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• W2752942423 abstract "TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53’s disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor-suppressive activities in cancer? TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53’s disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor-suppressive activities in cancer? p53 was discovered during the peak of tumor virus research as a 53 kD host protein bound to simian virus 40 large T antigen in virally transformed cells (Lane and Crawford, 1979Lane D.P. Crawford L.V. T antigen is bound to a host protein in SV40-transformed cells.Nature. 1979; 278: 261-263Crossref PubMed Google Scholar, Linzer and Levine, 1979Linzer D.I. Levine A.J. Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells.Cell. 1979; 17: 43-52Abstract Full Text PDF PubMed Scopus (1067) Google Scholar). First classified as an oncogene, subsequent work established that wild-type p53, encoded by TP53, suppresses growth and oncogenic transformation in cell culture (Finlay et al., 1989Finlay C.A. Hinds P.W. Levine A.J. The p53 proto-oncogene can act as a suppressor of transformation.Cell. 1989; 57: 1083-1093Abstract Full Text PDF PubMed Scopus (1455) Google Scholar) and that inactivating TP53 mutations are common in human tumors (Baker et al., 1990Baker S.J. Preisinger A.C. Jessup J.M. Paraskeva C. Markowitz S. Willson J.K. Hamilton S. Vogelstein B. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis.Cancer Res. 1990; 50: 7717-7722PubMed Google Scholar). In many cancers, TP53 mutation is linked to poor patient prognosis (Olivier et al., 2010Olivier M. Hollstein M. Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use.Cold Spring Harb. Perspect. Biol. 2010; 2: a001008Crossref PubMed Scopus (537) Google Scholar). Consistent with its action as a tumor suppressor, TP53 mutations are a hallmark of a hereditary cancer predisposition disorder known as Li-Fraumeni syndrome (Malkin et al., 1990Malkin D. Li F.P. Strong L.C. Fraumeni Jr., J.F. Nelson C.E. Kim D.H. Kassel J. Gryka M.A. Bischoff F.Z. Tainsky M.A. et al.Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.Science. 1990; 250: 1233-1238Crossref PubMed Google Scholar), and Trp53 knockout mice develop tumors at high penetrance (Donehower et al., 1992Donehower L.A. Harvey M. Slagle B.L. McArthur M.J. Montgomery Jr., C.A. Butel J.S. Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.Nature. 1992; 356: 215-221Crossref PubMed Scopus (3646) Google Scholar). p53 is a sequence-specific DNA binding protein that regulates transcription (reviewed in Laptenko and Prives, 2006Laptenko O. Prives C. Transcriptional regulation by p53: one protein, many possibilities.Cell Death Differ. 2006; 13: 951-961Crossref PubMed Scopus (305) Google Scholar). The p53 protein consists of two N-terminal transactivation domains followed by a conserved proline-rich domain, a central DNA binding domain, and a C terminus encoding its nuclear localization signals and an oligomerization domain needed for transcriptional activity. Consistent with the importance of p53-mediated transcription in tumor suppression, the vast majority of tumor-derived TP53 mutations occur in the region encoding p53’s DNA binding domain. In normal cells, p53 protein is maintained at low levels by a series of regulators including MDM2, which functions as a p53 ubiquitin ligase to facilitate its degradation (Haupt et al., 1997Haupt Y. Maya R. Kazaz A. Oren M. Mdm2 promotes the rapid degradation of p53.Nature. 1997; 387: 296-299Crossref PubMed Scopus (3071) Google Scholar, Honda et al., 1997Honda R. Tanaka H. Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.FEBS Lett. 1997; 420: 25-27Crossref PubMed Scopus (1358) Google Scholar, Kubbutat et al., 1997Kubbutat M.H. Jones S.N. Vousden K.H. Regulation of p53 stability by Mdm2.Nature. 1997; 387: 299-303Crossref PubMed Scopus (2451) Google Scholar). However, p53 is stabilized in response to various cellular stresses, including DNA damage and replication stress produced by deregulated oncogenes. Mechanisms leading to p53 activation can be stimulus dependent: for example, DNA damage promotes p53 phosphorylation, blocking MDM2-mediated degradation (Shieh et al., 1997Shieh S.Y. Ikeda M. Taya Y. Prives C. DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2.Cell. 1997; 91: 325-334Abstract Full Text Full Text PDF PubMed Scopus (1533) Google Scholar), whereas oncogenic signaling induces the ARF tumor suppressor to inhibit MDM2 (Pomerantz et al., 1998Pomerantz J. Schreiber-Agus N. Liégeois N.J. Silverman A. Alland L. Chin L. Potes J. Chen K. Orlow I. Lee H.W. et al.The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53.Cell. 1998; 92: 713-723Abstract Full Text Full Text PDF PubMed Scopus (1240) Google Scholar, Quelle et al., 1995Quelle D.E. Zindy F. Ashmun R.A. Sherr C.J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest.Cell. 1995; 83: 993-1000Abstract Full Text PDF PubMed Scopus (1217) Google Scholar, Zhang et al., 1998Zhang Y. Xiong Y. Yarbrough W.G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways.Cell. 1998; 92: 725-734Abstract Full Text Full Text PDF PubMed Scopus (1279) Google Scholar). The best-understood functions of p53 focus on its ability to promote cell cycle arrest and apoptosis. Indeed, seminal studies from the early 1990s showed that p53 is crucial for a reversible DNA damage-induced G1 phase checkpoint (Kastan et al., 1991Kastan M.B. Onyekwere O. Sidransky D. Vogelstein B. Craig R.W. Participation of p53 protein in the cellular response to DNA damage.Cancer Res. 1991; 51: 6304-6311PubMed Google Scholar) that is mediated, in part, by its ability to transcriptionally activate the p21 cyclin-dependent kinase inhibitor gene (el-Deiry et al., 1993el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. WAF1, a potential mediator of p53 tumor suppression.Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7280) Google Scholar, Harper et al., 1993Harper J.W. Adami G.R. Wei N. Keyomarsi K. Elledge S.J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.Cell. 1993; 75: 805-816Abstract Full Text PDF PubMed Scopus (4826) Google Scholar), presumably facilitating DNA repair prior to further cell division. In some circumstances, p53 induces cellular senescence, a stable if not permanent cell cycle arrest program that also involves the retinoblastoma (RB) gene product (Serrano et al., 1997Serrano M. Lin A.W. McCurrach M.E. Beach D. Lowe S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.Cell. 1997; 88: 593-602Abstract Full Text Full Text PDF PubMed Scopus (3208) Google Scholar, Shay et al., 1991Shay J.W. Pereira-Smith O.M. Wright W.E. A role for both RB and p53 in the regulation of human cellular senescence.Exp. Cell Res. 1991; 196: 33-39Crossref PubMed Scopus (551) Google Scholar). p53 can also promote apoptosis (Clarke et al., 1993Clarke A.R. Purdie C.A. Harrison D.J. Morris R.G. Bird C.C. Hooper M.L. Wyllie A.H. Thymocyte apoptosis induced by p53-dependent and independent pathways.Nature. 1993; 362: 849-852Crossref PubMed Scopus (2185) Google Scholar, Lowe et al., 1993Lowe S.W. Schmitt E.M. Smith S.W. Osborne B.A. Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes.Nature. 1993; 362: 847-849Crossref PubMed Scopus (2624) Google Scholar, Yonish-Rouach et al., 1991Yonish-Rouach E. Resnitzky D. Lotem J. Sachs L. Kimchi A. Oren M. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6.Nature. 1991; 352: 345-347Crossref PubMed Scopus (1868) Google Scholar), relying on the induction of pro-apoptotic BCL-2 family members whose action facilitates caspase activation and cell death (Miyashita et al., 1994Miyashita T. Krajewski S. Krajewska M. Wang H.G. Lin H.K. Liebermann D.A. Hoffman B. Reed J.C. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo.Oncogene. 1994; 9: 1799-1805PubMed Google Scholar). Why p53 promotes cell cycle arrest in some cell types and apoptosis in others is incompletely understood (see below). The settings in which p53 can be activated to arrest or eliminate pre-malignant cells have guided current thinking as to why p53 is such a potent tumor suppressor. On one hand, its ability to arrest or eliminate cells after DNA damage suggests that it might prevent cancer by preventing the accumulation of oncogenic mutations (Livingstone et al., 1992Livingstone L.R. White A. Sprouse J. Livanos E. Jacks T. Tlsty T.D. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53.Cell. 1992; 70: 923-935Abstract Full Text PDF PubMed Scopus (1214) Google Scholar, Yin et al., 1992Yin Y. Tainsky M.A. Bischoff F.Z. Strong L.C. Wahl G.M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles.Cell. 1992; 70: 937-948Abstract Full Text PDF PubMed Scopus (992) Google Scholar). In this model, p53 loss indirectly promotes cancer by increasing the number of mutations in surviving daughter cells. On the other hand, the ability of p53 to halt the proliferation in response to aberrant oncogene expression suggests a role in limiting the consequences of oncogenic mutations. Here, p53 loss directly enables cancer development by allowing oncogene-expressing cells to proliferate unabated, explaining why TP53 mutations cooperate with oncogenes in transformation (Lowe et al., 1994Lowe S.W. Jacks T. Housman D.E. Ruley H.E. Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells.Proc. Natl. Acad. Sci. USA. 1994; 91: 2026-2030Crossref PubMed Google Scholar, Serrano et al., 1997Serrano M. Lin A.W. McCurrach M.E. Beach D. Lowe S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.Cell. 1997; 88: 593-602Abstract Full Text Full Text PDF PubMed Scopus (3208) Google Scholar). In both models, p53 acts as the “guardian of the genome” to limit the deleterious consequences of mutation (Lane, 1992Lane D.P. Cancer. p53, guardian of the genome.Nature. 1992; 358: 15-16Crossref PubMed Scopus (3830) Google Scholar). Although this historic view provides a basic conceptual framework as to why TP53 mutations are so common in human tumors, more recent work paints a much more nuanced picture of p53 action that highlights its context-dependent regulation and the broadly diverse consequences of its activation. Upon DNA damage, p53 is activated to promote either the elimination or repair of damaged cells, ultimately reducing their risk of propagating mutations. DNA damage response (DDR) kinases phosphorylate p53, driving cell-cycle arrest, senescence, or apoptosis (reviewed in Williams and Schumacher, 2016Williams A.B. Schumacher B. p53 in the DNA-damage-repair process.Cold Spring Harb. Perspect. Med. 2016; 6: 6Crossref Scopus (15) Google Scholar). Additionally, p53 stimulates DNA repair by activating target genes that encode components of the DNA repair machinery, and p53-null cells are defective in certain DNA repair activities in vitro (Williams and Schumacher, 2016Williams A.B. Schumacher B. p53 in the DNA-damage-repair process.Cold Spring Harb. Perspect. Med. 2016; 6: 6Crossref Scopus (15) Google Scholar). While TP53 mutation can correlate with patterns of single-nucleotide variants and specific co-mutated genes, what is striking is that the association between TP53 mutation and copy-number variation (CNV) is strong and universal in a pan-cancer analysis (Ciriello et al., 2013Ciriello G. Miller M.L. Aksoy B.A. Senbabaoglu Y. Schultz N. Sander C. Emerging landscape of oncogenic signatures across human cancers.Nat. Genet. 2013; 45: 1127-1133Crossref PubMed Scopus (483) Google Scholar). Also, cancers harboring TP53 mutations are typically aneuploid, with gross changes in numbers of whole chromosomes (Ciriello et al., 2013Ciriello G. Miller M.L. Aksoy B.A. Senbabaoglu Y. Schultz N. Sander C. Emerging landscape of oncogenic signatures across human cancers.Nat. Genet. 2013; 45: 1127-1133Crossref PubMed Scopus (483) Google Scholar). Various biological explanations for this association have been proposed, but one mechanism contributing to this relationship is the ability of p53 to regulate processes in G2/M transitions (reviewed in Vitre and Cleveland, 2012Vitre B.D. Cleveland D.W. Centrosomes, chromosome instability (CIN) and aneuploidy.Curr. Opin. Cell Biol. 2012; 24: 809-815Crossref PubMed Scopus (56) Google Scholar). For example, p53 loss dysregulates the spindle assembly checkpoint by derepressing MAD2, leading to an increased rate of chromosome missegregation and tetraploidization (Schvartzman et al., 2011Schvartzman J.M. Duijf P.H. Sotillo R. Coker C. Benezra R. Mad2 is a critical mediator of the chromosome instability observed upon Rb and p53 pathway inhibition.Cancer Cell. 2011; 19: 701-714Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). In the context of tetraploid cells, p53 loss leads to an increased rate of multipolar mitoses and subsequent chromosome missegregation (Vitale et al., 2010Vitale I. Senovilla L. Jemaà M. Michaud M. Galluzzi L. Kepp O. Nanty L. Criollo A. Rello-Varona S. Manic G. et al.Multipolar mitosis of tetraploid cells: inhibition by p53 and dependency on Mos.EMBO J. 2010; 29: 1272-1284Crossref PubMed Scopus (96) Google Scholar). In an alternative but non-mutually exclusive explanation, p53 can restrict chromosomal instability through its ability to cull cells at risk of aberrant mitoses, particularly following centrosome amplification and/or telomere dysfunction (Eischen, 2016Eischen C.M. Genome stability requires p53.Cold Spring Harb. Perspect. Med. 2016; 6: 6Crossref Scopus (0) Google Scholar, Lanni and Jacks, 1998Lanni J.S. Jacks T. Characterization of the p53-dependent postmitotic checkpoint following spindle disruption.Mol. Cell. Biol. 1998; 18: 1055-1064Crossref PubMed Google Scholar). Extra centrosomes lead to Hippo pathway upregulation that, in turn, activates p53 by inhibiting MDM2 (Aylon et al., 2006Aylon Y. Michael D. Shmueli A. Yabuta N. Nojima H. Oren M. A positive feedback loop between the p53 and Lats2 tumor suppressors prevents tetraploidization.Genes Dev. 2006; 20: 2687-2700Crossref PubMed Scopus (178) Google Scholar, Ganem et al., 2014Ganem N.J. Cornils H. Chiu S.Y. O’Rourke K.P. Arnaud J. Yimlamai D. Théry M. Camargo F.D. Pellman D. Cytokinesis failure triggers hippo tumor suppressor pathway activation.Cell. 2014; 158: 833-848Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Accordingly, TP53 mutations are also associated with whole genome doubling events in human tumors (Dewhurst et al., 2014Dewhurst S.M. McGranahan N. Burrell R.A. Rowan A.J. Grönroos E. Endesfelder D. Joshi T. Mouradov D. Gibbs P. Ward R.L. et al.Tolerance of whole-genome doubling propagates chromosomal instability and accelerates cancer genome evolution.Cancer Discov. 2014; 4: 175-185Crossref PubMed Scopus (112) Google Scholar). Additional studies suggest that p53-deficient cells are better at tolerating proteomic stress produced by aberrant gene dosage (Tang et al., 2011Tang Y.C. Williams B.R. Siegel J.J. Amon A. Identification of aneuploidy-selective antiproliferation compounds.Cell. 2011; 144: 499-512Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar), yet others suggest that p53-mediated culling of aneuploid cells is more efficient against structural aneuploidy than whole chromosome imbalances, implicating the role of DDR in response to chromosome shearing (Soto et al., 2017Soto M. Raaijmakers J.A. Bakker B. Spierings D.C.J. Lansdorp P.M. Foijer F. Medema R.H. p53 prohibits propagation of chromosome segregation errors that produce structural aneuploidies.Cell Rep. 2017; 19: 2423-2431Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Hence, it appears that the absence of p53 both facilitates the accumulation and permits the survival of aneuploid cells. p53 also appears to suppress a particular type of chromosome shattering and rearrangement event known as chromothripsis. Cells that bypass replicative senescence after p53 and RB inactivation can proliferate despite telomere erosion (Hayashi et al., 2012Hayashi M.T. Cesare A.J. Fitzpatrick J.A. Lazzerini-Denchi E. Karlseder J. A telomere-dependent DNA damage checkpoint induced by prolonged mitotic arrest.Nat. Struct. Mol. Biol. 2012; 19: 387-394Crossref PubMed Scopus (91) Google Scholar). Failing this checkpoint, telomere dysfunction initiates chromosome breakage-fusion-bridge cycles that contribute to chromothripsis (Maciejowski et al., 2015Maciejowski J. Li Y. Bosco N. Campbell P.J. de Lange T. Chromothripsis and kataegis induced by telomere crisis.Cell. 2015; 163: 1641-1654Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar). Although the extent to which chromothripsis fosters tumorigenesis remains an open question, the phenomenon is significantly more prevalent in tumors harboring TP53 mutations (Rausch et al., 2012Rausch T. Jones D.T. Zapatka M. Stütz A.M. Zichner T. Weischenfeldt J. Jäger N. Remke M. Shih D. Northcott P.A. et al.Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations.Cell. 2012; 148: 59-71Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar). An unanticipated way in which p53 helps maintain genomic integrity is by suppressing the mobilization of retrotransposons, which are latent virus-derived genetic elements whose aberrant expression can lead to mutagenesis through their mobilization and re-insertion throughout the genome (reviewed in Levine et al., 2016Levine A.J. Ting D.T. Greenbaum B.D. P53 and the defenses against genome instability caused by transposons and repetitive elements.BioEssays. 2016; 38: 508-513Crossref PubMed Scopus (8) Google Scholar). Experimental activation of mobile elements in Drosophila induces DNA double-strand breaks and p53-mediated apoptosis (Wylie et al., 2014Wylie A. Lu W.J. D’Brot A. Buszczak M. Abrams J.M. p53 activity is selectively licensed in the Drosophila stem cell compartment.eLife. 2014; 3: e01530Crossref PubMed Scopus (0) Google Scholar) that could, in principle, reduce their mutagenic effects. However, the association between p53 mutation and retrotransposon expression is more than simply a culling effect: indeed, p53 binding to target sites within LINE elements and other transposon sequences are associated with their downregulation (Chang et al., 2007Chang N.T. Yang W.K. Huang H.C. Yeh K.W. Wu C.W. The transcriptional activity of HERV-I LTR is negatively regulated by its cis-elements and wild type p53 tumor suppressor protein.J. Biomed. Sci. 2007; 14: 211-222Crossref PubMed Scopus (7) Google Scholar). p53-mediated repression is dependent on epigenetic silencing of retrotransposon loci and not apoptosis, and derepressed retrotransposons are competent for reintegration into the genome (Leonova et al., 2013Leonova K.I. Brodsky L. Lipchick B. Pal M. Novototskaya L. Chenchik A.A. Sen G.C. Komarova E.A. Gudkov A.V. p53 cooperates with DNA methylation and a suicidal interferon response to maintain epigenetic silencing of repeats and noncoding RNAs.Proc. Natl. Acad. Sci. USA. 2013; 110: E89-E98Crossref PubMed Scopus (97) Google Scholar, Wylie et al., 2016Wylie A. Jones A.E. D’Brot A. Lu W.J. Kurtz P. Moran J.V. Rakheja D. Chen K.S. Hammer R.E. Comerford S.A. et al.p53 genes function to restrain mobile elements.Genes Dev. 2016; 30: 64-77Crossref PubMed Scopus (37) Google Scholar), promoting mutagenesis (Tubio et al., 2014Tubio J.M.C. Li Y. Ju Y.S. Martincorena I. Cooke S.L. Tojo M. Gundem G. Pipinikas C.P. Zamora J. Raine K. et al.ICGC Breast Cancer GroupICGC Bone Cancer GroupICGC Prostate Cancer GroupMobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes.Science. 2014; 345: 1251343Crossref PubMed Scopus (117) Google Scholar). Genomic analyses have revealed that retrotransposon mobilization is common in human cancers (Ting et al., 2011Ting D.T. Lipson D. Paul S. Brannigan B.W. Akhavanfard S. Coffman E.J. Contino G. Deshpande V. Iafrate A.J. Letovsky S. et al.Aberrant overexpression of satellite repeats in pancreatic and other epithelial cancers.Science. 2011; 331: 593-596Crossref PubMed Scopus (213) Google Scholar, Tubio et al., 2014Tubio J.M.C. Li Y. Ju Y.S. Martincorena I. Cooke S.L. Tojo M. Gundem G. Pipinikas C.P. Zamora J. Raine K. et al.ICGC Breast Cancer GroupICGC Bone Cancer GroupICGC Prostate Cancer GroupMobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes.Science. 2014; 345: 1251343Crossref PubMed Scopus (117) Google Scholar). While the precise impact remains to be determined, there is a significant association between repetitive element expression and p53 status in mouse and human tumors (Wylie et al., 2016Wylie A. Jones A.E. D’Brot A. Lu W.J. Kurtz P. Moran J.V. Rakheja D. Chen K.S. Hammer R.E. Comerford S.A. et al.p53 genes function to restrain mobile elements.Genes Dev. 2016; 30: 64-77Crossref PubMed Scopus (37) Google Scholar). The immediacy with which p53 cooperates with oncogenes to transform cells indicates that genomic instability is not absolutely required for tumor initiation (Lowe et al., 1994Lowe S.W. Jacks T. Housman D.E. Ruley H.E. Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells.Proc. Natl. Acad. Sci. USA. 1994; 91: 2026-2030Crossref PubMed Google Scholar, Serrano et al., 1997Serrano M. Lin A.W. McCurrach M.E. Beach D. Lowe S.W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.Cell. 1997; 88: 593-602Abstract Full Text Full Text PDF PubMed Scopus (3208) Google Scholar). Still, the genomic instability fueled by p53 loss enables acquisition of additional driver events with the potential to accelerate transformation, metastasis, and drug resistance (reviewed in McGranahan and Swanton, 2017McGranahan N. Swanton C. Clonal heterogeneity and tumor evolution: past, present, and the future.Cell. 2017; 168: 613-628Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar). Just as species diversity in an ecosystem is associated with its robustness, subclonal diversity, not the total number of mutations in a tumor, dictates the resilience of a cancer cell population to changing conditions and challenges. In this regard, p53 inactivation may be unique in its ability to both promote genomic instability (by increasing the rate of new variants) and permit the survival of a wider pool of genetic configurations (decreasing the likelihood of extinction of variants). Together, these observations raise the possibility that p53 inactivation contributes to intratumoral heterogeneity. As if regulating genome integrity, cell cycle arrest, and apoptosis were not enough functions for a single gene, an ever-growing body of work suggests that p53 also controls additional “non-canonical” programs that contribute to its effects (Figure 1). As examples, p53 can modulate autophagy, alter metabolism, repress pluripotency and cellular plasticity, and facilitate an iron-dependent form of cell death known as ferroptosis (reviewed in Aylon and Oren, 2016Aylon Y. Oren M. The paradox of p53: what, how, and why?.Cold Spring Harb. Perspect. Med. 2016; 6: 6Crossref Scopus (5) Google Scholar). Even basal levels of p53 can reinforce multiple other tumor suppressive networks (Pappas et al., 2017Pappas K. Xu J. Zairis S. Resnick-Silverman L. Abate F. Steinbach N. Ozturk S. Saal L.H. Su T. Cheung P. et al.p53 maintains baseline expression of multiple tumor suppressor genes.Mol. Cancer Res. 2017; 15: 1051-1062Crossref PubMed Scopus (1) Google Scholar). Given extensive past research, it is surprising that there is no clear and simple answer to the question of what exactly p53 does and how. Nevertheless, a take-home message is that the p53 response is remarkably flexible and depends on the cell type, its differentiation state, stress conditions, and collaborating environmental signals. The varied functions of p53 are anchored in its ability to control distinct sets of its many target genes (Figure 1). For example, observations that cell cycle arrest and apoptosis are associated with upregulation of p21 or pro-apoptotic Bcl-2 proteins, respectively, obscure the fact that the global transcriptional response to p53 activation includes many other potential modifiers of outcome. Historically, genes have been implicated as p53 targets if p53 binds the locus and the mRNA is induced. More recently, Global Run-On Sequencing has improved specificity by enabling detection of nascent transcripts induced upon p53 activation (Allen et al., 2014Allen M.A. Andrysik Z. Dengler V.L. Mellert H.S. Guarnieri A. Freeman J.A. Sullivan K.D. Galbraith M.D. Luo X. Kraus W.L. et al.Global analysis of p53-regulated transcription identifies its direct targets and unexpected regulatory mechanisms.eLife. 2014; 3: e02200Crossref PubMed Google Scholar). The nature of p53 targets identified in this analysis provides strong confirmation that non-canonical processes including ROS control, tissue remodeling, autophagy, and metabolism are bona fide processes controlled by p53 (Figure 1). Efforts to identify a universal set of p53 target genes have invariably failed. Meta-analyses from 16 genome-wide datasets revealed that only about 60 genes were implicated as common targets (Fischer, 2017Fischer M. Census and evaluation of p53 target genes.Oncogene. 2017; 36: 3943-3956Crossref PubMed Scopus (45) Google Scholar). It is noteworthy that these surveys involved a restricted number of different cell types and employed distinct methods for p53 induction. However, a central theme is that cellular context and various stimuli incite transcription of qualitatively different sets of genes, not just different levels of the same set of genes. It seems naive to expect that oncogene activation in different tissues (for example, KRAS activation in colon, pancreas, and lung) would precipitate an identical p53 transcriptional response. Moreover, one would not presume a priori that the p53 output generated by DNA damage would exactly mirror the gene expression signature elicited by oncogene activation, even in a single cell type. Despite data indicating that p53 can, in principle, control a wide variety of biological processes (reviewed in Olivos and Mayo, 2016Olivos D.J. Mayo L.D. Emerging non-canonical functions and regulation by p53: p53 and stemness.Int. J. Mol. Sci. 2016; 17: 17Crossref Scopus (1) Google Scholar), the physiological settings in which one or more processes predominate are incompletely understood and deserve more systematic study. Cellular metabolism is one non-canonical p53-controlled process that has received much attention (reviewed in Kruiswijk et al., 2015Kruiswijk F. Labuschagne C.F. Vousden K.H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill.Nat. Rev. Mol. Cell Biol. 2015; 16: 393-405Crossref PubMed Scopus (214) Google Scholar). The collection of metabolic target genes controlled by p53 affect many individual processes: p53 is reported to increase glutamine catabolism, support anti-oxidant activity, downregulate lipid synthesis, increase fatty acid oxidation, and stimulate gluconeogenesis (Kruiswijk et al., 2015Kruiswijk F. Labuschagne C.F. Vousden K.H. p53 in survival, death and metabolic health: a lifeguard with a licence to kill.Nat. Rev. Mol. Cell Biol. 2015; 16: 393-405Crossref PubMed Scopus (214) Google Scholar). Depending on the cell type, p53 can also have opposing effects on the same metabolic processes. For example, in breast and lung cancer cells, p53 inhibits glycolysis by attenuating glucose uptake (Zhang et al., 2013Zhang C. Liu J. Liang Y. Wu R. Zhao Y. Hong X. Lin M. Yu H. Liu L. Levine A.J. et al.Tumour-associated mutant p53 drives the Warburg effect.Nat. Commun. 2013; 4: 2935Crossref PubMed Scopus (55) Google Scholar) or repressing the expression of glycolytic enzymes (Kim et al., 2013Kim H.R. Roe J.S. Lee J.E. Cho E.J. Youn H.D. p53 regulates glucose metabolism by miR-34a.Biochem. Biophys. Res. Commun. 2013; 437: 225-231Crossref PubMed Scopus (0) Google Scholar). By contrast, in muscle cells, p53 induces glycolytic en" @default.
• W2752942423 created "2017-09-15" @default.
• W2752942423 creator A5013514856 @default.
• W2752942423 creator A5025451142 @default.
• W2752942423 date "2017-09-01" @default.
• W2752942423 modified "2023-10-16" @default.
• W2752942423 title "Putting p53 in Context" @default.
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