypoxia-dependent manner. Knockdown of REST using RNAi increases the expression of HIF-1α mRNA, protein and transcriptional activity. Furthermore REST knockdown increases glucose consumption and lactate production in a HIF-1α-(but not HIF-2α-) dependent manner. Finally, REST promotes the resolution of HIF-1α protein expression in prolonged hypoxia. In conclusion, we hypothesize that REST represses transcription of HIF-1α in prolonged hypoxia, thus contributing to the resolution of the HIF-1α response. Hypoxia is a key microenvironmental feature of a range of physiological and pathophysiological conditions including embryonic development, exercise, cancer, ischemia and inflammation 1. Adaptive transcriptional pathways have evolved to help an organism deal with the metabolic threat posed by hypoxia. The best-described transcrip-tional adaptive response in cells is mediated by the hypoxia inducible factor (HIF) signalling pathway, which up-regulates genes which restore oxygen and energy homeostasis 2–4. In normoxia, HIFα is hydroxylated by the prolyl-hydroxylase domain (PHD) family of dioxygenases targeting it for proteosomal degradation 5. This process is reversed in hypoxia and HIFα is stabilized, dimerizes with HIFβ and binds to hypoxia response elements (HRE) in the regulatory regions of target genes 6. HIF drives an adaptive response to hypoxia by promoting the expression of genes including those that regulate erythropoiesis, angiogenesis and glycolysis 6. However in cancer, HIF signalling can be maladaptive and contribute to tumour survival 1. Because of the potentially deleterious effects of over-activation of the HIF pathway, a resolution mechanism is required to resolve its activity in prolonged hypoxia. In the absence of such a resolving mechanism, deleterious consequences such as pathologic angiogenesis and excessive haematocrit due to chronic HIF stabilization may occur 7–9. While several regulators of HIF expression exist, only a few have been shown to be involved in the resolution of the HIF response to hypoxia. PHD2 and PHD3 are, for example, part of an auto-regulatory mechanism, whereby HIF-1α which is stabilized in hypoxia, transcriptionally induces the expression of EGLN1 and EGLN3 genes coding for PHD2 and PHD3 proteins respectively 10–12. The increased expression of the PHD enzymes in turn promotes HIFα hydroxylation, and reduction of its expression in prolonged hypoxia 10. Less is known about the control of HIF1A mRNA stability 11. Interestingly, while HIF-1α protein is transiently up-regulated in hypoxia, the mRNA is frequently found to be repressed 12–15. This transcript attenuation can be conveyed through mRNA destabilization by the protein tristetraprolin in endothelial cells 14 and by miR155 in intestinal epithelial cells 12 .</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="acb327469b8e3627688d02df2b6a2522" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":45073645,"asset_id":24744858,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/45073645/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="24744858"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="24744858"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 24744858; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=24744858]").text(description); $(".js-view-count[data-work-id=24744858]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 24744858; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='24744858']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 24744858, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "acb327469b8e3627688d02df2b6a2522" } } $('.js-work-strip[data-work-id=24744858]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":24744858,"title":"REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia OPEN","translated_title":"","metadata":{"abstract":"The hypoxia-inducible factor (HIF) is a key regulator of the cellular response to hypoxia which promotes oxygen delivery and metabolic adaptation to oxygen deprivation. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="13940629"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940629/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility"><img alt="Research paper thumbnail of Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility" class="work-thumbnail" src="https://attachments.academia-assets.com/44783453/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940629/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility">Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility</a></div><div class="wp-workCard_item"><span>Nanomedicine : nanotechnology, biology, and medicine</span><span>, 2011</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery s...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples...</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="ec5f9344514e1de53067efedc56e2579" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783453,"asset_id":13940629,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783453/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2Myw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940629"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940629"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940629; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13940629]").text(description); $(".js-view-count[data-work-id=13940629]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13940629; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='13940629']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 13940629, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "ec5f9344514e1de53067efedc56e2579" } } $('.js-work-strip[data-work-id=13940629]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":13940629,"title":"Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility","translated_title":"","metadata":{"abstract":"The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples...","publication_date":{"day":null,"month":null,"year":2011,"errors":{}},"publication_name":"Nanomedicine : nanotechnology, biology, and medicine"},"translated_abstract":"The Mononuclear Phagocyte System (MPS) is a major constraint to nanocarrier-based drug-delivery systems (DDS) by exerting a negative impact on blood circulation times and biodistribution. Current approaches rely on the protein- and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="13940627"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940627/Gold_nanoparticle_based_fluorescence_immunoassay_for_malaria_antigen_detection"><img alt="Research paper thumbnail of Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection" class="work-thumbnail" src="https://attachments.academia-assets.com/44783444/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940627/Gold_nanoparticle_based_fluorescence_immunoassay_for_malaria_antigen_detection">Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://unl-pt.academia.edu/IsabelSilva">Isabel Silva</a>, <a class="" data-click-track="profile-work-strip-authors" href="https://unl-pt.academia.edu/In%C3%AAsGomes">Inês Gomes</a>, and <a class="" data-click-track="profile-work-strip-authors" href="https://unl-pt.academia.edu/PedroBaptista">Pedro Baptista</a></span></div><div class="wp-workCard_item"><span>Analytical and bioanalytical chemistry</span><span>, 2012</span></div><div class="wp-workCard_item"><span class="js-work-more-abstract-truncated">The development of rapid detection assays for malaria diagnostics is an area of intensive researc...</span><a class="js-work-more-abstract" data-broccoli-component="work_strip.more_abstract" data-click-track="profile-work-strip-more-abstract" href="javascript:;"><span> more </span><span><i class="fa fa-caret-down"></i></span></a><span class="js-work-more-abstract-untruncated hidden">The development of rapid detection assays for malaria diagnostics is an area of intensive research, as the traditional microscopic analysis of blood smears is cumbersome and requires skilled personnel. Here, we describe a simple and sensitive immunoassay that successfully detects malaria antigens in infected blood cultures. This homogeneous assay is based on the fluorescence quenching of cyanine 3B (Cy3B)-labeled recombinant Plasmodium falciparum heat shock protein 70 (PfHsp70) upon binding to gold nanoparticles (AuNPs) functionalized with an anti-Hsp70 monoclonal antibody. Upon competition with the free antigen, the Cy3B-labeled recombinant PfHsp70 is released to solution resulting in an increase of fluorescence intensity. Two types of AuNP-antibody conjugates were used as probes, one obtained by electrostatic adsorption of the antibody on AuNPs surface and the other by covalent bonding using protein cross-linking agents. In comparison with cross-linked antibodies, electrostatic ad...</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="d09d1929bcef57147ab57186f0126d41" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783444,"asset_id":13940627,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783444/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940627"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940627"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940627; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13940627]").text(description); $(".js-view-count[data-work-id=13940627]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13940627; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='13940627']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 13940627, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "d09d1929bcef57147ab57186f0126d41" } } $('.js-work-strip[data-work-id=13940627]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":13940627,"title":"Gold nanoparticle-based fluorescence immunoassay for malaria antigen detection","translated_title":"","metadata":{"abstract":"The development of rapid detection assays for malaria diagnostics is an area of intensive research, as the traditional microscopic analysis of blood smears is cumbersome and requires skilled personnel. 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thumbnail of Regulation of IL-1 -induced NF- B by hydroxylases links key hypoxic and inflammatory signaling pathways" class="work-thumbnail" src="https://attachments.academia-assets.com/44783493/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940616/Regulation_of_IL_1_induced_NF_B_by_hydroxylases_links_key_hypoxic_and_inflammatory_signaling_pathways">Regulation of IL-1 -induced NF- B by hydroxylases links key hypoxic and inflammatory signaling pathways</a></div><div class="wp-workCard_item"><span>Proceedings of the National Academy of Sciences</span><span>, 2013</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="bcec1135b7827543332f90cdfeb75448" class="wp-workCard--action" rel="nofollow" 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inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor κB (NF-κB), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1β, a major proinflammatory cytokine that regulates NF-κB, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1β-induced NF-κB at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1β-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. 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/></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940615/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility">Pathogen-mimetic stealth nanocarriers for drug delivery: a future possibility</a></div><div class="wp-workCard_item"><span>Nanomedicine: Nanotechnology, Biology and Medicine</span><span>, 2011</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="231438d9cb53b22b57c9c1116d2affe2" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783456,"asset_id":13940615,"asset_type":"Work","button_location":"profile"}" 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Current approaches rely on the protein-and cell-repelling properties of inert hydrophilic polymers, to enable escape from the MPS. Poly(ethylene glycol) (PEG) has been particularly useful in this regard, and it also exerts positive effects in other blood compatibility parameters, being correlated with decreased hemolysis, thrombogenicity, complement activation and protein adsorption, due to its uncharged and hydrophilic nature. However, PEGylated nanocarriers are commonly found in the liver and spleen, the major MPS organs. In fact, a hydrophilic and cell-repelling delivery system is not always beneficial, as it might decrease the interaction with the target cell and hinder drug release. Here, a full scope of the immunological and biochemical barriers is presented along with some selected examples of alternatives to PEGylation. We present a novel conceptual approach that includes virulence factors for the engineering of bioactive, immune system-evasive stealth nanocarriers.","publication_date":{"day":null,"month":null,"year":2011,"errors":{}},"publication_name":"Nanomedicine: Nanotechnology, Biology and Medicine","grobid_abstract_attachment_id":44783456},"translated_abstract":null,"internal_url":"https://www.academia.edu/13940615/Pathogen_mimetic_stealth_nanocarriers_for_drug_delivery_a_future_possibility","translated_internal_url":"","created_at":"2015-07-12T04:00:50.198-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":2923020,"work_id":13940615,"tagging_user_id":32999621,"tagged_user_id":null,"co_author_invite_id":751136,"email":"r***o@dq.fct.unl.pt","display_order":0,"name":"Ricardo Franco","title":"Pathogen-mimetic stealth nanocarriers for drug delivery: a future 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data-work-id="13940614"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940614/A_dynamic_model_of_the_hypoxia_inducible_factor_1_HIF_1_network"><img alt="Research paper thumbnail of A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network" class="work-thumbnail" src="https://attachments.academia-assets.com/44783429/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940614/A_dynamic_model_of_the_hypoxia_inducible_factor_1_HIF_1_network">A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network</a></div><div class="wp-workCard_item wp-workCard--coauthors"><span>by </span><span><a class="" data-click-track="profile-work-strip-authors" href="https://gulbenkian.academia.edu/MiguelCavadas">Miguel Cavadas</a> and <a class="" data-click-track="profile-work-strip-authors" href="https://independent.academia.edu/MManresa">M. Manresa</a></span></div><div class="wp-workCard_item"><span>Journal of Cell Science</span><span>, 2013</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="25dc81634af1896200c3ecd333d86ffb" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783429,"asset_id":13940614,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783429/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940614"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940614"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940614; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=13940614]").text(description); $(".js-view-count[data-work-id=13940614]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 13940614; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='13940614']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 13940614, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "25dc81634af1896200c3ecd333d86ffb" } } $('.js-work-strip[data-work-id=13940614]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":13940614,"title":"A dynamic model of the hypoxia-inducible factor 1 (HIF-1 ) network","translated_title":"","metadata":{"publication_date":{"day":null,"month":null,"year":2013,"errors":{}},"publication_name":"Journal of Cell Science"},"translated_abstract":null,"internal_url":"https://www.academia.edu/13940614/A_dynamic_model_of_the_hypoxia_inducible_factor_1_HIF_1_network","translated_internal_url":"","created_at":"2015-07-12T04:00:50.102-07:00","preview_url":null,"current_user_can_edit":null,"current_user_is_owner":null,"owner_id":32999621,"coauthors_can_edit":true,"document_type":"paper","co_author_tags":[{"id":2922987,"work_id":13940614,"tagging_user_id":32999621,"tagged_user_id":3667510,"co_author_invite_id":null,"email":"l***n@ucd.ie","display_order":0,"name":"Lan K. 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$(this).data('initialized', true); } }); $a.trackClickSource(".js-work-strip-work-link", "profile_work_strip") }); </script> <div class="js-work-strip profile--work_container" data-work-id="13940613"><div class="profile--work_thumbnail hidden-xs"><a class="js-work-strip-work-link" data-click-track="profile-work-strip-thumbnail" href="https://www.academia.edu/13940613/Hypoxia_inducible_factor_HIF_network_insights_from_mathematical_models"><img alt="Research paper thumbnail of Hypoxia-inducible factor (HIF) network: insights from mathematical models" class="work-thumbnail" src="https://attachments.academia-assets.com/44783439/thumbnails/1.jpg" /></a></div><div class="wp-workCard wp-workCard_itemContainer"><div class="wp-workCard_item wp-workCard--title"><a class="js-work-strip-work-link text-gray-darker" data-click-track="profile-work-strip-title" href="https://www.academia.edu/13940613/Hypoxia_inducible_factor_HIF_network_insights_from_mathematical_models">Hypoxia-inducible factor (HIF) network: insights from mathematical models</a></div><div class="wp-workCard_item"><span>Cell Communication and Signaling</span><span>, 2013</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="7344531f9648a9645bde56008d9c625b" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":44783439,"asset_id":13940613,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/44783439/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="13940613"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="13940613"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 13940613; 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When oxygen demand exceeds supply, the oxygen sensing pathway centred on the hypoxia inducible factor (HIF) is switched on and promotes adaptation to hypoxia by upregulating genes involved in angiogenesis, erythropoiesis and glycolysis. The regulation of HIF is tightly modulated through intricate regulatory mechanisms. Notably, its protein stability is controlled by the oxygen sensing prolyl hydroxylase domain (PHD) enzymes and its transcriptional activity is controlled by the asparaginyl hydroxylase FIH (factor inhibiting HIF-1). To probe the complexity of hypoxia-induced HIF signalling, efforts in mathematical modelling of the pathway have been underway for around a decade. In this paper, we review the existing mathematical models developed to describe and explain specific behaviours of the HIF pathway and how they have contributed new insights into our understanding of the network. Topics for modelling included the switch-like response to decreased oxygen gradient, the role of micro environmental factors, the regulation by FIH and the temporal dynamics of the HIF response. We will also discuss the technical aspects, extent and limitations of these models. Recently, HIF pathway has been implicated in other disease contexts such as hypoxic inflammation and cancer through crosstalking with pathways like NFκB and mTOR. We will examine how future mathematical modelling and simulation of interlinked networks can aid in understanding HIF behaviour in complex pathophysiological situations. 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The interplay of transcription factors can be viewed as nonlinear dynamics underlying the biological complexity. Here we analyse the regulation of the cyclooxygenase 2 promoter by NF-κB using thermostatistical and quantitative kinetic modelling and propose the presence of a genetic Boolean AND logic gate controlling the differential expression of cyclooxygenase 2 among species.</span></div><div class="wp-workCard_item wp-workCard--actions"><span class="work-strip-bookmark-button-container"></span><a id="9700f057e3bf2183842c7f0f6dea8338" class="wp-workCard--action" rel="nofollow" data-click-track="profile-work-strip-download" data-download="{"attachment_id":52047922,"asset_id":31738879,"asset_type":"Work","button_location":"profile"}" href="https://www.academia.edu/attachments/52047922/download_file?st=MTczMzAwNzk2NCw4LjIyMi4yMDguMTQ2&s=profile"><span><i class="fa fa-arrow-down"></i></span><span>Download</span></a><span class="wp-workCard--action visible-if-viewed-by-owner inline-block" style="display: none;"><span class="js-profile-work-strip-edit-button-wrapper profile-work-strip-edit-button-wrapper" data-work-id="31738879"><a class="js-profile-work-strip-edit-button" tabindex="0"><span><i class="fa fa-pencil"></i></span><span>Edit</span></a></span></span><span id="work-strip-rankings-button-container"></span></div><div class="wp-workCard_item wp-workCard--stats"><span><span><span class="js-view-count view-count u-mr2x" data-work-id="31738879"><i class="fa fa-spinner fa-spin"></i></span><script>$(function () { var workId = 31738879; window.Academia.workViewCountsFetcher.queue(workId, function (count) { var description = window.$h.commaizeInt(count) + " " + window.$h.pluralize(count, 'View'); $(".js-view-count[data-work-id=31738879]").text(description); $(".js-view-count[data-work-id=31738879]").attr('title', description).tooltip(); }); });</script></span></span><span><span class="percentile-widget hidden"><span class="u-mr2x work-percentile"></span></span><script>$(function () { var workId = 31738879; window.Academia.workPercentilesFetcher.queue(workId, function (percentileText) { var container = $(".js-work-strip[data-work-id='31738879']"); container.find('.work-percentile').text(percentileText.charAt(0).toUpperCase() + percentileText.slice(1)); container.find('.percentile-widget').show(); container.find('.percentile-widget').removeClass('hidden'); }); });</script></span><span><script>$(function() { new Works.PaperRankView({ workId: 31738879, container: "", }); });</script></span></div><div id="work-strip-premium-row-container"></div></div></div><script> require.config({ waitSeconds: 90 })(["https://a.academia-assets.com/assets/wow_profile-f77ea15d77ce96025a6048a514272ad8becbad23c641fc2b3bd6e24ca6ff1932.js","https://a.academia-assets.com/assets/work_edit-ad038b8c047c1a8d4fa01b402d530ff93c45fee2137a149a4a5398bc8ad67560.js"], function() { // from javascript_helper.rb var dispatcherData = {} if (true){ window.WowProfile.dispatcher = window.WowProfile.dispatcher || _.clone(Backbone.Events); dispatcherData = { dispatcher: window.WowProfile.dispatcher, downloadLinkId: "9700f057e3bf2183842c7f0f6dea8338" } } $('.js-work-strip[data-work-id=31738879]').each(function() { if (!$(this).data('initialized')) { new WowProfile.WorkStripView({ el: this, workJSON: {"id":31738879,"title":"Non linear Dynamics in Transcriptional 1 Regulation Biological Logic Gates","translated_title":"","metadata":{"abstract":"Gene expression relies on the interaction of numerous transcriptional signals at the promoter to elicit a response—to read or not to read the genomic code, and if read, the strength of the read. 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