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Previous studies have shown that the pro-inflammatory cytokines TNFα and INFγ reduce the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in HT-29 and T84 cells by acting post-transcriptionally. We have investigated the effect of the pro-inflammatory peptide IL-1β on the expression of t he CFTR gene in Calu-3 cells. IL-1β increased the production of CFTR mRNA in a dose-and time-dependent manner. Its action was inhibited by inhibitors of the NF-κB pathway, including N-acetyl-L-cysteine (NAC), pyrrolidine dithiocarbamate (PDTC) and a synthetic cell-permeable peptide containing the NF-κΒ NLS sequence. Gel shift analysis showed that IL-1β activated NF-κB in Calu-3 cells, and transfection experiments using p50 and RelA expressing vectors showed that exogenous transfected NF-κB subunits increased the concentration of CFTR mRNA. Gel shift analysis with antibody supershifting also showed that IL-1β caused the binding of NF-κB to a κB-like response element at position (-1103/-1093) in the CFTR 5' flanking region. Transfection experiments using (-2150/+52) CFTR reporter gene constructs showed that the activity of the CFTR promoter is enhanced by exogenous transfected NF-κB and IL-1β and that this enhancement is due, at least in part, to the (-1103/-1093) κB site. We conclude that the intracellular signaling that leads to increased CFTR mRNA in response to IL-1β in Calu-3 cells includes the binding of NF-κB to the (-1103) κB element and a subsequent increase in CFTR promoter activity. by guest on</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"NF-kappa B Mediates Up-regulation of CFTR Gene Expression in Calu-3 Cells by Interleukin-1beta","attachmentId":60046186,"attachmentType":"pdf","work_url":"https://www.academia.edu/39862888/NF_kappa_B_Mediates_Up_regulation_of_CFTR_Gene_Expression_in_Calu_3_Cells_by_Interleukin_1beta","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/39862888/NF_kappa_B_Mediates_Up_regulation_of_CFTR_Gene_Expression_in_Calu_3_Cells_by_Interleukin_1beta"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="1" data-entity-id="105963580" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/105963580/An_unexpected_effect_of_TNF_%CE%B1_on_F508del_CFTR_maturation_and_function">An unexpected effect of TNF-α on F508del-CFTR maturation and function</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="252567396" href="https://independent.academia.edu/ValerieUrbach">Valerie Urbach</a></div><p class="ds-related-work--metadata ds2-5-body-xs">F1000Research, 2015</p><p class="ds-related-work--abstract ds2-5-body-sm">Cystic fibrosis (CF) is a multifactorial disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR),which encodes a cAMP-dependent Cl-channel. The most frequent mutation, F508del, leads to the synthesis of a prematurely degraded, otherwise partially functional protein. CFTR is expressed in many epithelia, with major consequences in the airways of patients with CF, characterized by both fluid transport abnormalities and persistent inflammatory responses. The relationship between the acute phase of inflammation and the expression of wild type (WT) CFTR or F508del-CFTR is poorly understood. The aim of the present study was to investigate this effect. The results show that 10 min exposure to TNF-alpha (0.5-50ng/ml) of F508del-CFTR-transfected HeLa cells and human bronchial cells expressing F508del-CFTR in primary culture (HBE) leads to the maturation of F508del-CFTR and induces CFTR chloride currents. The enhanced CFTR expression and function upon...</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"An unexpected effect of TNF-α on F508del-CFTR maturation and function","attachmentId":105287282,"attachmentType":"pdf","work_url":"https://www.academia.edu/105963580/An_unexpected_effect_of_TNF_%CE%B1_on_F508del_CFTR_maturation_and_function","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/105963580/An_unexpected_effect_of_TNF_%CE%B1_on_F508del_CFTR_maturation_and_function"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="2" data-entity-id="14772865" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/14772865/A_combinatorial_F_box_protein_directed_pathway_controls_TRAF_adaptor_stability_to_regulate_inflammation">A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="33791513" href="https://independent.academia.edu/ChunbinZou">Chunbin Zou</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="33734847" href="https://pitt.academia.edu/BillChen">Bill Chen</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Nature Immunology, 2013</p><p class="ds-related-work--abstract ds2-5-body-sm">Uncontrolled activation of tumor necrosis factor receptor-associated factor (TRAF) proteins may result in profound tissue injury by linking surface signals to cytokine release. Here we show that a ubiquitin E3 ligase component, Fbxo3, potently stimulates cytokine secretion from human inflammatory cells by destabilizing a sentinel TRAF inhibitor, Fbxl2. Fbxo3 and TRAF protein in circulation positively correlated with cytokine responses in septic subjects and we furthermore identified a hypofunctional Fbxo3 human polymorphism. A small molecule inhibitor targeting Fbxo3 was sufficient to lessen severity of cytokine-driven inflammation in several murine disease models. These studies identify a pathway of innate immunity that may characterize subjects with altered immune responses during critical illness or provide a basis for therapeutic intervention targeting TRAF protein abundance.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A combinatorial F box protein directed pathway controls TRAF adaptor stability to regulate inflammation","attachmentId":43905913,"attachmentType":"pdf","work_url":"https://www.academia.edu/14772865/A_combinatorial_F_box_protein_directed_pathway_controls_TRAF_adaptor_stability_to_regulate_inflammation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/14772865/A_combinatorial_F_box_protein_directed_pathway_controls_TRAF_adaptor_stability_to_regulate_inflammation"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="3" data-entity-id="33335138" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/33335138/Competition_between_TRAF2_and_TRAF6_Regulates_NF_%CE%BAB_Activation_in_Human_B_Lymphocytes">Competition between TRAF2 and TRAF6 Regulates NF-κB Activation in Human B Lymphocytes</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="65162683" href="https://independent.academia.edu/LiushengHe">Liusheng He</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Chinese Medical Sciences Journal, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Objective To investigate the role of TNF receptor-associated factor 2 (TRAF-2) and TRAF6 in CD40-induced nuclear factor-κB (NF-κB) signaling pathway and whether CD40 signaling requires TRAF2.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Competition between TRAF2 and TRAF6 Regulates NF-κB Activation in Human B Lymphocytes","attachmentId":53395200,"attachmentType":"pdf","work_url":"https://www.academia.edu/33335138/Competition_between_TRAF2_and_TRAF6_Regulates_NF_%CE%BAB_Activation_in_Human_B_Lymphocytes","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/33335138/Competition_between_TRAF2_and_TRAF6_Regulates_NF_%CE%BAB_Activation_in_Human_B_Lymphocytes"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="4" data-entity-id="56068350" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/56068350/A_Complex_Relationship_between_TRAF3_and_Non_Canonical_NF_%CE%BAB2_Activation_in_B_Lymphocytes">A Complex Relationship between TRAF3 and Non-Canonical NF-κB2 Activation in B Lymphocytes</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="48422990" href="https://independent.academia.edu/HildebrandJoanne">Joanne Hildebrand</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Frontiers in Immunology, 2013</p><p class="ds-related-work--abstract ds2-5-body-sm">The adaptor protein TRAF3 restrains B cell activating factor receptor (BAFFR) and CD40mediated activation of the NF-κB2 pathway in B cells. Mice lacking TRAF3 specifically in B cells revealed the critical role of TRAF3 in restraining homeostatic B cell survival. Furthermore, loss-of-function mutations of the traf3 gene have been associated with human B cell malignancies, especially multiple myeloma (MM). It has been proposed that receptorinduced TRAF3 degradation leads to stabilization of the NF-κB inducing kinase (NIK), and subsequent NF-κB2 activation. However, it is unclear how receptor-mediated TRAF3 degradation or loss-of-function contributes to B cell-specific NF-κB2 activation. In the current study, we employed two complementary models to address this question. One utilized a mutant traf3 gene found in a human MM-derived cell line called LP1.The LP1 mutantTRAF3 protein lacks the TRAF-N and TRAF-C domains. Consistent with the paradigm described, expression of LP1 TRAF3 in B cells promoted higher basal levels of NF-κB2 activation compared to Wt TRAF3. However, LP1 did not associate with TRAF2, CD40, or BAFFR, and no LP1 degradation was observed following receptor engagement. Interestingly, LP1 showed enhanced NIK association. Thus, TRAF3 degradation becomes dispensable to activate NF-κB2 when it is unable to associate with TRAF2. In a second model, we examined several mutant forms of BAFFR that are unable to induce NF-κB2 activation in B cells. Signaling to B cells by each of these BAFFR mutants, however, induced levels of TRAF3 degradation similar to those induced by Wt BAFFR. Thus, in B cells, receptor-mediated TRAF3 degradation is not sufficient to promote NF-κB2 activation. We thus conclude that there is not a simple linear relationship in B lymphocytes between relative levels of cellular TRAF3, induced TRAF3 degradation, NIK activation, and NF-κB2 activation.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A Complex Relationship between TRAF3 and Non-Canonical NF-κB2 Activation in B Lymphocytes","attachmentId":71636337,"attachmentType":"pdf","work_url":"https://www.academia.edu/56068350/A_Complex_Relationship_between_TRAF3_and_Non_Canonical_NF_%CE%BAB2_Activation_in_B_Lymphocytes","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/56068350/A_Complex_Relationship_between_TRAF3_and_Non_Canonical_NF_%CE%BAB2_Activation_in_B_Lymphocytes"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="5" data-entity-id="24778962" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/24778962/CFTR_negatively_regulates_cyclooxygenase_2_PGE_2_positive_feedback_loop_in_inflammation">CFTR negatively regulates cyclooxygenase-2-PGE 2 positive feedback loop in inflammation</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="47776668" href="https://independent.academia.edu/MeiYu6">Mei Yu</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Cellular Physiology, 2012</p><p class="ds-related-work--abstract ds2-5-body-sm">Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent anion channel mostly expressed in epithelia. Accumulating evidence suggests that CF airway epithelia are overwhelmed by excessive inflammatory cytokines and prostaglandins (PGs), which eventually lead to the over-inflammatory condition observed in CF lung disease. However, the exact underlying mechanism remains elusive. In this study, we observed increased cyclooxygenase-2 (COX-2) expression and over-production of prostaglandin E 2 (PGE 2 ) in human CF bronchial epithelia cell line (CFBE41oÀ) with elevated NF-kB activity compared to a wild-type airway epithelial cell line (16HBE14oÀ). Moreover, we demonstrated that CFTR knockout mice had inherently higher levels of COX-2 and NF-kB activity, supporting the notion that lack of CFTR results in hyper-inflammatory signaling. In addition, we identified a positive feedback loop for production of PGE 2 involving PKA and transcription factor, CREB. More importantly, overexpression of wild-type CFTR significantly suppressed COX-2 expression in CFBE41oÀ cells, and wild-type CFTR protein expression was significantly increased when 16HBE14oÀ cells were challenged with LPS as well as PGE 2 , indicating possible involvement of CFTR in negative regulation of COX-2/PGE 2 . In conclusion, CFTR is a negative regulator of PGE 2 -mediated inflammatory response, defect of which may result in excessive activation of NF-kB, leading to over production of PGE 2 as seen in inflammatory CF tissues.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"CFTR negatively regulates cyclooxygenase-2-PGE 2 positive feedback loop in inflammation","attachmentId":45107104,"attachmentType":"pdf","work_url":"https://www.academia.edu/24778962/CFTR_negatively_regulates_cyclooxygenase_2_PGE_2_positive_feedback_loop_in_inflammation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/24778962/CFTR_negatively_regulates_cyclooxygenase_2_PGE_2_positive_feedback_loop_in_inflammation"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="6" data-entity-id="20017641" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/20017641/TRADD_TRAF2_and_TRADD_FADD_Interactions_Define_Two_Distinct_TNF_Receptor_1_Signal_Transduction_Pathways">TRADD–TRAF2 and TRADD–FADD Interactions Define Two Distinct TNF Receptor 1 Signal Transduction Pathways</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="40929137" href="https://independent.academia.edu/DGoeddel">David Goeddel</a><span>, </span><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="41135512" href="https://independent.academia.edu/HailingHsu">Hailing Hsu</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Cell, 1996</p><p class="ds-related-work--abstract ds2-5-body-sm">Pan, whereas the 23 kDa FADD Chinnaiyan et al., 1995) and the 74 kDa RIP and David V. Goeddel interact with Fas. In fact, death domains now appear Tularik, Incorporated to define interaction domains that are capable of both 270 East Grand Avenue homotypic and heterotypic associations (Song et al., South San Francisco, California 94080 1994; Chinnaiyan et al., 1995;. These observations suggest that death domains may function as adap-Summary tors to couple some members of the TNFR superfamily (at least TNFR1 and Fas) to other signaling proteins.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"TRADD–TRAF2 and TRADD–FADD Interactions Define Two Distinct TNF Receptor 1 Signal Transduction Pathways","attachmentId":41190109,"attachmentType":"pdf","work_url":"https://www.academia.edu/20017641/TRADD_TRAF2_and_TRADD_FADD_Interactions_Define_Two_Distinct_TNF_Receptor_1_Signal_Transduction_Pathways","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/20017641/TRADD_TRAF2_and_TRADD_FADD_Interactions_Define_Two_Distinct_TNF_Receptor_1_Signal_Transduction_Pathways"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="7" data-entity-id="51386120" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/51386120/The_RING_Domain_of_TRAF2_Plays_an_Essential_Role_in_the_Inhibition_of_TNF%CE%B1_Induced_Cell_Death_but_Not_in_the_Activation_of_NF_%CE%BAB">The RING Domain of TRAF2 Plays an Essential Role in the Inhibition of TNFα-Induced Cell Death but Not in the Activation of NF-κB</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="67834091" href="https://independent.academia.edu/BlackwellKen">Ken Blackwell</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular Biology, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and receptor-interacting protein 1 (RIP1) play critical roles in activating c-Jun Nterminal kinase (JNK) and inhibitor of κB kinase (IKK), as well as in inhibiting apoptosis induced by TNFα. The TRAF2 RING domain-mediated polyubiquitination of RIP1 is believed to be essential for TNFα-induced IKK activation, and the RING-domain-deleted TRAF2 (TRAF2-ΔR) has been widely used as a dominant negative in transient overexpression systems to block TNFα-induced JNK and IKK activation. Here, we report that stable expression of TRAF2-ΔR at a physiological level in TRAF2 and TRAF5 double knockout (TRAF2/5 DKO) cells almost completely restores normal TNFα-induced IKK activation, but not RIP1 polyubiquitination. In addition, stable expression of TRAF2-ΔR in TRAF2/5 DKO cells efficiently inhibited the TNFα-induced later phase of prolonged JNK activation, yet failed to inhibit TNFα-induced cell death. Although the basal and inducible expression of anti-apoptotic proteins in TRAF2-ΔR-expressing TRAF2/5 DKO cells was normal, the cells remained sensitive to TNFα-induced cell death because anti-apoptotic proteins were not recruited to the TNFR1 complex efficiently. Moreover, stable expression of TRAF2-ΔR in TRAF2/5 DKO cells failed to suppress constitutive p100 processing in these cells. These data suggest that (i) the TRAF2 RING domain plays a critical role in inhibiting cell death induced by TNFα and is essential for suppressing the noncanonical nuclear factor κB pathway in unstimulated cells; (ii) RIP1 polyubiquitination is not essential for TNFα-induced IKK activation; and (iii) prolonged JNK activation has no obligate role in TNFα-induced cell death.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The RING Domain of TRAF2 Plays an Essential Role in the Inhibition of TNFα-Induced Cell Death but Not in the Activation of NF-κB","attachmentId":69132959,"attachmentType":"pdf","work_url":"https://www.academia.edu/51386120/The_RING_Domain_of_TRAF2_Plays_an_Essential_Role_in_the_Inhibition_of_TNF%CE%B1_Induced_Cell_Death_but_Not_in_the_Activation_of_NF_%CE%BAB","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/51386120/The_RING_Domain_of_TRAF2_Plays_an_Essential_Role_in_the_Inhibition_of_TNF%CE%B1_Induced_Cell_Death_but_Not_in_the_Activation_of_NF_%CE%BAB"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="8" data-entity-id="99513540" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/99513540/TRAF2_Is_Essential_for_JNK_but_Not_NF_%CE%BAB_Activation_and_Regulates_Lymphocyte_Proliferation_and_Survival">TRAF2 Is Essential for JNK but Not NF-κB Activation and Regulates Lymphocyte Proliferation and Survival</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="264229227" href="https://independent.academia.edu/AngelaSantana63">Angela Santana</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Immunity, 1997</p><p class="ds-related-work--abstract ds2-5-body-sm">Discrete signaling functions are thought to be initiated by recruiting different types of intracellular signal transducers to the TNFR superfamily complexes. Thus far, two major classes of signal transducers have been identified. The first is characterized by a conserved death</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"TRAF2 Is Essential for JNK but Not NF-κB Activation and Regulates Lymphocyte Proliferation and Survival","attachmentId":100581843,"attachmentType":"pdf","work_url":"https://www.academia.edu/99513540/TRAF2_Is_Essential_for_JNK_but_Not_NF_%CE%BAB_Activation_and_Regulates_Lymphocyte_Proliferation_and_Survival","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/99513540/TRAF2_Is_Essential_for_JNK_but_Not_NF_%CE%BAB_Activation_and_Regulates_Lymphocyte_Proliferation_and_Survival"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-wsj-grid-card" data-collection-position="9" data-entity-id="5295123" data-sort-order="default"><a class="ds-related-work--title js-wsj-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/5295123/Interaction_of_the_TNFR_Receptor_Associated_Factor_TRAF1_with_I_Kappa_B_Kinase2_and_TRAF2_Indicates_a_Regulatory_Function_for_NF_Kappa_B_Signaling">Interaction of the TNFR-Receptor Associated Factor TRAF1 with I-Kappa B Kinase2 and TRAF2 Indicates a Regulatory Function for NF-Kappa B Signaling</a><div class="ds-related-work--metadata"><a class="js-wsj-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="7292249" href="https://universityofgujrat.academia.edu/KalsoomSughra">Kalsoom Sughra</a></div><p class="ds-related-work--metadata ds2-5-body-xs">PLOS One, 2010</p><p class="ds-related-work--abstract ds2-5-body-sm">Background: I-kappa B kinase 2 (IKK2 or IKK-beta) is one of the most crucial signaling kinases for activation of NF-kappa B, a transcription factor that is important for inflammation, cell survival and differentiation. Since many NF-kappa B activating pathways converge at the level of IKK2, molecular interactions of this kinase are pivotal for regulation of NF-kappa B signaling.</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Interaction of the TNFR-Receptor Associated Factor TRAF1 with I-Kappa B Kinase2 and TRAF2 Indicates a Regulatory Function for NF-Kappa B Signaling","attachmentId":32464493,"attachmentType":"pdf","work_url":"https://www.academia.edu/5295123/Interaction_of_the_TNFR_Receptor_Associated_Factor_TRAF1_with_I_Kappa_B_Kinase2_and_TRAF2_Indicates_a_Regulatory_Function_for_NF_Kappa_B_Signaling","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-wsj-grid-card-view-pdf" href="https://www.academia.edu/5295123/Interaction_of_the_TNFR_Receptor_Associated_Factor_TRAF1_with_I_Kappa_B_Kinase2_and_TRAF2_Indicates_a_Regulatory_Function_for_NF_Kappa_B_Signaling"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div></div></div><div class="ds-sticky-ctas--wrapper js-loswp-sticky-ctas hidden"><div class="ds-sticky-ctas--grid-container"><div class="ds-sticky-ctas--container"><button class="ds2-5-button js-swp-download-button" data-signup-modal="{"location":"continue-reading-button--sticky-ctas","attachmentId":119920308,"attachmentType":"pdf","workUrl":null}">See full PDF</button><button class="ds2-5-button ds2-5-button--secondary js-swp-download-button" data-signup-modal="{"location":"download-pdf-button--sticky-ctas","attachmentId":119920308,"attachmentType":"pdf","workUrl":null}"><span class="material-symbols-outlined" style="font-size: 20px" translate="no">download</span>Download PDF</button></div></div></div><div class="ds-below-fold--grid-container"><div class="ds-work--container js-loswp-embedded-document"><div class="attachment_preview" data-attachment="Attachment_119920308" style="display: none"><div class="js-scribd-document-container"><div class="scribd--document-loading js-scribd-document-loader" style="display: block;"><img alt="Loading..." src="//a.academia-assets.com/images/loaders/paper-load.gif" /><p>Loading Preview</p></div></div><div style="text-align: center;"><div class="scribd--no-preview-alert js-preview-unavailable"><p>Sorry, preview is currently unavailable. You can download the paper by clicking the button above.</p></div></div></div></div><div class="ds-sidebar--container js-work-sidebar"><div class="ds-related-content--container"><h2 class="ds-related-content--heading">Related papers</h2><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="0" data-entity-id="112589542" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/112589542/NF_%CE%BAB_Is_Essential_for_Induction_of_CYLD_the_Negative_Regulator_of_NF_%CE%BAB">NF-κB Is Essential for Induction of CYLD, the Negative Regulator of NF-κB</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="35332564" href="https://independent.academia.edu/GeorgeMosialos">George Mosialos</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Biological Chemistry, 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Responses","attachmentId":49369291,"attachmentType":"pdf","work_url":"https://www.academia.edu/5275644/TRAF2_Deficiency_Results_in_Hyperactivity_of_Certain_TNFR1_Signals_and_Impairment_of_CD40_Mediated_Responses","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/5275644/TRAF2_Deficiency_Results_in_Hyperactivity_of_Certain_TNFR1_Signals_and_Impairment_of_CD40_Mediated_Responses"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="3" data-entity-id="29204627" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/29204627/Tuning_NF_%CE%BAB_activity_A_touch_of_COMMD_proteins">Tuning NF-κB activity: A touch of COMMD proteins</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="33229494" href="https://umcg.academia.edu/BartSluis">Bart Sluis</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2013</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Tuning NF-κB activity: A touch of COMMD proteins","attachmentId":49655664,"attachmentType":"pdf","work_url":"https://www.academia.edu/29204627/Tuning_NF_%CE%BAB_activity_A_touch_of_COMMD_proteins","alternativeTracking":true}"><span class="material-symbols-outlined" 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class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32931375" href="https://independent.academia.edu/HongYe1">Hong Ye</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Cell, 2000</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"A Novel Mechanism of TRAF Signaling Revealed by Structural and Functional Analyses of the TRADD–TRAF2 Interaction","attachmentId":44892985,"attachmentType":"pdf","work_url":"https://www.academia.edu/13839099/A_Novel_Mechanism_of_TRAF_Signaling_Revealed_by_Structural_and_Functional_Analyses_of_the_TRADD_TRAF2_Interaction","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a 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href="https://independent.academia.edu/LuisGalietta">Luis Galietta</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Current Opinion in Pharmacology, 2004</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Identification of CFTR activators and inhibitors: chance or design?","attachmentId":43221378,"attachmentType":"pdf","work_url":"https://www.academia.edu/15410923/Identification_of_CFTR_activators_and_inhibitors_chance_or_design","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/15410923/Identification_of_CFTR_activators_and_inhibitors_chance_or_design"><span 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Hsu</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Cell, 1995</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"The TNF receptor 1-associated protein TRADD signals cell death and NF-?B activation","attachmentId":41189364,"attachmentType":"pdf","work_url":"https://www.academia.edu/20017640/The_TNF_receptor_1_associated_protein_TRADD_signals_cell_death_and_NF_B_activation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/20017640/The_TNF_receptor_1_associated_protein_TRADD_signals_cell_death_and_NF_B_activation"><span class="ds2-5-text-link__content">View PDF</span><span 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Chemistry, 2009</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"TRAF2 Must Bind to Cellular Inhibitors of Apoptosis for Tumor Necrosis Factor (TNF) to Efficiently Activate NF-κB and to Prevent TNF-induced Apoptosis","attachmentId":113137312,"attachmentType":"pdf","work_url":"https://www.academia.edu/117224149/TRAF2_Must_Bind_to_Cellular_Inhibitors_of_Apoptosis_for_Tumor_Necrosis_Factor_TNF_to_Efficiently_Activate_NF_%CE%BAB_and_to_Prevent_TNF_induced_Apoptosis","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/117224149/TRAF2_Must_Bind_to_Cellular_Inhibitors_of_Apoptosis_for_Tumor_Necrosis_Factor_TNF_to_Efficiently_Activate_NF_%CE%BAB_and_to_Prevent_TNF_induced_Apoptosis"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="8" data-entity-id="28540796" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/28540796/TRAF3_Forms_Heterotrimers_with_TRAF2_and_Modulates_Its_Ability_to_Mediate_NF_B_Activation">TRAF3 Forms Heterotrimers with TRAF2 and Modulates Its Ability to Mediate NF- B Activation</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="53524680" href="https://independent.academia.edu/GrammerA">A. Grammer</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Biological Chemistry, 2004</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"TRAF3 Forms Heterotrimers with TRAF2 and Modulates Its Ability to Mediate NF- B Activation","attachmentId":48892302,"attachmentType":"pdf","work_url":"https://www.academia.edu/28540796/TRAF3_Forms_Heterotrimers_with_TRAF2_and_Modulates_Its_Ability_to_Mediate_NF_B_Activation","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/28540796/TRAF3_Forms_Heterotrimers_with_TRAF2_and_Modulates_Its_Ability_to_Mediate_NF_B_Activation"><span 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data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/83550697/Correctors_Rescue_CFTR_Mutations_in_Nucleotide_Binding_Domain_1_NBD1_by_Modulating_Proteostasis">Correctors Rescue CFTR Mutations in Nucleotide-Binding Domain 1 (NBD1) by Modulating Proteostasis</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="143139397" href="https://umaryland.academia.edu/ISabirzhanova">Inna Sabirzhanova</a></div><p class="ds-related-work--metadata ds2-5-body-xs">ChemBioChem, 2016</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Correctors Rescue CFTR Mutations in Nucleotide-Binding Domain 1 (NBD1) by Modulating Proteostasis","attachmentId":88857569,"attachmentType":"pdf","work_url":"https://www.academia.edu/83550697/Correctors_Rescue_CFTR_Mutations_in_Nucleotide_Binding_Domain_1_NBD1_by_Modulating_Proteostasis","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/83550697/Correctors_Rescue_CFTR_Mutations_in_Nucleotide_Binding_Domain_1_NBD1_by_Modulating_Proteostasis"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="11" data-entity-id="28446409" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/28446409/Noncanonical_NF_%CE%BAB_activation_requires_coordinated_assembly_of_a_regulatory_complex_of_the_adaptors_cIAP1_cIAP2_TRAF2_and_TRAF3_and_the_kinase_NIK">Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="53346162" href="https://independent.academia.edu/HermanCheung3">Herman Cheung</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Nature Immunology, 2008</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK","attachmentId":48795877,"attachmentType":"pdf","work_url":"https://www.academia.edu/28446409/Noncanonical_NF_%CE%BAB_activation_requires_coordinated_assembly_of_a_regulatory_complex_of_the_adaptors_cIAP1_cIAP2_TRAF2_and_TRAF3_and_the_kinase_NIK","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/28446409/Noncanonical_NF_%CE%BAB_activation_requires_coordinated_assembly_of_a_regulatory_complex_of_the_adaptors_cIAP1_cIAP2_TRAF2_and_TRAF3_and_the_kinase_NIK"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="12" data-entity-id="857439" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/857439/NF_%CE%BAB_signal_triggering_and_termination_by_tumor_necrosis_factor_receptor_2">NF-κB signal triggering and termination by tumor necrosis factor receptor 2</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="674918" href="https://dana-farber.academia.edu/LuciaCabalHierro">Lucia Cabal-Hierro</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Biological …, 2011</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" data-signup-modal="{"location":"wsj-grid-card-download-pdf-modal","work_title":"NF-κB signal triggering and termination by tumor necrosis factor receptor 2","attachmentId":5171613,"attachmentType":"pdf","work_url":"https://www.academia.edu/857439/NF_%CE%BAB_signal_triggering_and_termination_by_tumor_necrosis_factor_receptor_2","alternativeTracking":true}"><span class="material-symbols-outlined" style="font-size: 18px" translate="no">download</span><span class="ds2-5-text-link__content">Download free PDF</span></button><a class="ds2-5-text-link ds2-5-text-link--inline js-related-work-grid-card-view-pdf" href="https://www.academia.edu/857439/NF_%CE%BAB_signal_triggering_and_termination_by_tumor_necrosis_factor_receptor_2"><span class="ds2-5-text-link__content">View PDF</span><span class="material-symbols-outlined" style="font-size: 18px" translate="no">chevron_right</span></a></div></div><div class="ds-related-work--container js-related-work-sidebar-card" data-collection-position="13" data-entity-id="13331552" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/13331552/Beyond_tumor_necrosis_factor_receptor_TRADD_signaling_in_toll_like_receptors">Beyond tumor necrosis factor receptor: TRADD signaling in toll-like receptors</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32607437" href="https://independent.academia.edu/MakTak">Tak Mak</a><span>, </span><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="26310842" href="https://independent.academia.edu/HaoZhenyue">Zhenyue Hao</a><span>, </span><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="32571773" href="https://utoronto.academia.edu/JuancarlosZ%C3%BA%C3%B1igapfl%C3%BCcker">Juan-carlos Zúñiga-pflücker</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Proceedings of the National Academy of Sciences, 2008</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link 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js-related-work-sidebar-card" data-collection-position="14" data-entity-id="86723402" data-sort-order="default"><a class="ds-related-work--title js-related-work-grid-card-title ds2-5-body-md ds2-5-body-link" href="https://www.academia.edu/86723402/Suppression_of_CFTR_premature_termination_codons_and_rescue_of_CFTR_protein_and_function_by_the_synthetic_aminoglycoside_NB54">Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54</a><div class="ds-related-work--metadata"><a class="js-related-work-grid-card-author ds2-5-body-sm ds2-5-body-link" data-author-id="231528424" href="https://independent.academia.edu/INudelman">Igor Nudelman</a></div><p class="ds-related-work--metadata ds2-5-body-xs">Journal of Molecular Medicine, 2011</p><div class="ds-related-work--ctas"><button class="ds2-5-text-link ds2-5-text-link--inline js-swp-download-button" 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