A History of Cancer Research: The P53 Pathway

<!DOCTYPE html PUBLIC "-//W3C//DTD XHTML 1.0 Strict//EN" "http://www.w3.org/TR/xhtml1/DTD/xhtml1-strict.dtd"> <html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" lang="en"> <head> <meta http-equiv="Content-Type" content="text/html; charset=UTF-8" /> <title>A History of Cancer Research: The P53 Pathway </title> <meta name="googlebot" content="NOODP" /> <meta name="HW.ad-path" content="/cgi/content/full/15/2/a035931" /> <meta content="/cshperspectmed/15/2/a035931.atom" name="HW.identifier" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta content="A History of Cancer Research: The P53 Pathway" name="DC.Title" /> <meta content="10.1101/cshperspect.a035931" name="DC.Identifier" /> <meta content="2025-02-01" name="DC.Date" /> <meta content="Cold Spring Harbor Laboratory Press" name="DC.Publisher" /> <meta content="Joseph Lipsick" name="DC.Contributor" /> <meta content="144" name="citation_collection_id" /> <meta content="Cold Spring Harbor Perspectives in Medicine" name="citation_journal_title" /> <meta content="Cold Spring Harb Perspect Med" name="citation_journal_abbrev" /> <meta content="" name="citation_issn" /> <meta content="2157-1422" name="citation_issn" /> <meta name="citation_author" content="Joseph Lipsick" /> <meta name="citation_author_institution" content="Departments of Pathology, Genetics, and Biology, Stanford University, Stanford, California 94305-5324, USA" /> <meta content="A History of Cancer Research: The P53 Pathway" name="citation_title" /> <meta content="02/01/2025" name="citation_date" /> <meta content="15" name="citation_volume" /> <meta content="2" name="citation_issue" /> <meta content="a035931" name="citation_firstpage" /> <meta content="15/2/a035931" name="citation_id" /> <meta content="15/2/a035931" name="citation_id_from_sass_path" /> <meta content="cshperspectmed;15/2/a035931" name="citation_mjid" /> <meta content="10.1101/cshperspect.a035931" name="citation_doi" /> <meta content="http://perspectivesinmedicine.cshlp.org/content/15/2/a035931.abstract" name="citation_abstract_html_url" /> <meta content="http://perspectivesinmedicine.cshlp.org/content/15/2/a035931.full" name="citation_fulltext_html_url" /> <meta content="http://perspectivesinmedicine.cshlp.org/content/15/2/a035931.full.pdf" name="citation_pdf_url" /> <meta content="/content/15/2.cover.gif" name="issue_cover_image" /> <meta content="http://perspectivesinmedicine.cshlp.org/content/15/2/a035931" name="citation_public_url" /> <meta content="39900457" name="citation_pmid" /> <meta name="citation_section" content="Retrospective" /> <meta name="robots" content="noarchive,nofollow" /> <meta name="googlebot" content="noarchive" /> <link href="/content/15/1/a041815.short" rel="prev" /> <link href="/content/15/2/a041160.short" rel="next" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/hw-global.css" /> <link rel="stylesheet" type="text/css" media="print" href="/shared/css/hw-print.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/standard-designs/design2/main.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/standard-designs/design2/main.css" /> <link rel="stylesheet" type="text/css" media="all" href="/publisher/css/hw-cshljnls-global.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/hw-citation-2.0-hacks.css" /> <link rel="stylesheet" type="text/css" media="print" href="/publisher/css/hw-cshljnls-print.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/standard-designs/design2/main.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/hw-citation-2.0-hacks.css" /> <link rel="stylesheet" type="text/css" media="all" href="/local/css/hw-journal-global.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/hw-page-content.css" /> <link rel="stylesheet" type="text/css" media="all" href="/shared/css/jquery.fancybox-1.3.4.css" /> <link rel="stylesheet" type="text/css" media="all" href="/publisher/css/hw-cshljnls-page-content.css" /> <link rel="stylesheet" type="text/css" media="all" href="/local/css/hw-journal-page-content.css" /> <link rel="stylesheet" type="text/css" media="all" href="/site/misc/custom-global.css" /><script type="text/javascript" id="session-d1853134e1">var callbackToken='51566EC03DDCACB';</script><script type="text/javascript" src="/shared/js/jquery-min.js"></script><script type="text/javascript" src="/shared/js/fingerprint.js"></script><script type="text/javascript" src="/shared/js/hw-shared.js"></script><script type="text/javascript" src="/shared/js/design/hw-design1.js"></script><script type="text/javascript" src="/publisher/js/cshl-shared.js"></script><script type="text/javascript" src="/publisher/js/cshl-shared.js"></script><script type="text/javascript" src="/shared/js/pages/hw-content.js"></script><script type="text/javascript" src="/shared/js/util/AccessCheckLib.js"></script><script type="text/javascript" src="/shared/js/util/executeAccessCheck.js"></script><script type="text/javascript" src="/shared/js/fancybox/jquery.fancybox-1.3.4.js"></script><script type="text/javascript" src="/shared/js/fancybox/jquery.easing-1.3.pack.js"></script><script type="text/javascript" src="/shared/js/fancybox/jquery.mousewheel-3.0.4.pack.js"></script><script type="text/javascript" src="/shared/js/util/content.jquery.addVariantLink.js"></script><script type="text/javascript" src="/publisher/js/cshl-content.js"></script><script type="text/javascript" async="async" src="https://scholar.google.com/scholar_js/casa.js"></script><script type="text/javascript" src="/site/misc/custom-global.js"></script></head> <body> <div class="hw-gen-page pagetype-content" id="pageid-content" itemscope="itemscope" itemtype="http://schema.org/ScholarlyArticle"> <div id="header"> <a href="/"><img title="Cold Spring Harbor Perspectives in Medicine" alt="Cold Spring Harbor Perspectives in Medicine" width="390" height="83" src="/local/img/journal_logo_standalone.gif" /></a> <p id="skip-link"> <a href="#content-block">Skip to main page content</a> </p> <ul class="button-list header-buttons"> <li class="first"><a href="/" title="HOME"><span>HOME</span></a></li> <li><a href="/site/misc/about.xhtml" title="ABOUT"><span>ABOUT</span></a></li> <li><a href="/cgi/collection/" title="SUBJECT COLLECTIONS"><span>SUBJECT COLLECTIONS</span></a></li> <li><a href="/content/by/year" title="ARCHIVE"><span>ARCHIVE</span></a></li> <li><a href="/site/misc/subscribe.xhtml" title="SUBSCRIBE"><span>SUBSCRIBE</span></a></li> <li><a href="/site/misc/adinfo.xhtml" title="ADVERTISE"><span>ADVERTISE</span></a></li> <li><a href="/site/misc/alertland.xhtml" title="ALERTS"><span>ALERTS</span></a></li> <li><a href="/feedback" title="FEEDBACK"><span>FEEDBACK</span></a></li> <li class="last"><a href="/help/" title="HELP"><span>HELP</span></a></li> </ul> <div class="header-qs"> <form class="searchbox" action="/search" method="get"> <div> <label for="header-qs-input" id="header-qs-search-label">Search for Keyword:</label> <input value="" title="Search Cold Spring Harbor Perspectives in Medicine" type="text" name="fulltext" id="header-qs-input" /><input type="hidden" name="submit" value="yes" /><label for="header-qs-search" id="header-qs-search-label">GO</label><input value="GO" alt="Link: Go" type="image" id="header-qs-search-go" src="/shared/img/standard-design/design2/go.gif" /> </div> <div class="adv-search-link"><a href="/search">Advanced Search</a></div> </form> </div> <div class="header-ac-elements"> <div class="inst-branding"> </div> <div id="authstring" class="suppress-header-login"> </div> <div id="hdr-login" class="suppress-header-login"></div> </div> <div class="bar"> <div class="bar-inner"></div> </div> </div> <div id="content-block"> <div class="article fulltext-view " itemprop="articleBody"><span class="highwire-journal-article-marker-start"></span><h1 id="article-title-1" itemprop="headline">A History of Cancer Research: The P53 Pathway</h1> <div class="contributors"> <ol class="contributor-list" id="contrib-group-1"> <li class="last" id="contrib-1"><span class="name"><a class="name-search" href="/search?author1=Joseph+Lipsick&sortspec=date&submit=Submit">Joseph Lipsick</a></span></li> </ol> <ol class="affiliation-list"> <li class="aff"><a id="aff-1" name="aff-1"></a><address>Departments of Pathology, Genetics, and Biology, Stanford University, Stanford, California 94305-5324, USA</address> </li> </ol> <ol class="corresp-list"> <li class="corresp" id="corresp-1"><em>Correspondence:</em> <span class="em-link"><span class="em-addr">lipsick{at}stanford.edu</span></span></li> </ol> </div> <div class="section abstract" id="abstract-1" itemprop="description"> <div class="section-nav"> <div class="nav-placeholder"> </div><a href="#sec-1" title="p53 PROTEIN AS A FELLOW TRAVELER" class="next-section-link"><span>Next Section</span></a></div> <h2>Abstract</h2> <p id="p-3">The p53 tumor suppressor was first identified as a cellular protein that bound to the large T antigen in SV40-transformed cells. Initially thought to be the product of an oncogene, p53 turned out to be an anticancer protein whose loss or mutation could promote tumorigenesis. Subsequent work revealed it functions as a DNA-binding transcription factor central to the DNA damage response and cell cycle control. In this excerpt from his forthcoming book on the history of cancer research, Joe Lipsick looks back at the discovery of p53 and the groundbreaking work that revealed its role as “guardian of the genome.” </p> </div> <div class="section" id="sec-1"> <div class="section-nav"><a href="#abstract-1" title="Abstract" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-2" title="P53 AS AN ONCOGENE" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">p53 PROTEIN AS A FELLOW TRAVELER</h2> <p id="p-4">Simian vacuolating virus 40 (SV40) was discovered in 1960 by Maurice Hilleman's laboratory in extracts of monkey cells and in polio vaccines prepared from them. SV40 caused cytopathic effects in cells cultured from some but not all species of monkeys, with prominent cytoplasmic vacuolization visible a few days after initial infection followed by cell death. The following year, Bernice Eddy's group reported that extracts of monkey kidney cells caused tumors when injected into newborn hamsters. The Eddy and Hilleman laboratories soon showed that SV40 was the causative agent. Several laboratories then reported that SV40-transformed human and rodent cells in culture (<a id="xref-fig-1-1" class="xref-fig" href="#F1">Fig. 1</a>). </p> <div id="F1" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F1.expansion.html"><img alt="Figure 1." src="a035931/F1.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F1.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F1.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F1">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 1.</span> <p id="p-5" class="first-child">Oncogenic transformation of human kidney cells by simian vacuolating virus 40 (SV40). Uninfected control cells (<em>left</em>); infected cells 114 days after inoculation (<em>right</em>). Both samples were fixed and stained with hematoxylin and eosin. (Reprinted, with permission, from Shein HM, Enders JF. 1962. <em>Proc Natl Acad Sci</em> <strong>48</strong>: 1164–1172. © H.M. Shein and J.F. Enders.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-6">These findings raised significant public health concerns because the active SV40 virus was found in stocks of the inactivated polio virus vaccine (Salk) that had been used to vaccinate 98 million people in the United States from 1955 to 1963. Furthermore, stocks of the oral live-virus polio vaccine (Sabin) used in clinical trials of ∼10,000 people also contained SV40. From 1961 onward, newly produced commercial polio vaccines were required by the National Institute of Biological Standards to be free of SV40 contamination. However, previously approved vaccine lots were not recalled and may have been used for another 2 years before their expiration dates. In all, nearly 100 million people in the United States, and likely millions more via vaccines produced in the Soviet Union, were potentially at risk for SV40-induced cancers. Despite sporadic reports of an association between SV40 and various types of human cancer, fortunately, this scenario did not materialize. Nevertheless, this episode served as a cautionary tale for those interested in the therapeutic transplantation of cells and tissues from other species into humans. </p> <p id="p-7">In 1964, Fred Rapp and Wallace Rowe identified tumor antigens (T antigens) present in SV40-transformed cells using sera from SV40-infected tumor-bearing rodents. The large T antigen protein primarily localized to the nucleus and had an apparent molecular weight of 94 kDa. During the 1970s, several laboratories showed that this protein was required for viral DNA replication, viral RNA transcription, and oncogenic transformation (see Lipsick 2024). A major clue to the mechanism of oncogenic transformation came in 1979 with the identification of a 50–60-kDa phosphoprotein that was immunoprecipitated along with large T antigen from extracts of SV40-transformed rodent cells (<a id="xref-fig-2-1" class="xref-fig" href="#F2">Fig. 2</a>). The laboratories of Robert Carroll, Lionel Crawford, François Cuzin, Arnold Levine, Pierre May, Peter Mora, and Alan Smith all published similar results using polyclonal antisera from SV40-infected tumor-bearing hamsters. Although they assigned different names and apparent molecular weights to this protein, the community settled on “p53” at an international meeting in 1983. Peptide mapping and a detailed immunologic characterization performed by David Lane and Lionel Crawford showed that p53 was neither a breakdown product of nor a smaller isoform of large T antigen. A similarly sized protein known as middle T was encoded by the related mouse polyoma virus, raising the possibility that p53 might be encoded by SV40. However, Daniel Linzer and Arnold Levine found that p53 was also present in uninfected mouse embryonal carcinoma cell lines, demonstrating conclusively that p53 was a cellular rather than a viral protein. Further studies using monoclonal antibodies against T antigen and against p53 clearly demonstrated that SV40 large T antigen and the cellular p53 protein physically associated, because anti-T antibodies could immunoprecipitate p53 only in the presence of T antigen. </p> <div id="F2" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F2.expansion.html"><img alt="Figure 2." src="a035931/F2.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F2.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F2.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F2">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 2.</span> <p id="p-8" class="first-child">Immunoprecipitation of p53 from extracts of simian vacuolating virus 40 (SV40)-transformed mouse cells with antiserum from a tumor-bearing SV40-infected hamster. T = SV40 large T antigen. (Lanes <em>1</em>–<em>3</em>) [<sup>32</sup>P]-phosphate-labeled cells. (Lanes <em>4</em>,<em>5</em>) [<sup>35</sup>S]-methionine-labeled cells. (Lane <em>1</em>) Normal hamster serum. (Lanes <em>2</em>–<em>5</em>) Hamster antitumor serum. (Reprinted, with permission, from Shein HM, Enders JF, et al. 1962. <em>Proc Natl Acad Sci</em> <strong>48:</strong> 1164–1172.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-9">The sequencing of SV40 and polyoma virus revealed that their genomes were similarly organized and the corresponding proteins they encoded had similar sequences. However, the middle T antigen of polyoma virus was mostly encoded by an open reading frame absent in SV40 (<a id="xref-fig-3-1" class="xref-fig" href="#F3">Fig. 3</a>). Additional studies showed that, unlike SV40 large T, polyoma large T was not required for transformation and did not bind to p53. On the other hand, polyoma middle T was oncogenic and instead bound to other cellular proteins including C-SRC and PI3K (Lipsick 2019, 2025a). </p> <div id="F3" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F3.expansion.html"><img alt="Figure 3." src="a035931/F3.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F3.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F3.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F3">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 3.</span> <p id="p-10" class="first-child">Genome organization of the simian vacuolating virus 40 (SV40) and mouse polyoma (Py) viruses. Thick bars indicate open reading frames. Gaps indicate mRNA splicing. O<sub>R</sub> indicates the origin of replication. Nucleotide numbering is shown inside the circles. Note that by convention the nucleotide numberings of these two related viruses are in the opposite orientation. (Reprinted, with permission, from Eckhardt W. 1989. Oncogenes of DNA tumor viruses: papovaviruses. In <em>Oncogenes and the molecular origin of cancer</em> [ed. RA Weinberg], pp. 223–228, © Cold Spring Harbor Laboratory Press.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-11">A potential role for p53 in oncogenic transformation was further supported by the Levine laboratory, who showed it associated with the adenovirus E1B 55-kDa oncoprotein. The association of p53 with two different oncoproteins of apparently unrelated DNA tumor viruses spurred an intensive investigation of this protein. This discovery also motivated the search for additional cellular proteins associated with viral oncoproteins, resulting in the identification of RB as an adenovirus E1A-associated protein that also interacted with the SV40 large T antigen and the E7 oncoprotein of human papilloma virus (HPV) (Lipsick 2025b). </p> <p id="p-12">Lloyd Old's laboratory independently discovered p53 in 1979 via a different experimental route. While pursuing studies of tumor immunology, they used antisera from syngeneic mice immunized with two different methylcholanthrene-induced sarcomas to identify a common protein of 53 kDa. They could not detect this protein in a variety of normal mouse cells and tissues, but did find it in chemically induced tumors, in spontaneously transformed cells, and in cells transformed by SV40 or murine sarcoma viruses. Experiments performed with monoclonal antibodies raised against this protein led to the conclusion that it was identical to the p53 protein that was associated with SV40 large T antigen. </p> </div> <div class="section" id="sec-2"> <div class="section-nav"><a href="#sec-1" title="p53 PROTEIN AS A FELLOW TRAVELER" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-3" title="P53 AS A TUMOR SUPPRESSOR GENE" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">P53 AS AN ONCOGENE</h2> <p id="p-13">In the early 1980s, several laboratories isolated murine and human <em>P53</em> cDNA clones that were verified by in vitro translation and immunoprecipitation. (Note that the mouse gene was later renamed <em>Trp53</em>, whereas the human gene was named <em>TP53.</em>) In 1984, three independent studies showed that <em>P53</em> could function as a dominant oncogene, which was consistent with the presence of high levels of p53 protein in cancer cells but not in normal cells. These experiments were based in part on observations reported the previous year by Earl Ruley and Robert Weinberg's laboratories, who showed that a pair of oncogenes (e.g., adenovirus <em>E1A</em> and mutant <em>HRAS</em>, or <em>MYC</em> and mutant <em>HRAS</em>) were needed to transform primary rodent cells, whereas mutant <em>HRAS</em> alone could transform some established contact-inhibited nontumorigenic immortal cell lines, including NIH 3T3 and Rat-1 cells. </p> <p id="p-14">Moshe Oren's laboratory reported that <em>P53</em> could cooperate with a mutant <em>HRAS</em> to oncogenically transform primary rodent cells in culture. Furthermore, these cells caused malignant tumors when injected into syngeneic animals. A collaboration between Varda Rotter and Robert Weinberg and work in John Jenkins’ laboratory yielded similar results. In addition, the Jenkins group showed that <em>P53</em> was sufficient for immortalization of rat chondrocytes that normally display a limited life span in culture. </p> <p id="p-15">These experiments suggested that <em>P53</em> was a typical dominantly acting oncogene. However, Samuel Benchimol and Alan Bernstein's laboratories over the next few years showed that the <em>P53</em> gene was a recurrent target of integration by the Friend murine leukemia virus in erythroleukemia cells, resulting in the absence of p53 protein. In some cases, this was accompanied by large deletions within the <em>P53</em> gene. These results instead suggested a tumor suppressor function for p53. </p> <p id="p-16">Another twist in this story occurred a few years later when Moshe Oren and Arnold Levine's laboratories reported that wild-type <em>P53</em> clones were not oncogenic, but mutant clones containing several different amino acid substitutions were oncogenic. Confusingly, a nontransforming wild-type cDNA clone had been isolated from the murine F9 embryonal carcinoma cell line that expressed high levels of p53, whereas a “normal” genomic DNA clone isolated from a mouse library contained a substitution mutation that caused the transformation. Puzzlingly, the activation of the oncogenic potential of <em>P53</em> by amino acid substitutions remained difficult to reconcile with an apparent selection for the complete loss of p53 in Friend virus–induced erythroleukemias. </p> </div> <div class="section" id="sec-3"> <div class="section-nav"><a href="#sec-2" title="P53 AS AN ONCOGENE" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-4" title="p53 AS A TRANSCRIPTION FACTOR" class="next-section-link"><span>Next Section</span></a></div> <h2 class=""><em>P53</em> AS A TUMOR SUPPRESSOR GENE </h2> <p id="p-17">In 1989, Cathy Finlay and Philip Hinds in the Levine laboratory settled the matter, reporting that wild-type <em>P53</em> could function as a tumor suppressor gene. They found that, whereas mutant <em>P53</em> and mutant <em>HRAS</em> together caused the oncogenic transformation of primary rodent cells in culture, adding wild-type <em>P53</em> could suppress this. Furthermore, wild-type but not mutant <em>P53</em> could also suppress oncogenic transformation caused by adenovirus <em>E1A</em> plus mutant <em>HRAS</em>. Moshe Oren's laboratory reported similar results. In 1990, Peter Howley's laboratory showed that the E6 oncoprotein of HPV bound to wild-type p53 and caused its ubiquitin-dependent degradation. This explained the previously observed absence of p53 in HeLa cells, which were derived from an HPV-induced cancer of the uterine cervix. These observations led to the reclassification of <em>P53</em> as a tumor suppressor gene rather than a proto-oncogene. </p> <p id="p-18">Concurrently, Bert Vogelstein's laboratory provided evidence for the importance of <em>P53</em> mutations in human colorectal cancer. Frequent somatic deletions within the short arm of chromosome 17 had previously been reported in 75% of such cancers. Suzanne Baker in Vogelstein's group together with their collaborators used molecular markers to identify a common region displaying loss of heterozygosity, as had been shown for the <em>RB1</em> tumor suppressor gene in retinoblastomas (Lipsick 2025b). The <em>P53</em> gene lay in the region, and, remarkably, the retained alleles encoded activating amino acid substitutions in conserved domains of p53. These results were extended to many other types of human cancer in collaboration with Curtis Harris's laboratory (<a id="xref-fig-4-1" class="xref-fig" href="#F4">Fig. 4</a>). Unlike “classic” tumor suppressor genes that frequently display a loss-of-function mutation accompanied by loss of the normal allele, p53 most frequently displayed a gain-of-function mutation accompanied by loss of the normal allele. </p> <div id="F4" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F4.expansion.html"><img alt="Figure 4." src="a035931/F4/graphic-4.small.gif" /></a><a href="a035931/F4.expansion.html"><img alt="Figure 4." src="a035931/F4/graphic-5.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F4.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F4.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F4">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 4.</span> <p id="p-19" class="first-child">p53 substitution mutations in human cancers cluster in evolutionarily conserved domains. Cancer types: (B) Bladder, (C) colon, (E) esophagus, (H) liver, (K) leukemias and lymphomas, (L) lung, (M) breast, (N) brain, (O) ovary, (S), sarcoma. (Reprinted, with permission, from Hollstein M, et al. 1991. <em>Science</em> <strong>253:</strong> 49–53, © AAAS.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-20">Additional evidence for this unusual combination of an activating oncogenic mutation followed by loss of the wild-type allele came from studies of a rare familial cancer syndrome. In 1969, Frederick Li and Joseph Fraumeni described four families in which two children had soft tissue sarcomas, and one parent and other relatives developed other types of cancer at an early age. In 1990, collaborative efforts led by Esther Chang and Stephen Friend identified heterozygous germline missense mutations in <em>P53</em> that segregated with the cancer phenotype in several families with Li–Fraumeni syndrome. The Chang group then analyzed genomic DNA from normal fibroblasts and tumors of affected individuals and found that loss of the wild-type <em>P53</em> allele was a consistent feature of the tumors. </p> <p id="p-21">Genetically engineered mouse models supported the dual nature of <em>P53</em> as both an activated oncogene and a tumor suppressor gene. In 1989, Alan Bernstein's laboratory reported that mice bearing an oncogenic mutant <em>P53</em> transgene had a high incidence of bone, lung, and lymphoid cancers. These results presaged the discovery of germline <em>P53</em> mutations as the cause of Li–Fraumeni syndrome in humans. Evidence that wild-type <em>P53</em> could function as a tumor suppressor in vivo then came from Lawrence Donehower's laboratory, who reported in 1992 that homozygous <em>P53</em><sup>−/−</sup> knockout mice developed normally but were highly tumor-prone. Similar results were later reported by Tyler Jacks and Alan Clarke, whose groups showed that heterozygous <em>P53</em><sup>+/−</sup> mice were also tumor-prone, but with a longer latency. Furthermore, the resulting tumors displayed a loss of heterozygosity due to the absence of the normal <em>P53</em> allele. </p> </div> <div class="section" id="sec-4"> <div class="section-nav"><a href="#sec-3" title="P53 AS A TUMOR SUPPRESSOR GENE" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-5" title="p53 AS A POISON PILL" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">p53 AS A TRANSCRIPTION FACTOR</h2> <p id="p-22">The structure and functions of the wild-type p53 protein were revealed in a flurry of publications in the early 1990s. Stanley Fields’ group identified a strong transcriptional activation domain at the amino terminus (residues 1–74) in yeast two-hybrid experiments aimed at identifying binding partners for p53. They then fused fragments of p53 to the carboxyl terminus of the yeast GAL4 DNA-binding domain and tested for their ability to activate transcription of a GAL4-responsive reporter gene in Chinese hamster ovary (CHO) cells. Guillermina Lozano's group reached a similar conclusion using human HeLa cells, identifying a strong transcriptional activation domain within amino acids 1–330 when fused to the amino terminus of the same GAL4 DNA-binding domain (<a id="xref-fig-5-1" class="xref-fig" href="#F5">Fig. 5</a>). Furthermore, they found that an amino acid substitution (A135V) that oncogenically activated wild-type p53 abolished transcriptional activation when introduced into a p53 (1–343)-GAL4 fusion protein. These results indicated that oncogenic mutants of p53 might function by inhibiting transcriptional activation. </p> <div id="F5" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F5.expansion.html"><img alt="Figure 5." src="a035931/F5.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F5.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F5.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F5">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 5.</span> <p id="p-23" class="first-child">p53 contains a transcriptional activation domain. HeLa cells were transiently transfected with plasmid DNAs encoding the indicated effectors and reporters. Cell lysates were assayed for the enzymatic activity of the chloramphenicol acetyltransferase (CAT) reporter. A = no effector; B = GAL4 DNA-binding domain (4–147); C = wild-type p53 (1–343) fused to GAL4 (4–147); D = mutant p53 (1–343) A135V fused to GAL4 (4–147); E = full-length GAL4 (4–881). Autoradiograms of thin-layer chromatography are shown on the <em>right</em>. The <em>bottom</em> spots contain unmodified [<sup>14</sup>C]-chloramphenicol substrate. The upwardly migrating spots are mono- and diacetylated forms of [<sup>14</sup>C]-chloramphenicol produced by the CAT enzyme. (Reprinted, with permission, from Raycroft L, et al. 1990. <em>Science</em> <strong>249:</strong> 1049–1051, © AAAS.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-24">The ability of the mammalian p53 transcriptional activation domain to function when fused to either end of a heterologous yeast DNA-binding domain was consistent with experiments from Mark Ptashne's laboratory, which had revealed a modular “mix and match” domain structure of eukaryotic transcription factors. Subsequent experiments performed by a number of laboratories defined two adjacent transcriptional activation domains within the amino-terminal region of p53, both of which were subsequently found to interact with the CBP/p300 family of coactivator proteins and bind to several general transcription factors, including the TATA-binding protein (TBP). </p> <p id="p-25">The next question was whether p53 itself contained a DNA-binding domain. In 1991, a collaboration led by Jill Bargonetti in Carol Prives's laboratory and Scott Kern in Bert Vogelstein's laboratory reported that recombinant wild-type p53 could bind directly to sequences near the SV40 origin of replication, whereas some oncogenic mutants of p53 could not. Furthermore, the SV40 large T antigen protein inhibited this DNA binding. They then used a McKay assay in which fragments of human genomic DNA were immunoprecipitated by anti-p53 antibodies in the presence of recombinant p53 to define the motifs required for sequence-specific DNA binding. A comparative analysis of these fragments revealed a consensus sequence consisting of two copies of a 10-bp motif [5′-PuPuPuC(A/T)(T/A)GPyPyPy-3′] separated by a variable nonspecific linker 0–13 bp in length. Both copies of this motif were required for p53 binding. Jerry Shay's laboratory independently used a library of double-stranded synthetic oligonucleotides with a 35-bp randomized core flanked by fixed sequences for PCR amplification to reiteratively enrich for sequences bound by human p53 protein. They selected a p53-binding site [5′-GGACATGCCCGGGCATGTCC-3′] that turned out to be a no-linker version of the Vogelstein group's broader consensus sequence. Several laboratories then showed that p53 could activate the transcription of model reporter genes containing p53-binding sites, both in vitro and in vivo. </p> <p id="p-26">In 1993, the laboratories of Steve Maxwell, Carl Pabo, Carol Prives, and Peter Tegtmeyer showed that a central domain of the p53 protein was required for sequence-specific DNA binding (<a id="xref-fig-6-1" class="xref-fig" href="#F6">Fig. 6</a>). A protease-resistant domain spanning amino acids 102–292 was sufficient for this DNA binding and contained four of the five previously defined regions of evolutionary conservation in p53. Furthermore, the missense mutations most frequently found in human cancers affected this domain (<a id="xref-fig-4-2" class="xref-fig" href="#F4">Figs. 4</a> and <a id="xref-fig-6-2" class="xref-fig" href="#F6">6</a>). In 1994, Nikolai Pavletich's laboratory determined the structure of the p53 DNA-binding domain in complex with its recognition site using X-ray crystallography (<a id="xref-fig-6-3" class="xref-fig" href="#F6">Fig. 6</a>). Remarkably, the most frequent oncogenic amino acid substitutions affected residues that directly contacted DNA or lay adjacent to them. Additional structures reported by Zippora Shakked's group in 2006 showed that each DNA half-site was bound by a dimer of p53 DNA-binding domains, that the interface between two dimers varied according to the spacing between the half-sites, and that the overall affinity for DNA changed accordingly. </p> <div id="F6" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F6.expansion.html"><img alt="Figure 6." src="a035931/F6.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F6.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F6.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F6">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 6.</span> <p id="p-27" class="first-child">Structure of the p53 DNA-binding domain. (<em>Top</em>) Schematic diagram showing the location of p53 functional domains, the frequency of amino acid substitutions in human cancer (peak height), and the regions (I–V) that are highly conserved among vertebrate p53 proteins. (<em>Bottom left</em>, <em>A</em>) The sequence of the p53 DNA-binding domain, the frequency of amino acid substitutions in cancer, and the location of elements of secondary structure. (<em>Bottom right</em>, <em>B</em>) Ribbon diagram showing the structure of the p53 DNA-binding domain (green), highlighting frequently mutated amino acids (yellow) and their relationship to DNA (blue). (Reprinted, with permission, from Cho Y, et al. 1994. <em>Science</em> <strong>265:</strong> 346–355, © AAAS.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-28">In 1992, David Lane's laboratory showed that a monoclonal antibody directed against the extreme carboxyl terminus of wild-type p53 could greatly increase DNA binding. Deletion of the carboxy-terminal 30 amino acids had a similar effect, as did mild proteolysis, addition of the bacterial dnaK protein chaperone, or addition of casein kinase II. These results suggested a “closed” conformation of wild-type p53 that could be “opened” by physiological regulation. Candidates proposed as regulators included posttranslational modification, interaction with a variety of other proteins, or nonspecific binding to DNA. </p> </div> <div class="section" id="sec-5"> <div class="section-nav"><a href="#sec-4" title="p53 AS A TRANSCRIPTION FACTOR" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-6" title="MUTANT P53: ANTIMORPH OR NEOMORPH?" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">p53 AS A POISON PILL</h2> <p id="p-29">Several laboratories have reported on the tendency of p53 to form aggregates in solution. In 1989, Gerald Hurwitz's laboratory showed that SV40 T antigen formed double hexamers that bound to the viral origin of replication. These observations motivated Peter Tegtmeyer's group to search for a higher-order structure of p53. In 1992, they used chemical cross-linking of purified recombinant p53 protein followed by denaturing gel electrophoresis to show that p53 predominantly formed stable tetramers. Furthermore, tetramer–tetramer interactions could cause the looping of intervening DNA separating distant p53-binding sites. Similar results were soon reported by Carol Prives's group, who also showed that p53 behaved anomalously in gel filtration chromatography, suggesting a nonglobular shape (<a id="xref-fig-7-1" class="xref-fig" href="#F7">Fig. 7</a>). </p> <div id="F7" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F7.expansion.html"><img alt="Figure 7." src="a035931/F7.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F7.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F7.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F7">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 7.</span> <p id="p-30" class="first-child">(<em>Left</em>) Tetramerization of purified full-length p53 revealed by SDS-PAGE after cross-linking with the following concentrations of glutaraldehyde for 15 min at 37°C: A = 0%; B = 0.01%; C = 0.1%. M indicates molecular weight markers with sizes shown in kilodaltons. (<em>Right</em>) Ribbon diagram of the structure of the tetramerization domain of p53. (<em>Left</em> panel reprinted, with permission, from Friedman PN, et al. 1993. <em>Proc Natl Acad Sci</em> <strong>90:</strong> 3319–3323, © National Academy of Sciences; <em>right</em> panel reprinted, with permission, from Jeffrey PD, et al. 1995. <em>Science</em> <strong>267:</strong> 1498–1502, © AAAS.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-31">The laboratories of Carl Pabo and Peter Tegtmeyer mapped the domain required for tetramerization near to the carboxyl terminus of p53 (amino acids 323–355). Nikolai Pavletich's group then solved the structure by X-ray crystallography, revealing hydrophobic interactions among four α-helices, one from each monomer (<a id="xref-fig-7-2" class="xref-fig" href="#F7">Fig. 7</a>). The frequent retention of the tetramerization domain in mutant p53 proteins in human cancer argued for its importance in transformation. Remarkably, this domain in isolation enhanced the oncogenic transformation of rat embryo fibroblasts by adenovirus <em>E1A</em> plus mutant <em>HRAS</em>. Experiments in the laboratories of David Lane, Arnold Levine, and Moshe Oren had shown that some (but not all) oncogenic mutant p53 proteins adopted a conformation different from that of wild-type p53. Furthermore, the mutant proteins were more stable in living cells and associated with an Hsc70 chaperone protein. Together, these observations supported a model in which mutant forms of p53 primarily functioned as dominant inhibitors that could “poison” tetramers of wild-type p53, thereby inhibiting its DNA-binding and/or transcriptional activation. Subsequent loss of the wild-type <em>P53</em> gene would then result in all-mutant tetramers of p53. </p> </div> <div class="section" id="sec-6"> <div class="section-nav"><a href="#sec-5" title="p53 AS A POISON PILL" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-7" title="ACTIVATION OF P53 BY DNA DAMAGE" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">MUTANT P53: ANTIMORPH OR NEOMORPH?</h2> <p id="p-32">Herman Muller's classification of mutants in <em>Drosophila</em> in the 1930s included two types of alleles that were subsequently proposed to explain the unusual genetics of <em>P53</em> in human cancer: antimorph and neomorph. An antimorph is a dominant loss-of-function mutant that inhibits the function of the wild-type allele. In the 1980s, Ira Herskowitz popularized the term “dominant negative” to describe this type of mutant. In contrast, a neomorph is a dominant mutant that has an activity different from that of the wild-type allele. The prevalence of missense mutants that disrupted the DNA-binding domain of p53 while preserving a functional carboxy-terminal tetramerization domain argued in favor of an antimorphic role for <em>P53</em> mutants in human cancer. On the other hand, the relative paucity of <em>RB</em>-like loss-of-function mutants caused by nonsense or by frameshift mutations of <em>P53</em> argued that perhaps the more common missense mutants act as neomorphs. </p> <p id="p-33">Experiments in Varda Rotter's laboratory in 1984 showing that exogenous <em>P53</em>, which was later found to be a missense mutant, could increase the malignancy of cells lacking any wild-type p53 protein were the first to support a neomorphic function of mutant p53 protein. In 2004, the groups of Tyler Jacks and Gigi Lozano showed that knockin mice encoding amino acid substitutions in p53 frequently seen in human cancers developed allele-specific tumor spectra different from that seen in mice devoid of p53. These results argued strongly for neomorphism, and the underlying mechanisms remain a topic of active investigation. Reported activities include indirect regulation of nuclear gene expression via interaction of mutant p53 with other transcription factors, heterodimerization with the paralogous p63 and p73 proteins, direct interaction of mutant p53 with the DNA repair machinery, cytoplasmic inhibition of apoptosis, and regulation of mitochondrial metabolism. </p> </div> <div class="section" id="sec-7"> <div class="section-nav"><a href="#sec-6" title="MUTANT P53: ANTIMORPH OR NEOMORPH?" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-8" title="DOWNSTREAM FROM p53: CELL CYCLE ARREST AND APOPTOSIS" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">ACTIVATION OF P53 BY DNA DAMAGE</h2> <p id="p-34">A breakthrough in understanding the function and regulation of p53 came from an unexpected quarter. Cellular mechanisms for repairing DNA damage have been intensely studied since Ruth Hill's discovery of radiation-sensitive mutants of <em>Escherichia coli</em> in 1958. Much of this work focused on characterizing the types of DNA damage caused by different physical and chemical agents and then purifying the enzymes required for repair. In 1988, Ted Weinert and Lee Hartwell showed that the <em>RAD9</em> gene in budding yeast was required for X-ray-induced cell cycle arrest in the G<sub>2</sub> phase, regardless of the phase in which the damage had occurred. Loss-of-function mutants of <em>RAD9</em> failed to arrest in response to X-irradiation, continued to proliferate, and eventually died. However, the <em>RAD9</em> gene was not required for viability and proliferation in the absence of DNA damage. Furthermore, <em>RAD9</em> mutants could be rescued from lethal doses of X-rays by low doses of microtubule poisons that caused a <em>RAD9</em>-independent delay in G<sub>2</sub>. <em>RAD9</em> thus seemed to encode part of a “cell cycle checkpoint” not essential for the normal cell cycle, but only for cell cycle arrest in response to DNA damage. This concept led to the discovery of other cell cycle checkpoints that monitored essential events and caused cell cycle arrest until their proper execution. </p> <p id="p-35">Several laboratories had recently shown that wild-type p53 caused a G<sub>1</sub> phase cell cycle arrest—Edward Mercer's group used stable transfection with a glucocorticoid-inducible promoter, Stephen Friend's laboratory used transient DNA transfection, and Moshe Oren and Arnold Levine's laboratories used a temperature-sensitive A135V mutant of p53 that adopted a completely wild-type conformation at 32.5°C and a completely mutant conformation at 39.5°C (<a id="xref-fig-8-1" class="xref-fig" href="#F8">Fig. 8</a>). </p> <div id="F8" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F8.expansion.html"><img alt="Figure 8." src="a035931/F8.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F8.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F8.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F8">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 8.</span> <p id="p-36" class="first-child">A temperature-sensitive mutant of p53 causes G<sub>1</sub> arrest at the “wild-type” temperature (32.5°C) but not the “mutant” temperature (39.5°C). (<em>Top</em>) Phase contrast images and anti-p53 immunofluorescence of rat embryo fibroblast transformed by <em>HRAS</em> + <em>ts-p53</em>. Note the nuclear localization of “wild-type” p53 at 32.5°C. (<em>Bottom</em>) Analysis of cell cycle progression by flow cytometry of isolated nuclei (<em>X</em>-axis = relative DNA content per nucleus; <em>Y</em>-axis = number of nuclei). (Reprinted, with permission, from Martinez J, et al. 1991. <em>Genes Dev</em> <strong>5:</strong> 151–159, © Cold Spring Harbor Laboratory Press.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-37">Therefore, in 1991, the Kastan laboratory tested whether p53 might be required for the inhibition of DNA synthesis by ionizing irradiation that was discovered by George de Hevesy in the 1940s. Kastan's group found that p53 protein but not mRNA levels increased significantly in response to X-rays, suggesting posttranscriptional regulation. They then showed that cells lacking p53 did not arrest in the G<sub>1</sub> phase in response to X-rays, but this response could be restored by exogenous wild-type p53. Conversely, the normal G<sub>1</sub> arrest in cells with wild-type p53 was abolished by exogenous mutant p53 protein. </p> <p id="p-38">The Kastan group and their collaborators then showed that radiation-sensitive cells from patients with ataxia telangiectasia failed to arrest in G<sub>1</sub> or induce p53 in response to ionizing radiation (<a id="xref-fig-9-1" class="xref-fig" href="#F9">Fig. 9</a>). This human disease was caused by homozygous loss-of-function germline mutations in the <em>ATM</em> gene. Furthermore, a gene induced by growth arrest and DNA damage (<em>GADD45</em>) that had been previously identified in Albert Fornace's laboratory was not induced by ionizing radiation in the absence of either <em>ATM</em> or <em>p53</em>. These results indicated the existence of a DNA damage response pathway:<span class="disp-formula" id="disp-formula-1"><img class="math mml" alt="Formula" src="a035931/embed/mml-math-1.gif" /> </span> </p> <div id="F9" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F9.expansion.html"><img alt="Figure 9." src="a035931/F9.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F9.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F9.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F9">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 9.</span> <p id="p-39" class="first-child">ATM is required for the induction of p53 protein by ionizing radiation. Cells from wild-type (NL), ATM<em>/+</em> (Ht), or ATM/ATM (AT) individuals were metabolically labeled for 1 hour after treatment with or without ionizing radiation, then extracts were immunoprecipitated with anti-p53 antibodies and subjected to denaturing gel electrophoresis and autoradiography. (Reprinted, with permission, from Kastan MB, et al. 1992. <em>Cell</em> <strong>71:</strong> 587–597, © Elsevier.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-40">In 1995, Yosef Shiloh's group cloned the <em>ATM</em> gene, which encoded a protein with sequence similarity to the PI3K lipid kinase. Shortly thereafter, Stephen Jackson and Carl Anderson's laboratories reported that a gene encoding a DNA-dependent protein kinase (DNA-PK) showed even greater similarity to ATM, suggesting that ATM might also be a protein kinase rather than a lipid kinase. Several groups then cloned another ATM-related gene (<em>ATR</em>). As Susan Lees-Miller in the Anderson laboratory had initially shown for DNA-PK, all three of these protein kinases phosphorylated serine 15 within the amino-terminal transcriptional activation domain of p53. In 2000, Christine Canman, Stephen Elledge, and Clare McGowan's groups showed that ATM phosphorylated Chk2 protein kinase, the mammalian homolog of the budding yeast Rad53 and fission yeast Cds1 checkpoint proteins, thereby activating it in response to DNA damage. The laboratories of Thanos Halazonetis, Tak Mak, and Carol Prives showed that Chk2 in turn phosphorylated p53 on serine 20, which resulted in the stabilization of p53. These results explained a recent report by Daniel Haber's group that germline mutations in the <em>CHEK2</em> gene that encoded Chk2 caused some cases of Li–Fraumeni syndrome that lacked <em>P53</em> mutations. Several laboratories then elucidated a similar pathway in which UV damage activated ATR, which then phosphorylated the Chk1 protein, which then phosphorylated and stabilized p53. </p> <p id="p-41">Unexpectedly, the stability of p53 was directly regulated by a recently discovered oncogene. In 1991, Donna George's laboratory discovered <em>MDM2</em> (<em>mouse double minute 2</em>) as a proto-oncogene amplified in a transformed tumorigenic variant of murine 3T3 cells containing double minute chromosomes, a hallmark of gene amplification (Lipsick 2025c). In 1992, Arnold Levine's group purified a 90-kDa protein that coimmunoprecipitated with p53, sequenced three tryptic peptides, and identified it as the MDM2 protein. They also showed that ectopic expression of MDM2 inhibited transcriptional activation of a p53-responsive reporter gene. Bert Vogelstein's laboratory then reported that <em>MDM2</em> was amplified fivefold to 50-fold in 17 of 47 human sarcomas tested but neither in benign soft tissue tumors nor in malignant carcinomas. In 1993, the laboratories of Arnold Levine, Moshe Oren, and Bert Vogelstein provided evidence for a negative feedback loop in which p53 activated transcription of the <em>MDM2</em> gene, and the MDM2 protein then bound to and occluded the transcriptional activation domain of p53. Four years later, Karen Vousden and Moshe Oren's laboratories showed that MDM2 also caused the degradation of p53 via a proteasome-dependent mechanism that required the MDM2-binding domain of p53. Hideyo Yasuda's group then showed that purified MDM2 functioned as an E3 ubiquitin ligase in vitro. The phosphorylation of p53 by the Chk2 kinase prevented its binding to MDM2. Furthermore, Yosef Shiloh and Moshe Oren's laboratories showed that MDM2 itself was phosphorylated by ATM, thereby decreasing its ability to promote the degradation of p53. Together these results led to a model in which p53 functioned as a central node in the G<sub>1</sub> phase DNA damage checkpoint (<a id="xref-fig-10-1" class="xref-fig" href="#F10">Fig. 10</a>). </p> <div id="F10" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F10.expansion.html"><img alt="Figure 10." src="a035931/F10.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F10.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F10.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F10">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 10.</span> <p id="p-42" class="first-child">The activation of wild-type p53 by DNA damage. (dsbs) Double-stranded breaks. (Reprinted, with permission, from Abraham RT. 2001. <em>Genes Dev</em> <strong>15:</strong> 2177–2196, © Cold Spring Harbor Laboratory Press.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-43">Guillermina Lozano and Alan Bradley's laboratories created <em>MDM2-</em>knockout mice, and, in 1995, they reported that the absence of MDM2 caused early embryonic lethality. Remarkably, double homozygous mutants that lacked both MDM2 and p53 developed normally and were viable. The essential target for ubiquitylation by MDM2 was thus p53, and an excess of p53 was lethal. Subsequent studies showed that MDM2 formed heterodimers with the closely related MDM4/MDMX protein, constituting the predominant E3 ubiquitin ligase for p53 in vivo. As was the case for MDM2, the absence of MDM4 was lethal but could be rescued by loss of p53. Amplification of the <em>MDM4</em> gene was also identified in a subset of human cancer types. </p> </div> <div class="section" id="sec-8"> <div class="section-nav"><a href="#sec-7" title="ACTIVATION OF P53 BY DNA DAMAGE" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-9" title="OLD DOG, NEW TRICKS? ARF!" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">DOWNSTREAM FROM p53: CELL CYCLE ARREST AND APOPTOSIS</h2> <p id="p-44">The molecular effector of G<sub>1</sub> phase arrest caused by p53 was discovered in 1993 by Wafik El-Diery in Bert Vogelstein's laboratory. They used a human glioblastoma cell line developed in Ed Mercer's laboratory that contained endogenous mutant p53 plus a stably integrated glucocorticoid-inducible transgene expressing wild-type p53 to search for p53-inducible mRNAs by subtractive hybridization. They identified a single gene (initially called <em>WAF1</em> but later renamed <em>CDKN1A</em>) that was induced by wild-type p53 but not by mutant p53. Furthermore, the <em>WAF1</em> promoter contained a p53-binding site sufficient to confer p53 inducibility on a synthetic reporter gene. Remarkably, <em>WAF1</em> encoded the p21<sup>CIP1</sup> (Cdk-interacting protein) inhibitor of cyclin-dependent kinases that was discovered independently by the laboratories of David Beach, Stephen Elledge, David Morgan, and James Smith. Subsequent experiments by these and other laboratories showed that p21<sup>CIP1</sup> protein inhibited CDK2-Cyclin E and CDK2-Cyclin A in vitro, arrested the cell cycle in G<sub>1</sub>, and was induced in irradiated cells in a p53-dependent manner. </p> <p id="p-45">A few years later, work from several laboratories unexpectedly showed that p21<sup>CIP1</sup> and the related p27<sup>KIP1</sup> inhibitor of CDK2-Cyclin E and A complexes were redundantly required for the activation of the CDK4-Cyclin D complex in the G<sub>1</sub> phase. These results led to a model in which normally low levels of p21<sup>CIP1</sup> prevent entry into and progression through the S phase until CDK4-Cyclin D increases to levels sufficient to sequester p21<sup>CIP1</sup> and permit the activation of CDK2-Cyclin E kinase (<a id="xref-fig-11-1" class="xref-fig" href="#F11">Fig. 11</a>). The p53-mediated expression of higher levels of p21<sup>CIP1</sup> in response to DNA damage could override this sequestration, resulting in the G<sub>1</sub> phase arrest even in the presence of increased levels of CDK4-Cyclin D. </p> <div id="F11" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F11.expansion.html"><img alt="Figure 11." src="a035931/F11.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F11.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F11.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F11">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 11.</span> <p id="p-46" class="first-child">A model for the complex role of p21<sup>Cip</sup> and p27<sup>Kip</sup> in normal cell cycle progression. (Reprinted, with permission, from Sherr CJ, Roberts JM. 1999. <em>Genes Dev</em> <strong>13:</strong> 1501–1512, © Cold Spring Harbor Laboratory Press.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-47">In 1991, Moshe Oren and his colleagues used a transgene encoding a temperature-sensitive p53 mutant to show that wild-type p53 could induce apoptosis in a murine myeloid leukemia cell line lacking endogenous p53. This p53-induced cell death could be prevented by the exogenous growth and survival factor IL-6. In 1993, Eileen White's group used temperature-sensitive p53 to show that the adenovirus E1A oncoprotein caused p53-dependent apoptosis that could be inhibited by the adenovirus E1B 55 kDa protein, which Arnold Berk's laboratory had recently reported could inhibit transcriptional activation by p53. That same year, Scott Lowe in Tyler Jacks’ laboratory reported that thymic lymphocytes from p53-deficient mice were resistant to apoptosis induced by ionizing irradiation, but not by glucocorticoids or other stimuli. Lowe and colleagues used p53-deficient mouse embryonic fibroblasts (MEFs) to show that p53 was also required to sensitize <em>E1A</em> + <em>HRAS</em> transformed cells to apoptosis induced by some commonly used cancer chemotherapy drugs (5-fluoro-uracil, etoposide, and doxorubicin). Two years later, Toshiyuki Miyashita and John Reed showed that p53 directly activated transcription of the <em>BAX</em> gene known to encode a BCL2-related proapoptotic protein (J Lipsick, in prep.). Karen Vousden and Tadatsugu Taniguchi's laboratories then identified two p53-inducible genes encoding new BH3-domain proapoptotic proteins, PUMA and NOXA. </p> <p id="p-48">Experiments testing the role of these effectors of cell cycle arrest and apoptosis in tumor suppression by p53 gave conflicting results. For example, Philip Leder's laboratory reported in 1995 that, unlike <em>P53</em>-deficient mice, <em>CDKN1A</em>-deficient mice did not develop spontaneous cancer within 7 months. Six years later, Manuel Serrano's laboratory reported that <em>CDKN1A</em>-deficient mice did develop a variety of different cancers at an average age of 16 months. On the other hand, Wei Gu's laboratory showed in 2012 that mice with a triple-acetylation-site knockin mutant of <em>P53</em> incapable of activating <em>CDKN1A</em> or <em>PUMA</em> gene expression were resistant to the development of spontaneous cancers. Similarly, Andreas Strasser's group showed that mice triply deficient in <em>CDKN1A</em>, <em>NOXA</em>, and <em>PUMA</em> were also resistant to cancer development. Over 100 other genes have been reported to be directly regulated by p53, as have several “noncanonical” cellular functions including metabolism, ferroptosis, self-renewal, and differentiation. A plethora of posttranslational modifications of p53 have also been reported to occur in a variety of different conditions. Perhaps this complexity results in context-specific roles for different effectors of tumor suppression by p53. </p> </div> <div class="section" id="sec-9"> <div class="section-nav"><a href="#sec-8" title="DOWNSTREAM FROM p53: CELL CYCLE ARREST AND APOPTOSIS" class="prev-section-link"><span>Previous Section</span></a><a href="#sec-10" title="P53 PATHWAY IN CLINICAL ONCOLOGY" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">OLD DOG, NEW TRICKS? ARF!</h2> <p id="p-49">Although p53 had been dubbed “guardian of the genome” by David Lane in 1992, tumor suppression by p53 occurred in the absence of abnormal levels of DNA damage. In addition, cellular stresses other than DNA damage also increased levels of p53, including activation of oncogenic pathways, defects in ribosome biogenesis, hypoxia, oxidative stress, and mitotic spindle abnormalities. Therefore, the mechanisms by which these stresses activated p53 became a topic of considerable interest. </p> <p id="p-50">In 1995, Dawn Quelle in Charles Sherr's laboratory made a startling discovery. They found that <em>INK4a</em> (later renamed <em>CDKN2A</em>), a tumor suppressor locus that encoded an inhibitor of the Cyclin D-CDK4/6 kinases (p16<sup>INK4a</sup>), produced two different mRNAs from two different transcriptional initiation sites. Although both mRNAs shared a common second exon, they were translated in different reading frames (<a id="xref-fig-12-1" class="xref-fig" href="#F12">Fig. 12</a>). They dubbed the previously unknown second protein p19<sup>ARF</sup> (for alternative reading frame). Surprisingly, cDNAs encoding either protein caused cell cycle arrest. Site-directed mutagenesis revealed that expression of the 62 amino acid amino terminus of p19<sup>ARF</sup>, encoded by its unique first exon, was sufficient to cause cell cycle arrest. Consistent with this observation, Gordon Peter's group later showed that chickens lacked an <em>INK4A</em> gene but did express a functional 60-residue ARF protein. In 1997, the Sherr laboratory reported that knockout mice lacking either p16<sup>INK4a</sup> or p19<sup>ARF</sup> were both tumor-prone, implying that two different tumor suppressor proteins were encoded within a single locus. </p> <div id="F12" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F12.expansion.html"><img alt="Figure 12." src="a035931/F12.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F12.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F12.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F12">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 12.</span> <p id="p-51" class="first-child">(<em>Left</em>) Structure of the <em>CDKN2A</em> locus encoding both p16<sup>INK4A</sup> and p19<sup>ARF</sup> using different reading frames. (<em>Right</em>) Mutation of p53 or loss/silencing of CDKN2A during establishment for four independent murine embryonic fibroblast lines. (<em>Left</em> panel reprinted, with permission, from Quelle DE, et al. 1995. <em>Cell</em> <strong>83:</strong> 993–1000, © Elsevier; <em>right</em> panel reprinted, with permission, from Kamijo T, et al. 1997. <em>Cell</em> <strong>91:</strong> 649–659, © Elsevier.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-52">MEFs are frequently isolated from knockout mice for experiments in cell culture. p19<sup>ARF</sup>-deficient MEFs were unusual in that they readily gave rise to stable cell lines without passing through a “crisis” phase during which most cells undergo senescence and death with only rare survivors becoming “immortal.” In addition, p19<sup>ARF</sup>-deficient MEFs could be transformed by mutant <em>HRAS</em> alone, unlike wild-type MEFs, which required an additional cooperating oncogene (e.g., <em>E1A</em> or <em>MYC</em>). Additional studies revealed that as wild-type MEFs were passaged in culture, levels of p19<sup>ARF</sup> rose from undetectable to relatively high. This was consistent with the virtual absence of p19<sup>ARF</sup> during normal embryonic development. Interestingly, existing mouse fibroblast cell lines (3T3) were found to either express mutant p53 or lack expression of p19<sup>ARF</sup>. In addition, one of these two events consistently occurred during the establishment of new mouse fibroblastic cell lines (<a id="xref-fig-12-2" class="xref-fig" href="#F12">Fig. 12</a>). Furthermore, cells lacking wild-type p53 were resistant to cell cycle arrest caused by p19<sup>ARF</sup>. Thus, p19<sup>ARF</sup> likely functioned upstream of p53, and increasing levels of p19<sup>ARF</sup> due to “culture shock” caused senescence (irreversible cell cycle arrest) during the routine establishment of cell lines. Several laboratories including those of Ronald DePinho, Gordon Peters, Charles Sherr, Karen Vousden, Yue Xiong, and Hideo Yasuda soon reported that p19<sup>ARF</sup> bound directly to the MDM2 protein and interfered with its ability to destabilize p53. However, p19<sup>ARF</sup> was not required for the stabilization of p53 induced by DNA damage. </p> <p id="p-53">In 1998, the Lowe, Sherr, Serrano, and Vousden laboratories showed that overexpression of various oncogenes including <em>E1A</em>, <em>MYC</em>, and <em>RAS</em> activated wild-type p53 in cell culture by increasing the expression of p19<sup>ARF</sup>. These experiments provided an explanation for the long-standing observation that many retroviral oncogenes initially caused senescence and massive cell death in culture, followed by the outgrowth of relatively rare transformed cells. John Cleveland's laboratory showed that somatic mutations of <em>ARF</em> or <em>P53</em> frequently occurred in vivo during the progression of lymphoid malignancies in <em>Eμ-MYC</em> transgenic mice, and that germline mutation of <em>ARF</em> greatly accelerated this disease. p19<sup>ARF</sup> thus appeared to activate p53 as a guardian against oncogenic transformation, rather than as a “guardian of the genome” (<a id="xref-fig-13-1" class="xref-fig" href="#F13">Fig. 13</a>). </p> <div id="F13" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F13.expansion.html"><img alt="Figure 13." src="a035931/F13.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F13.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F13.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F13">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 13.</span> <p id="p-54" class="first-child">A model for the RB and p53 pathways in cell cycle control. (Reprinted, with permission, from Sherr CJ. 2004. <em>Cell</em> <strong>116:</strong> 235–246, © Elsevier.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-55">The “double negative” logic of the p53 pathway was similar to that of the RB pathway (Lipsick 2025b), with an alternation of a tumor suppressor gene (<em>ARF</em>), a proto-oncogene (<em>MDM2</em>), and a tumor suppressor gene (<em>P53</em>). In addition, a negative feedback loop in which p53 induced <em>MDM2</em> expression acted as a control mechanism. Some later experiments in cell lines or genetically engineered mice indicated that ARF may have additional p53-independent functions in tumor suppression. However, this has remained a controversial topic with conflicting evidence obtained from different experimental settings. </p> </div> <div class="section" id="sec-10"> <div class="section-nav"><a href="#sec-9" title="OLD DOG, NEW TRICKS? ARF!" class="prev-section-link"><span>Previous Section</span></a><a href="#fn-group-1" title="Footnotes" class="next-section-link"><span>Next Section</span></a></div> <h2 class="">P53 PATHWAY IN CLINICAL ONCOLOGY</h2> <p id="p-56"><em>P53</em> was found to be one of the most frequently mutated genes in human cancer. In a study of cancers from 10,336 patients at Memorial Sloan Kettering Cancer Center published in 2017, 57% of cases contained somatic mutations in the P53 pathway (<a id="xref-fig-14-1" class="xref-fig" href="#F14">Fig. 14</a>). These mutational data likely underestimate the importance of the P53 pathway because of frequent epigenetic silencing by DNA methylation of the <em>CDKN2A</em> locus in some types of cancer. A majority of the mutations in the pathway were shown to occur within <em>P53</em> itself. Interestingly, although missense mutations causing amino acid substitutions were the most frequent class (67%), a substantial fraction of these cancers contained nonsense or frameshift mutations causing protein truncation. Because <em>P53</em> mutation was often a late event during the progression of sporadic cancer, as initially shown by the Vogelstein group, unsurprisingly it was associated with a poor prognosis. It was hoped that <em>P53</em> mutation status might be an important predictor for clinical responses to different types of cancer therapy but results thus far have been inconclusive and contradictory. </p> <div id="F14" class="fig pos-float odd"> <div class="fig-inline"><a href="a035931/F14.expansion.html"><img alt="Figure 14." src="a035931/F14/graphic-15.small.gif" /></a><a href="a035931/F14.expansion.html"><img alt="Figure 14." src="a035931/F14/graphic-16.small.gif" /></a><div class="callout"><span>View larger version:</span><ul class="callout-links"> <li><a href="a035931/F14.expansion.html">In this window</a></li> <li><a class="in-nw" href="a035931/F14.expansion.html">In a new window</a></li> </ul> <ul class="fig-services"> <li class="ppt-link"><a href="/powerpoint/15/2/a035931/F14">Download as PowerPoint Slide</a></li> </ul> </div> </div> <div class="fig-caption"><span class="fig-label">Figure 14.</span> <p id="p-57" class="first-child">p53 pathway mutations in human cancer. (<em>Top</em>) Frequency of p53 pathway somatic mutations in human cancer. (<em>Bottom</em>) Spectrum of <em>TP53</em> mutations in human tumors. Relationship between <em>TP53</em> mutations and patient survival. (Data from Zehir A, et al. 2017. <em>Nat Med</em> <strong>23:</strong> 703–713; and visualized using the cBioPortal web resource, <a href="http://www.cbioportal.org/index.do">www.cbioportal.org/index.do</a>.) </p> <div class="sb-div caption-clear"></div> </div> </div> <p id="p-58">Efforts to develop drugs that targeted the p53 pathway initially focused on two strategies. The first approach was to develop inhibitors of the MDM2-p53 interface to prevent the destruction of wild-type p53 in cancers that overexpress MDM2. Hoffman-LaRoche developed a small molecule called nutlin-3a for this purpose and reported its effectiveness in cell culture and in human tumor xenografts in nude mice in 2004. However, thus far, this drug and others like it have proven to be too toxic for use in humans. The second approach has been to develop small molecules that can induce mutant p53 to refold into a wild-type conformation. A promising compound called PRIMA-1 (for p53 reactivation and induction of massive apoptosis) was developed by Klas Wiman and colleagues in 2002. Derivatives of this compound have been approved for clinical trials and additional compounds are being sought by similar strategies. However, such drugs are likely to be allele-specific. </p> <p id="p-59">Recent clinical efficacy of nonspecific stimulation of antitumor immune responses in some types of human cancer has led to renewed interest in attempts to use mutant p53 peptides as specific antitumor immunogens, perhaps in the context of cell-mediated rather than humoral immunity. Another interesting strategy has been the use of E1B-55K-deficient adenovirus, which in theory should only replicate in cells that lack wild-type p53 protein. Such a virus was patented and tested in clinical trials that did not meet expectations in the United States. However, a similar virus was approved in China for the treatment of nasopharyngeal cancer. </p> </div> <div class="section fn-group" id="fn-group-1"> <div class="section-nav"><a href="#sec-10" title="P53 PATHWAY IN CLINICAL ONCOLOGY" class="prev-section-link"><span>Previous Section</span></a><a href="#ref-list-1" title="SUGGESTED READING" class="next-section-link"><span>Next Section</span></a></div> <h2>Footnotes</h2> <ul> <li class="fn" id="fn-1"> <p id="p-1">From the forthcoming volume <em>Stalking the Enemy Within: A History of Cancer Research</em>, by Joseph Lipsick </p> </li> <li class="fn" id="fn-2"> <p id="p-2">Additional Perspectives on A History of Cancer Research available at <a href="http://www.perspectivesinmedicine.org">www.perspectivesinmedicine.org</a></p> </li> </ul> </div> <ul class="copyright-statement"> <li class="fn" id="copyright-statement-1"><a href="http://www.perspectivesinmedicine.org/site/misc/terms.xhtml">Copyright © 2025 Joseph Lipsick; published by Cold Spring Harbor Laboratory Press; all rights reserved</a></li> </ul> <div class="section ref-list" id="ref-list-1"> <div class="section-nav"><a href="#fn-group-1" title="Footnotes" class="prev-section-link"><span>Previous Section</span></a><div class="nav-placeholder"> </div> </div> <h2 class="">SUGGESTED READING</h2> <p id="p-60">*<em>Reference is also in this subject collection</em>. </p> <ol class="cit-list ref-use-labels"> <li><span class="ref-label ref-label-empty"></span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.1" data-doi="10.1101/cshperspect.a026310"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Cheok</span> <span class="cit-name-given-names">CF</span></span>, <span class="cit-auth"><span class="cit-name-surname">Lane</span> <span class="cit-name-given-names">DP</span></span>. <span class="cit-pub-date">2017</span>. <span class="cit-article-title">Exploiting the p53 pathway for therapy</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Med</abbr> <span class="cit-vol">7</span>: <span class="cit-fpage">a026310</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1101/cshperspect.a026310</span></cite></div> <div class="cit-extra"><a href="/cgi/ijlink?linkType=ABST&journalCode=cshperspectmed&resid=7/3/a026310" class="cit-ref-sprinkles cit-ref-sprinkles-ijlinks"><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></a></div> </div> </li> <li><span class="ref-label ref-label-empty"></span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.2" data-doi="10.1101/gad.340976.120"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Gencel-Augusto</span> <span class="cit-name-given-names">J</span></span>, <span class="cit-auth"><span class="cit-name-surname">Lozano</span> <span class="cit-name-given-names">G</span></span>. <span class="cit-pub-date">2020</span>. <span class="cit-article-title">P53 tetramerization: at the center of the dominant-negative effect of mutant p53</span>. <abbr class="cit-jnl-abbrev">Genes Dev</abbr> <span class="cit-vol">34</span>: <span class="cit-fpage">1128</span>–<span class="cit-lpage">1146</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1101/gad.340976.120</span></cite></div> <div class="cit-extra"><a href="/cgi/ijlink?linkType=ABST&journalCode=genesdev&resid=34/17-18/1128" class="cit-ref-sprinkles cit-ref-sprinkles-ijlinks"><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></a></div> </div> </li> <li><span class="ref-label ref-label-empty"></span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.3" data-doi="10.1038/nrc2723"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Levine</span> <span class="cit-name-given-names">AJ</span></span>, <span class="cit-auth"><span class="cit-name-surname">Oren</span> <span class="cit-name-given-names">M</span></span>. <span class="cit-pub-date">2009</span>. <span class="cit-article-title">The first 30 years of p53: growing ever more complex</span>. <abbr class="cit-jnl-abbrev">Nat Rev Cancer</abbr> <span class="cit-vol">9</span>: <span class="cit-fpage">749</span>–<span class="cit-lpage">758</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1038/nrc2723</span></cite></div> <div class="cit-extra"><a href="/external-ref?access_num=10.1038/nrc2723&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=19776744&link_type=MED" class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a href="/external-ref?access_num=000270102800012&link_type=ISI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">Web of Science</a><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=The%20first%2030%20years%20of%20p53%3A%20growing%20ever%20more%20complex&publication_year=2009&journal=Nat%20Rev%20Cancer&volume=9&pages=749-758&doi=10.1038%2Fnrc2723">Google Scholar</a></div> </div> </li> <li><span class="ref-label">*.</span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.4" data-doi="10.1101/cshperspect.a035592"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Lipsick</span> <span class="cit-name-given-names">J</span></span>. <span class="cit-pub-date">2019</span>. <span class="cit-article-title">A history of cancer research: tyrosine kinases</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Biol</abbr> <span class="cit-vol">11</span>: <span class="cit-fpage">a035592</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>1101/cshperspect.a035592</span></cite></div> <div class="cit-extra"><a href="/cgi/ijlink?linkType=ABST&journalCode=cshperspect&resid=11/2/a035592" class="cit-ref-sprinkles cit-ref-sprinkles-ijlinks"><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></a></div> </div> </li> <li><span class="ref-label">*.</span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.5" data-doi="10.1101/cshperspect.a035881"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Lipsick</span> <span class="cit-name-given-names">J</span></span>. <span class="cit-pub-date">2024</span>. <span class="cit-article-title">A history of cancer research: oncogenic transcription factors</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Biol</abbr> <span class="cit-comment"><strong>16:</strong> a035881</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1101/cshperspect.a035881</span></cite></div> <div class="cit-extra"><a href="/cgi/ijlink?linkType=ABST&journalCode=cshperspect&resid=16/6/a035881" class="cit-ref-sprinkles cit-ref-sprinkles-ijlinks"><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></a></div> </div> </li> <li><span class="ref-label">*.</span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.6" data-doi="1101/cshperspect.a035782"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Lipsick</span> <span class="cit-name-given-names">J</span></span>. <span class="cit-pub-date">2025a</span>. <span class="cit-article-title">A history of cancer research: cancer cell growth and metabolism</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Med</abbr><span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>1101/cshperspect.a035782</span></cite></div> <div class="cit-extra"><a href="/external-ref?access_num=1101/cshperspect.a035782&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=A%20history%20of%20cancer%20research%3A%20cancer%20cell%20growth%20and%20metabolism&publication_year=2025a&journal=Cold%20Spring%20Harb%20Perspect%20Med&doi=1101%2Fcshperspect.a035782">Google Scholar</a></div> </div> </li> <li><span class="ref-label">*.</span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.7"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Lipsick</span> <span class="cit-name-given-names">J</span></span>. <span class="cit-pub-date">2025b</span>. <span class="cit-article-title">G1-S transition and the RB Pathway</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Biol</abbr> (in press).</cite></div> <div class="cit-extra"><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=G1-S%20transition%20and%20the%20RB%20Pathway&q=Lipsick J . 2025b . G1-S transition and the RB Pathway . Cold Spring Harb Perspect Biol (in press).&publication_year=2025b&journal=Cold%20Spring%20Harb%20Perspect%20Biol">Google Scholar</a></div> </div> </li> <li><span class="ref-label">*.</span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.8"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Lipsick</span> <span class="cit-name-given-names">J</span></span>. <span class="cit-pub-date">2025c</span>. <span class="cit-article-title">Proto-oncogene activation in human cancer</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Med</abbr> (in press).</cite></div> <div class="cit-extra"><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=Proto-oncogene%20activation%20in%20human%20cancer&q=Lipsick J . 2025c . Proto-oncogene activation in human cancer . Cold Spring Harb Perspect Med (in press).&publication_year=2025c&journal=Cold%20Spring%20Harb%20Perspect%20Med">Google Scholar</a></div> </div> </li> <li><span class="ref-label">*.</span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.9"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Lipsick</span> <span class="cit-name-given-names">J</span></span>. <span class="cit-article-title">Cell death and cancer</span>. <abbr class="cit-jnl-abbrev">Cold Spring Harb Perspect Med</abbr> (in prep.).</cite></div> <div class="cit-extra"><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=Cell%20death%20and%20cancer&q=Lipsick J . Cell death and cancer . Cold Spring Harb Perspect Med (in prep.).&journal=Cold%20Spring%20Harb%20Perspect%20Med">Google Scholar</a></div> </div> </li> <li><span class="ref-label ref-label-empty"></span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.10" data-doi="10.1016/S0092-8674(03)01075-4"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Sherr</span> <span class="cit-name-given-names">CJ</span></span>. <span class="cit-pub-date">2004</span>. <span class="cit-article-title">Principles of tumor suppression</span>. <abbr class="cit-jnl-abbrev">Cell</abbr> <span class="cit-vol">116</span>: <span class="cit-fpage">235</span>–<span class="cit-lpage">246</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1016/s0092-8674(03)01075-4</span></cite></div> <div class="cit-extra"><a href="/external-ref?access_num=10.1016/S0092-8674(03)01075-4&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=14744434&link_type=MED" class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a href="/external-ref?access_num=000188541700013&link_type=ISI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">Web of Science</a><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=Principles%20of%20tumor%20suppression&publication_year=2004&journal=Cell&volume=116&pages=235-246&doi=10.1016%2Fs0092-8674%2803%2901075-4">Google Scholar</a></div> </div> </li> <li><span class="ref-label ref-label-empty"></span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.11" data-doi="10.1016/j.cell.2009.04.037"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Vousden</span> <span class="cit-name-given-names">KH</span></span>, <span class="cit-auth"><span class="cit-name-surname">Prives</span> <span class="cit-name-given-names">C</span></span>. <span class="cit-pub-date">2009</span>. <span class="cit-article-title">Blinded by the light: the growing complexity of p53</span>. <abbr class="cit-jnl-abbrev">Cell</abbr> <span class="cit-vol">137</span>: <span class="cit-fpage">413</span>–<span class="cit-lpage">431</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1016/j.cell.2009.04.037</span></cite></div> <div class="cit-extra"><a href="/external-ref?access_num=10.1016/j.cell.2009.04.037&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=19410540&link_type=MED" class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a href="/external-ref?access_num=000265677200013&link_type=ISI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">Web of Science</a><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=Blinded%20by%20the%20light%3A%20the%20growing%20complexity%20of%20p53&publication_year=2009&journal=Cell&volume=137&pages=413-431&doi=10.1016%2Fj.cell.2009.04.037">Google Scholar</a></div> </div> </li> <li><span class="ref-label ref-label-empty"></span><div class="cit ref-cit ref-journal no-rev-xref" id="cit-15.2.a035931.12" data-doi="10.1146/annurev-pathol-042320-025840"> <div class="cit-metadata"><cite><span class="cit-auth"><span class="cit-name-surname">Wang</span> <span class="cit-name-given-names">M</span></span>, <span class="cit-auth"><span class="cit-name-surname">Attardi</span> <span class="cit-name-given-names">LD</span></span>. <span class="cit-pub-date">2022</span>. <span class="cit-article-title">A balancing act: p53 activity from tumor suppression to pathology and therapeutic implications</span>. <abbr class="cit-jnl-abbrev">Annu Rev Pathol</abbr> <span class="cit-vol">17</span>: <span class="cit-fpage">205</span>–<span class="cit-lpage">226</span>.<span class="cit-pub-id-sep cit-pub-id-doi-sep"> </span><span class="cit-pub-id cit-pub-id-doi"><span class="cit-pub-id-scheme-doi">doi:</span>10.1146/annurev-pathol-042320-025840</span></cite></div> <div class="cit-extra"><a href="/external-ref?access_num=10.1146/annurev-pathol-042320-025840&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-webofscience">CrossRef</a><a href="/external-ref?access_num=34699262&link_type=MED" class="cit-ref-sprinkles cit-ref-sprinkles-medline">Medline</a><a target="_blank" href="http://scholar.google.com/scholar_lookup?title=A%20balancing%20act%3A%20p53%20activity%20from%20tumor%20suppression%20to%20pathology%20and%20therapeutic%20implications&publication_year=2022&journal=Annu%20Rev%20Pathol&volume=17&pages=205-226&doi=10.1146%2Fannurev-pathol-042320-025840">Google Scholar</a></div> </div> </li> </ol> </div><span class="highwire-journal-article-marker-end"></span></div> <div class="social-bookmarking"> <ul class="social-bookmark-links"> <li class="social-bookmarking-item social-bookmarking-item-citeulike"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=CITEULIKE"><img src="/shared/img/common/social-bookmarking/citeulike.gif" alt="Add to CiteULike" title="CiteULike" /></a><span class="soc-bm-link-text">CiteULike</span></li> <li class="social-bookmarking-item social-bookmarking-item-delicious"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=DEL_ICIO_US"><img src="/shared/img/common/social-bookmarking/delicious.gif" alt="Add to Delicious" title="Delicious" /></a><span class="soc-bm-link-text">Delicious</span></li> <li class="social-bookmarking-item social-bookmarking-item-digg"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=DIGG"><img src="/shared/img/common/social-bookmarking/digg.gif" alt="Add to Digg" title="Digg" /></a><span class="soc-bm-link-text">Digg</span></li> <li class="social-bookmarking-item social-bookmarking-item-facebook"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/short/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=FACEBOOK" class="sb-facebook" rel="external-nw"><img src="/shared/img/common/social-bookmarking/facebook.gif" alt="Add to Facebook" title="Facebook" /></a><span class="soc-bm-link-text">Facebook</span></li> <li class="social-bookmarking-item social-bookmarking-item-googleplus"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=GOOGLEPLUS&log_only=yes"><img src="/shared/img/common/social-bookmarking/googleplus.jpg" alt="Add to Google+" title="Google+" /></a><span class="soc-bm-link-text">Google+</span></li> <li class="social-bookmarking-item social-bookmarking-item-reddit"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=REDDIT"><img src="/shared/img/common/social-bookmarking/reddit.gif" alt="Add to Reddit" title="Reddit" /></a><span class="soc-bm-link-text">Reddit</span></li> <li class="social-bookmarking-item social-bookmarking-item-twitter"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=TWITTER"><img src="/shared/img/common/social-bookmarking/twitter.gif" alt="Add to Twitter" title="Twitter" /></a><span class="soc-bm-link-text">Twitter</span></li> </ul> <p class="social-bookmarking-help"><a href="/help/social_bookmarks.dtl">What's this?</a></p> </div><span id="related-urls"></span></div> <div id="col-2"> <div class="article-nav sidebar-nav"> <a href="/content/15/1/a041815.short" title="Previous article" class="previous">« Previous</a><span class="article-nav-sep"> | </span><a href="/content/15/2/a041160.short" title="Next article" class="next">Next Article »</a> <span class="toc-link"> <a href="/content/15/2.toc" title="Table of Contents">Table of Contents</a> </span> </div> <div class="content-box" id="article-cb-main"> <div class="cb-contents"> <h3 class="cb-contents-header"><span>This Article</span></h3> <div class="cb-section cb-slug"> <ol> <li> <div id="slugline"> doi: <span title="10.1101/cshperspect.a035931" class="slug-doi">10.1101/cshperspect.a035931 </span> <cite> <abbr title="Cold Spring Harbor Perspectives in Medicine" class="slug-jnl-abbrev"> Cold Spring Harb Perspect Med</abbr><span class="slug-pub-date" itemprop="datePublished"> 2025. </span> <span class="slug-vol"> 15: </span> </cite> <a href="/site/misc/terms.xhtml"><span class="copyright-statement"> <nlm:ext-link xmlns:nlm="http://schema.highwire.org/NLM/Journal" xmlns:l="http://schema.highwire.org/Linking" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:hwp="http://schema.highwire.org/Journal" l:rel="related" l:ref-type="uri" l:ref="http://www.perspectivesinmedicine.org/site/misc/terms.xhtml" ext-link-type="uri" xlink:href="http://www.perspectivesinmedicine.org/site/misc/terms.xhtml" hwp:id="ext-link-1">Copyright © 2025 Joseph Lipsick; published by Cold Spring Harbor Laboratory Press; all rights reserved</nlm:ext-link></span></a> </div> </li> </ol> </div> <div class="cb-section cb-views"> <ol> <li class="abstract-view-link primary"><a href="/content/15/2/a035931.abstract" rel="view-abstract">Abstract</a><span class="viewspecificaccesscheck cshperspectmed;15/2/a035931 abstract"></span></li> <li class="notice full-text-view-link primary"><span class="variant-indicator">» <span>Full Text</span></span><span class="viewspecificaccesscheck cshperspectmed;15/2/a035931 full"></span></li> <li class="notice full-text-pdf-view-link primary"><a href="/content/15/2/a035931.full.pdf+html" rel="view-full-text.pdf">Full Text (PDF)</a><span class="viewspecificaccesscheck cshperspectmed;15/2/a035931 reprint"></span></li> </ol> </div> <div class="cb-section collapsible" id="cb-art-cat"> <h4 class="cb-section-header"><span>Article Category</span></h4> <ol> <li> <ul class="subject-headings last-child"> <li><a class="tocsection-search" href="/search?tocsectionid=RETROSPECTIVE&sortspec=date&submit=Submit">Retrospective</a></li> </ul> </li> </ol> </div> <div class="cb-section collapsible" id="cb-art-svcs"> <h4 class="cb-section-header"><span>Services</span></h4> <ol> <li class="alert-link icon-link"><a href="/cgi/alerts/ctalert?alertType=citedby&addAlert=cited_by&cited_by_criteria_resid=cshperspectmed%3B15%2F2%2Fa035931&saveAlert=no&return-type=article&return_url=http://perspectivesinmedicine.cshlp.org/content/15/2/a035931.full">Alert me when this article is cited</a></li> <li class="alert-link icon-link"><a href="/cgi/alerts/ctalert?alertType=correction&addAlert=correction&correction_criteria_value=15/2/a035931&saveAlert=no&return-type=article&return_url=http://perspectivesinmedicine.cshlp.org/content/15/2/a035931.full">Alert me if a correction is posted</a></li> <li class="similar-link"><a href="/search?qbe=cshperspectmed%3B15%2F2%2Fa035931&citation=Lipsick%2015%20%282%29&submit=yes">Similar articles in this journal</a></li> <li class="similar-link"><a href="/external-ref?access_num=cshperspectmed%3B15%2F2%2Fa035931&link_type=ISI_RELATEDRECORDS" id="cb-isi-similar-articles" class="similar-link">Similar articles in Web of Science</a></li> <li class="similar-link"><a href="/external-ref?access_num=39900457&link_type=MED_NBRS" class="similar-link">Similar articles in PubMed</a></li> <li class="cit-man-link icon-link cite-link"><a href="/citmgr?gca=cshperspectmed%3B15%2F2%2Fa035931">Download to citation manager</a></li> <li class="copyright-link icon-link"><a href="/site/misc/permissions_landing.xhtml"> Permissions </a></li> </ol> </div> <div class="cb-section collapsible default-closed" id="cb-letter-cit"> <h4 class="cb-section-header"><span>Updates/Comments</span></h4> <ol> <li class="eletter-link eletter-submit-link"><a href="/letters/submit/cshperspectmed;15/2/a035931" class="eletter-link eletter-submit-link">Submit updates/comments</a></li> <li class="eletter-link eletter-read-link"><span class="eletters-no-responses-published">No updates/comments published</span></li> <li><a href="/cgi/alerts/ctalert?alertType=eletter&addAlert=eletter&eletter_criteria_value=15/2/a035931&saveAlert=no&return-type=article&return_url=http://perspectivesinmedicine.cshlp.org/content/15/2/a035931.full">Alert me when Updates/Comments are published</a></li> </ol> </div> <div class="cb-section collapsible default-closed" id="cb-art-cit"> <h4 class="cb-section-header"><span>Citing Articles</span></h4> <ol> <li class="hw-citing-link"><a href="/content/15/2/a035931.full?cited-by=yes&legid=cshperspectmed;15/2/a035931#cited-by" id="cb-hw-citing-articles">Load citing article information</a></li> <li><a href="/external-ref?access_num=%2Fcshperspectmed%2F15%2F2%2Fa035931&link_type=ISI_CITING&accnum_type=native" rel="external-nw" id="cb-isi-citing-articles">Citing articles via Web of Science</a></li> </ol> </div> <div class="cb-section collapsible default-closed" id="cb-art-gs"> <h4 class="cb-section-header"><span>Google Scholar</span></h4> <ol> <li class="cb-art-gs-auth author-link"><a href="http://scholar.google.com/scholar?q=%22author%3ALipsick%20author%3AJ.%22" class="cb-art-gs-auth author-link">Articles by Lipsick, J.</a></li> </ol> </div> <div class="cb-section collapsible default-closed" id="cb-art-pm"> <h4 class="cb-section-header"><span>PubMed/NCBI</span></h4> <ol> <li><a href="/external-ref?access_num=39900457&link_type=PUBMED">PubMed citation</a></li> <li><a href="/external-ref?access_num=Lipsick%20J&link_type=AUTHORSEARCH">Articles by Lipsick, J.</a></li> <li> <div id="cb-entrez-links-placeholder"><a href="/entrez-links/39900457"></a></div> </li> </ol> </div> <div class="cb-section collapsible default-closed" id="cb-art-rel"> <h4 class="cb-section-header"><span>Related Content</span></h4> <ol> <li><a href="/content/15/2/a035931.full?related-urls=yes&legid=cshperspectmed;15/2/a035931#related-urls" id="cb-related-urls">Load related web page information</a></li> </ol> </div> <div class="cb-section collapsible default-open" id="cb-art-col"> <h4 class="cb-section-header"><span>Subject Collections</span></h4> <ol> <li><a href="/cgi/collection/ahistoryofcancerresearch">A History of Cancer Research</a></li> </ol> </div> <div class="cb-section collapsible default-closed" id="cb-art-soc"> <h4 class="cb-section-header"><span>Share</span></h4> <ol> <li><a href="/email?gca=cshperspectmed%3B15%2F2%2Fa035931&current-view-path=/content/15/2/a035931.full"></a></li> <li> <div class="social-bookmarking"> <ul class="social-bookmark-links"> <li class="social-bookmarking-item social-bookmarking-item-citeulike"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=CITEULIKE"><img src="/shared/img/common/social-bookmarking/citeulike.gif" alt="Add to CiteULike" title="CiteULike" /></a><span class="soc-bm-link-text">CiteULike</span></li> <li class="social-bookmarking-item social-bookmarking-item-delicious"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=DEL_ICIO_US"><img src="/shared/img/common/social-bookmarking/delicious.gif" alt="Add to Delicious" title="Delicious" /></a><span class="soc-bm-link-text">Delicious</span></li> <li class="social-bookmarking-item social-bookmarking-item-digg"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=DIGG"><img src="/shared/img/common/social-bookmarking/digg.gif" alt="Add to Digg" title="Digg" /></a><span class="soc-bm-link-text">Digg</span></li> <li class="social-bookmarking-item social-bookmarking-item-facebook"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/short/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=FACEBOOK" class="sb-facebook" rel="external-nw"><img src="/shared/img/common/social-bookmarking/facebook.gif" alt="Add to Facebook" title="Facebook" /></a><span class="soc-bm-link-text">Facebook</span></li> <li class="social-bookmarking-item social-bookmarking-item-googleplus"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=GOOGLEPLUS&log_only=yes"><img src="/shared/img/common/social-bookmarking/googleplus.jpg" alt="Add to Google+" title="Google+" /></a><span class="soc-bm-link-text">Google+</span></li> <li class="social-bookmarking-item social-bookmarking-item-reddit"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=REDDIT"><img src="/shared/img/common/social-bookmarking/reddit.gif" alt="Add to Reddit" title="Reddit" /></a><span class="soc-bm-link-text">Reddit</span></li> <li class="social-bookmarking-item social-bookmarking-item-twitter"><a href="/external-ref?tag_url=http://perspectivesinmedicine.cshlp.org/cgi/content/long/15/2/a035931&title=A%20History%20of%20Cancer%20Research%3A%20The%20P53%20Pathway+--+Lipsick%2015%20%282%29+--+cshperspectmed&doi=10.1101/cshperspect.a035931&link_type=TWITTER"><img src="/shared/img/common/social-bookmarking/twitter.gif" alt="Add to Twitter" title="Twitter" /></a><span class="soc-bm-link-text">Twitter</span></li> </ul> <p class="social-bookmarking-help"><a href="/help/social_bookmarks.dtl">What's this?</a></p> </div> </li> </ol> </div> </div> </div> <div class="content-box" id="author_chat1"> <div class="cb-contents"> <h3 class="cb-contents-header"><span>Richard Sever interviews Joan Brugge</span></h3> <center><iframe frameborder="0" scrolling="auto" width="165" height="70" src="https://www.youtube.com/embed/i2lRm_Civ7c" allowfullscreen="allowfullscreen"></iframe></center> </div> </div> <ul class="tower-ads"> <li class="no-ad tower_col_2"><span> </span></li> </ul> <div class="content-box" id="article-dyn-nav"> <div class="cb-contents"> <h3 class="cb-contents-header"><span>Navigate This Article</span></h3> <div class="cb-section" id="cb-art-nav"> <ol> <li><a href="#content-block">Top</a></li> <li><a href="#abstract-1">Abstract</a></li> <li><a href="#sec-1">p53 PROTEIN AS A FELLOW TRAVELER</a></li> <li><a href="#sec-2">P53 AS AN ONCOGENE</a></li> <li><a href="#sec-3"><em>P53</em> AS A TUMOR SUPPRESSOR GENE</a></li> <li><a href="#sec-4">p53 AS A TRANSCRIPTION FACTOR</a></li> <li><a href="#sec-5">p53 AS A POISON PILL</a></li> <li><a href="#sec-6">MUTANT P53: ANTIMORPH OR NEOMORPH?</a></li> <li><a href="#sec-7">ACTIVATION OF P53 BY DNA DAMAGE</a></li> <li><a href="#sec-8">DOWNSTREAM FROM p53: CELL CYCLE ARREST AND APOPTOSIS</a></li> <li><a href="#sec-9">OLD DOG, NEW TRICKS? ARF!</a></li> <li><a href="#sec-10">P53 PATHWAY IN CLINICAL ONCOLOGY</a></li> <li><a href="#fn-group-1">Footnotes</a></li> <li><a href="#ref-list-1">SUGGESTED READING</a></li> </ol> </div> </div> </div> </div> <div id="col-3"> <div class="content-box" id="sidebar-current-issue"> <div class="cb-contents"> <h3 class="cb-contents-header"><span>Current Issue</span></h3> <div class="cb-section"> <ol> <li><span><a href="/content/current" rel="current-issue">February 2025, 15 (2)</a></span></li> </ol> </div> <div class="cb-section"> <ol> <li> <div class="current-issue"><a href="/content/current" rel="current-issue"><img src="/content/15/2.cover.gif" width="67" height="89" alt="Current Issue" /></a></div> </li> </ol> </div> <cb:item xmlns:cb="http://schema.highwire.org/Site/Content-Box"> <div class="cb-section collapsible default-closed" id="sidebar-cur-issue-coverlines"> <h4 class="cb-section-header"> <span>From the cover</span> </h4> <ul> <li> <a>A collage of collection cover images</a> </li> </ul> </div> </cb:item> </div> </div> <div id="sidebar-global-nav"> <ul class="button-list pub-links"> <li class="first"><a href="/content/early/recent" title="Early Release Articles"><span>Early Release Articles</span></a></li> <li><a href="/site/misc/sample.xhtml" title="Featured Articles"><span>Featured Articles</span></a></li> <li><a href="/cgi/collection/" title="Subject Collections"><span>Subject Collections</span></a></li> <li><a href="/content/by/year" title="Archive by Date"><span>Archive by Date</span></a></li> <li><a href="/site/misc/alertland.xhtml" title="Alerts and RSS Feeds"><span>Alerts and RSS Feeds</span></a></li> <li><a href="http://www.cshlpress.com/library/?hwinfo" title="Recommend to Your Library"><span>Recommend to Your Library</span></a></li> <li class="last"><a href="/site/misc/permissions_landing.xhtml" title="Permissions"><span>Permissions</span></a></li> </ul> </div> <ul class="tower-ads"> <li class="no-ad tower_col_3"><span> </span></li> </ul> <div id="col-3-widget-placeholder" style="padding-top:0px;"> <p style="text-align:center;font-weight:bold;font-size:12px;line-height:15px;margin-top:0;padding-top:0;margin-bottom:0px;color:black;"> <a href="http://www.cshlpress.com/link/molclon4p.htm" style="color:black;">Molecular Cloning<br />The New Edition<br /> <span style=" color: red; ">Buy Now and Save 30%</span> </a> <br />Paperback only<br />(limited time offer) </p> <table style="border-spacing:6px;font-size: 80%;"> <tr> <td style="padding-bottom:6px;padding-top:2px;padding-left:12px;vertical-align:top;"> <a href="http://www.cshlpress.com/link/molclon4p.htm"> <img src="http://www.cshlpress.com/productgraphics/small/Molclon4-1.jpg" alt="Support Research and Save at CSHL Press" /> </a> </td> <td style="padding-bottom:9px;padding-left:6px;padding-right:12px;vertical-align:middle;"> <a href="http://www.cshlpress.com/link/molclon4p.htm">Molecular Cloning: A Laboratory Manual (Fourth Edition)</a> </td> </tr> </table> <br /> <br /> <center><img alt="CSH Perspectives in Medicine" src="/site/misc/covers_hompage/cshlp_med_ad.jpg" /></center> </div> </div> <div id="footer"> <div class="bar"> <div class="footer-group footer-col-left"> <ul class="button-list footer-buttons"> <li class="first"><a href="/" title="Home"><span>Home</span></a></li> <li><a href="/site/misc/about.xhtml" title="About"><span>About</span></a></li> <li><a href="/cgi/collection/" title="Subject Collections"><span>Subject Collections</span></a></li> <li><a href="/content/by/year" title="Archive"><span>Archive</span></a></li> <li><a href="/site/misc/subscribe.xhtml" title="Subscribe"><span>Subscribe</span></a></li> <li><a href="/site/misc/adinfo.xhtml" title="Advertise"><span>Advertise</span></a></li> <li><a href="/site/misc/alertland.xhtml" title="Alerts"><span>Alerts</span></a></li> <li><a href="/feedback" title="Feedback"><span>Feedback</span></a></li> <li class="last"><a href="/help/" title="Help"><span>Help</span></a></li> </ul> <p class="copyright"><a href="http://www.cshlpress.com/" rel="external-nw">Copyright © 2025 by Cold Spring Harbor Laboratory Press</a></p> </div> <div class="footer-group footer-col-right"> <ul class="issns"> <li> <span>Online ISSN: </span> <span class="issn">2157-1422</span> </li> </ul> </div> </div> <div class="block-2 sb-div"></div> <script type="text/javascript"> document.write(unescape("%3Cscript async src='https://www.googletagmanager.com/gtag/js?id=G-THYNWVK2VZ'%3E%3C/script%3E")); </script><script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'G-THYNWVK2VZ'); </script> </div><script type="text/javascript"> document.write(unescape("%3Cscript async src='https://www.googletagmanager.com/gtag/js?id=G-1CWXPJ6EVC'%3E%3C/script%3E")); </script><script> window.dataLayer = window.dataLayer || []; function gtag(){dataLayer.push(arguments);} gtag('js', new Date()); gtag('config', 'G-1CWXPJ6EVC'); </script></div> </body> </html>

CINXE.COM

A History of Cancer Research: The P53 Pathway