p53: 800 million years of evolution and 40 years of discovery

Abstract

The evolutionarily conserved p53 protein and its cellular pathways mediate tumour suppression through an informed, regulated and integrated set of responses to environmental perturbations resulting in either cellular death or the maintenance of cellular homeostasis. The p53 and MDM2 proteins form a central hub in this pathway that receives stressful inputs via MDM2 and respond via p53 by informing and altering a great many other pathways and functions in the cell. The MDM2–p53 hub is one of the hubs most highly connected to other signalling pathways in the cell, and this may be why TP53 is the most commonly mutated gene in human cancers. Initial or truncal TP53 gene mutations (the first mutations in a stem cell) are selected for early in cancer development inectodermal and mesodermal-derived tissue-specific stem and progenitor cells and then, following additional mutations, produce tumours from those tissue types. In endodermal-derived tissue-specific stem or progenitor cells, TP53 mutations are functionally selected as late mutations transitioning the mutated cell into a malignant tumour. The order in which oncogenes or tumour suppressor genes are functionally selected for in a stem cell impacts the timing and development of a tumour.

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Fig. 1: Stress signals leading to p53 activation.
Fig. 2: Stress signals leading to p53 inhibition.
Fig. 3: Transcriptional output of p53 responses to different types of stress.
Fig. 4: Excess risk of developing a specific cancer in patients with Li–Fraumeni syndrome.

References

  1. 1.

    Baker, S. J., Markowitz, S., Fearon, E. R., Willson, J. K. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).

    CAS  PubMed  Google Scholar 

  2. 2.

    Baker, S. J. et al. p53 gene mutations occur in combination with 17p allelic deletions as late events in colorectal tumorigenesis. Cancer Res. 50, 7717–7722 (1990).

    CAS  PubMed  Google Scholar 

  3. 3.

    Olivier, M. et al. The IARC TP53 database: new online mutations analysis and recommendations to users. Hum. Mutat. 19, 607–614 (2002).

    CAS  PubMed  Google Scholar 

  4. 4.

    Olivier, M., Hussain, S. P., Caron de Fromentel, C., Hainaut, P. & Harris, C. C. TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci. Public. 247-270 (2004).

  5. 5.

    Olivier, M., Hollstein, M. & Hainaut, P. TP53 mutations in human cancers: origins, consequences and clinical use. Cold Spring Harb. Perspect. Biol. 2, a001008 (2010).

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Hainaut, P. & Pfeifer, G. P. Somatic TP53 mutations in the era of genome sequencing. Cold Spring Harb. Perspect. Med. 6, a026179 (2016).

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Ho, T., Tan, B. X. & Lane, D. How the other half lives: what p53 does when it is not being a transcription factor. Int. J. Mol. Sci. 21, E13 (2019).

    PubMed  Google Scholar 

  8. 8.

    Levine, A. J. & Lane, D. P. (eds) The p53 Family (Cold Spring Harbor Laboratory Press, 2010).

  9. 9.

    Lozano, G. & Levine, A. J. (eds) The p53 Protein, From Cell Regulation to Cancer (Cold Spring Harbor Laboratory Press, 2016).

  10. 10.

    Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SY40-transformed cells. Nature 278, 261–263 (1979).

    CAS  PubMed  Google Scholar 

  11. 11.

    Linzer, D. I. H. & Levine, A. J. Characterization of a 54,000 MW cellular SV40 tumor antigen present in SV40 transformed cells and uninfected embryonal carcinoma cells. Cell 17, 43–52 (1979).

    Google Scholar 

  12. 12.

    Kress, M., May, E., Cassingena, R. & May, P. Simian virus 40-transformed cells express new species of proteins precipitable by anti-simian virus 40 tumor serum. J. Virol. 31, 472–483 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Sarnow, P., Ho, Y. S., Williams, J. & Levine, A. J. Adenovirus E1b-58 kd tumor antigen and SV40 large tumor antigen are physically associated with the same 54 kd cellular protein in transformed cells. Cell 28, 387–394 (1982).

    CAS  PubMed  Google Scholar 

  14. 14.

    Werness, B. A., Levine, A. J. & Howley, P. M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248, 76–79 (1990).

    CAS  PubMed  Google Scholar 

  15. 15.

    Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. The E6 oncoprotein encoded by human papillomavirus 16 or 18 promotes the degradation of p53. Cell 63, 1129–1136 (1990).

    CAS  PubMed  Google Scholar 

  16. 16.

    Wei, J. et al. Regulation of the p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells. Gastroenterology 139, 1333–1343 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Hong, Y., Filipovic, Z. M., Brown, D., Breit, S. M. & Vissilev, L. T. Macrophage inhibitory cytokine-1 a novel biomarker for p53 pathway activation. Mol. Cell. Therap. 2, 1023–1029 (2003).

    Google Scholar 

  18. 18.

    Coppé, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    PubMed  Google Scholar 

  19. 19.

    DeLeo, A. B. et al. Detection of a transformation-related antigen in chemically induced sarcomas and other transformed cells of the mouse. Proc. Natl Acad. Sci. USA 76, 2420–2424 (1979).

    CAS  PubMed  Google Scholar 

  20. 20.

    Yang, H. et al. p63, a p53 homologue at 3q27-29, encodes multiple products with transactivating, death inducing, dominant negative activities. Mol. Cell 2, 305–316 (1998).

    CAS  Google Scholar 

  21. 21.

    Jost, C. A., Marin, M. C. & Kaelin, W. G. Jr. p73 is a human p53 related protein that can induce apoptosis. Nature 389, 191–194 (1997).

    CAS  PubMed  Google Scholar 

  22. 22.

    Kaghad, M. et al. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90, 809–819 (1997).

    CAS  PubMed  Google Scholar 

  23. 23.

    Yoh, K. & Prywes, R. Pathway regulation of p63, a director of epithelial cell fate. Front. Endocrinol. 6, 51 (2015).

    Google Scholar 

  24. 24.

    Deutsch, G. B. DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer. Cell 144, 566–576 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Suh, E. K. et al. p63 protects the female germ line during meiotic arrest. Nature 444, 624–628 (2006).

    CAS  PubMed  Google Scholar 

  26. 26.

    Tomasini, R. et al. TAp63 knock-out shows genomic instability with infertility and tumor suppressor functions. Genes Dev. 22, 2677–2691 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Beyer, U., Moll-Rocek, J., Moll, U. M. & Dobbelstein, M. Endogenous retrovirus drives hitherto unknown proapoptotic p63 isoforms in the male germ line of humans and apes. Proc. Natl Acad. Sci. USA 108, 3624–3629 (2011).

    CAS  PubMed  Google Scholar 

  28. 28.

    Marshall, C. et al. p73 is required for multiciliogenesis and regulates the Foxj1-associated gene network. Cell Rep. 14, 2289–2300 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Lane, D. P. et al. Mdm2 and p53 are highly conserved from placozoans to man. Cell Cycle 9, 540–547 (2010).

    CAS  PubMed  Google Scholar 

  30. 30.

    Belyi, V. A. & Levine, A. J. One billion years of p53/p63/p73 evolution. Proc. Natl Acad. Sci. USA 106, 17609–17610 (2009).

    CAS  PubMed  Google Scholar 

  31. 31.

    Belyi, V. A. et al. The origins and evolution of the p53 family of genes. Cold Spring Harb. Perspect. Biol. 2, a001198 (2010).

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Belyi, V. A. et al. in p53 Research: The Past Thirty Years and the Next Thirty Years Ch. 1 (eds Lane, D. & Levine, A. J.) (Cold Spring Harbor Laboratory Press, 2010).

  33. 33.

    Rutkowski, R., Hoffman, K. & Gartner, A. in The p53 Family (eds Levine A. J. and Lane D.) 279–291 (Cold Spring Harbor Laboratory Press, 2010).

  34. 34.

    Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).

    CAS  PubMed  Google Scholar 

  35. 35.

    Newmark, P. A. & Alejandro, S. A. Bromodeoxyuridine specifically labels regenerative stem cells of planarians. Develop. Biol. 220, 142–153 (2000).

    CAS  PubMed  Google Scholar 

  36. 36.

    Brockes, J. P. & Kinnter, C. R. Glial growth factor and nerve dependent proliferation in the regeneration blastema of urodele amphibians. Cell 45, 301–306 (1986).

    CAS  PubMed  Google Scholar 

  37. 37.

    Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006).

    CAS  PubMed  Google Scholar 

  38. 38.

    Levine, A. J. & Greenbaum, B. The maintenance of epigenetic states by p53: guardian of the epigenome. Oncotarget 3, 1503–1504 (2012).

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Dubrovsky, G. & Dunn, J. C. Y. Mechanisms for intestinal regeneration. Curr. Opin. Pediatrics 30, 424–429 (2018).

    Google Scholar 

  40. 40.

    Takeo, M., Lee, W. & Ito, M. Wound healing and skin regeneration. Cold Spring Harb. Perspect. Med. 5, a023267 (2015).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

    Weissman, I. Stem cells are units of natural selection for tissue formation for germline development and cancer development. Proc. Natl Acad. Sci. USA 112, 8922–8928 (2015).

    CAS  PubMed  Google Scholar 

  42. 42.

    Szekely, P., Korem, Y., Moran, U., Mayo, A. & Alon, U. The mass longevity triangle, Pareto optimality and the geometry of life history trait space. PLoS Comput. Biol. 3, 1471–1483 (2015).

    Google Scholar 

  43. 43.

    Roper, C., Pignatelli, P. & Partridge, L. Evolutionary effects of selection on the age of reproduction in larval and adult Drosophila melanogaster. Evolution 47, 445–455 (1993).

    PubMed  Google Scholar 

  44. 44.

    Müller, H. G., Chiou, J. M., Carey, J. R. & Wang, J. L. Fertility and life span: late children enhance female longevity. J. Gerontol. 57, 202–206 (2002).

    Google Scholar 

  45. 45.

    Blokzijl, F. et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 538, 260–264 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Levine, A. J., Jenkins, N. A. & Copeland, N. G. The roles of initiating truncal mutations in human cancers: the order of mutations and tumor cell type matters. Cancer Cell 3, 10–15 (2019).

    Google Scholar 

  47. 47.

    Haigis, K. M., Cichowski, K. & Elledge, S. J. Tissue-specificity in cancer: the rule, not the exception. Science 363, 1150–1151 (2019).

    CAS  PubMed  Google Scholar 

  48. 48.

    Matano, M. et al. Modeling colorectal cancer using CRISPR–Cas9-mediated engineering of human intestinal organoids. Nat. Med. 21, 256–262 (2015).

    CAS  PubMed  Google Scholar 

  49. 49.

    Takeda, H. et al. Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression. Nat. Genet. 47, 142–150 (2015).

    CAS  PubMed  Google Scholar 

  50. 50.

    Levine, A. J., Chan, C., Dudgeon, C., Puzio-Kuter, A. & Hainaut, P. The evolution of tumors in mice and humans with germline p53 mutations. Cold Spring Harb. Symp. Quant. Biol. 80, 139–145 (2015).

    PubMed  Google Scholar 

  51. 51.

    Finlay, C. A., Hinds, P. W. & Levine, A. J. The p53 proto oncogene can act as a suppressor of transformation. Cell 57, 1083–1093 (1989).

    CAS  PubMed  Google Scholar 

  52. 52.

    Eliyahu, D., Raz, A., Gruss, P., Givol, D. & Oren, M. Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature 312, 646–649 (1984).

    CAS  PubMed  Google Scholar 

  53. 53.

    Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors. Nature 356, 215–221 (1992).

    CAS  PubMed  Google Scholar 

  54. 54.

    Levine, A. J. & Berger, S. L. The interplay between epigenetic changes and the p53 protein in stem cells. Genes Dev. 31, 1195–1200 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Demehri, S., Turkoz, A. & Kopan, R. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16, 55–66 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Martincorena, I. et al. Tumor evolution high burden and pervasive positive selection of somatic mutations in normal human skin. Science 348, 880–886 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Yokoyama, A. et al. Age-related remodelling of oesophageal epithelia by mutated cancer drivers. Nature 565, 312–317 (2019).

    CAS  PubMed  Google Scholar 

  58. 58.

    Martincorena, I. et al. Somatic mutant clones colonize the human esophagus with age. Science 362, 911–917 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Welch, J. S. et al. The origin and evolution of mutations in acute myelogenous leukemia. Cell 150, 264–278 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Busque, L. et al. Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat. Gen. 44, 1179–1181 (2012).

    CAS  Google Scholar 

  61. 61.

    Shulush, L. I. et al. Identification of preleukemic stem cells in acute leukemia. Nature 506, 328–333 (2014).

    Google Scholar 

  62. 62.

    Acuna-Hidalgo, R. et al. Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis associated mutations throughout adult life. Am. J. Hum. Genet. 101, 50–64 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Bowman, R. L., Busque, L. & Levine, R. L. Clonal hematopoiesis and evolution to hematopoietic malignancies. Cell Stem Cell 22, 157–170 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Chen, S. et al. Mutant p53 drives clonal hematopoiesis through modulatory epigenetic pathway. Nat. Commun. 10, 5649 (2019).

    PubMed  PubMed Central  Google Scholar 

  65. 65.

    Silver, A. J. & Jaiswal, S. Clonal hematopoiesis: pre-cancer PLUS. Adv. Canc. Res. 141, 85–128 (2019).

    Google Scholar 

  66. 66.

    Salk, J. J. et al. Ultra-sensitive TP53 sequencing for cancer detection reveals progressive clonal selection in normal tissue over a century of human lifespan. Cell Rep. 28, 132–144 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Nair, N. et al. Genomic analysis of uterine lavage fluid detects early endometrial cancers and reveals a prevalent landscape of driver mutations in women without histopathologic evidence of cancer: a prospective cross-sectional study. PLoS Med. 13, e1002206 (2016).

    PubMed  PubMed Central  Google Scholar 

  68. 68.

    Cancer Genome Atlas Research Network. et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).

    PubMed Central  Google Scholar 

  69. 69.

    Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancers. Nature 487, 330–337 (2012).

    Google Scholar 

  70. 70.

    Serrano, 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 88, 593–602 (1997).

    CAS  Google Scholar 

  71. 71.

    Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 1062–1078 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Lee, S. & Schmitt, C. A. The dynamic nature of senescence in cancer. Nat. Cell Biol. 21, 94–101 (2019).

    CAS  PubMed  Google Scholar 

  73. 73.

    Pearson, M., Carbone, R. & Sebastiani, C. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic RAS. Nature 406, 207–210 (2000).

    CAS  PubMed  Google Scholar 

  74. 74.

    Jackson-Grusby, L. et al. Loss of genomic methylation causes p53-dependent apoptosis and epigenetic deregulation. Nat. Genet. 27, 31–39 (2001).

    CAS  PubMed  Google Scholar 

  75. 75.

    Holm, T. M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005).

    CAS  PubMed  Google Scholar 

  76. 76.

    Yi, L., Lu, C., Hu, W., Sun, Y. & Levine, A. J. Multiple roles of p53 related pathways in somatic cell reprogramming and stem cell differentiation. Cancer Res. 72, 5635–5645 (2012).

    CAS  PubMed  Google Scholar 

  77. 77.

    Nieto, M. et al. The absence of p53 is critical for the induction of apoptosis by 5-aza-2-deoxycytidine. Oncogene 23, 735–743 (2004).

    CAS  PubMed  Google Scholar 

  78. 78.

    Yi, L., Sun, Y. & Levine, A. J. Selected drugs that inhibit DNA methylation can preferentially kill p53 deficient cells. Oncotarget 5, 8924–8936 (2014).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Levine, A. J. The p53 protein plays a central role in the mechanism of action of epigentic drugs that alter the methylation of cytosine residues in DNA. Oncotarget 8, 7228–7230 (2017).

    PubMed  PubMed Central  Google Scholar 

  80. 80.

    Levine, A. J. Targeting therapies for the p53 protein in cancer treatments. Ann. Rev. Cancer Biol. 3, 1.1–1.14 (2019).

    Google Scholar 

  81. 81.

    Rhee, A., Chenog, R. & Leochenko, A. The application of information theory to biochemical signaling systems. Phys. Biol. 9, 045011 (2012).

    PubMed  Google Scholar 

  82. 82.

    Smith, R. C. G. & MacArthur, B. D. Information theory and stem cell biology. Curr. Stem Cell Res. https://doi.org/10.1101/116673 (2017).

  83. 83.

    Pouryahya, M., Oh, J. H., Mathews, J. C., Deasy, J. O. & Tannenbaum, A. R. Characterizing cancer drug responses and biological correlates: a geometric network approach. Sci. Rep. 8, 1278–1281 (2018).

    Google Scholar 

  84. 84.

    Hamza, F., Chen, Y., Georgiou, T. T., Tannenbaum, A. & Lenglet, C. Network curvature as a hallmark of brain connectivity. Nat. Commun. https://doi.org/10.1038/s41467-019-12915-x (2019).

    Article  Google Scholar 

  85. 85.

    Sandhu, R., Georgiou, T. & Tannenbaum, A. R. Ricci curvature: an economic indicator for market fragility and systemic risk. Sci. Adv. 2, E1501495 (2016).

    PubMed  PubMed Central  Google Scholar 

  86. 86.

    Sandhu, R. et al. Graph curvature for differentiating cancer networks. Science Rep. 5, 12323 (2015).

    CAS  Google Scholar 

  87. 87.

    Tannenbaum, A. R. et al. Graph curvature and robustness of cancer networks, https://Arxiv.org/Abs/1502.04512 (2015).

  88. 88.

    Meeks, D. & Anderson, C. W. in The p53 Family (eds Levine A. J. & Lane D.) (Cold Spring Harbor Press, 2010).

  89. 89.

    El Deiry, S. W. p21(WAF-1) mediates cell cycle inhibition relevant to cancer suppression and therapy. Canc. Res. 76, 5189–5191 (2016).

    CAS  Google Scholar 

  90. 90.

    Giono, L. E., Resnick-Silverman, L., Carvajal, L. A., St. Clair, S. & Manfredi, J. J. MDM2 promotes Cdc25C protein degradation and delays cell cycle progression through the G2/M phase. Oncogene 36, 6762–6773 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    St. Clair, S. et al. DNA damaged induced downregulation of Cdc25C is mediated by two independent mechanisms, one involves direct binding to the cdc25C promotor. Mol. Cell 16, 725–736 (2004).

    CAS  Google Scholar 

  92. 92.

    Innocente, S. A., Abrahason, J. L. A., Cogswell, J. P. & Lee, J. M. p53 regulates a G2 checkpoint through cyclin B1. Proc. Natl Acad. Sci. USA 96, 2147–2152 (1999).

    CAS  PubMed  Google Scholar 

  93. 93.

    Cheung, E. C. et al. Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. Cancer Cell 37, 168–182 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Matobas, S. et al. p53 regulates mitochondrial respiration. Science 312, 1649–1653 (2006).

    Google Scholar 

  95. 95.

    Warburg, O. On the origins of cancer. Science 124, 269–276 (1956).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Zhang, C. et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc. Natl Acad. Sci. USA 108, 16259–16264 (2011).

    CAS  PubMed  Google Scholar 

  97. 97.

    Hu, W. et al. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl Acad. Sci. USA 107, 7455–7460 (2010).

    CAS  PubMed  Google Scholar 

  98. 98.

    Budanov, A. V. Stress responsive sestrins link p53 with redox regulation and mammalian target of rapamycin signaling. Antioxid. Redox Signal. 15, 1679–1690 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Feng, Z. & Levine, A. J. The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein. Trends Cell Biol. 20, 427–434 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Filbin, M. & Monje, M. Developmental origins and emerging therapeutic opportunities for childhood cancer. Nat. Med. 25, 367–376 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Bar-Or, R. L. et al. Generation of oscillations by the p53–Mdm2 feedback loop: a theoretical and experimental study. Proc. Natl Acad. Sci. USA 97, 11250–11255 (2000).

    CAS  Google Scholar 

  102. 102.

    Batchelor, E., Loewer, A., Mock, C. & Lahav, G. Stimulus-dependent dynamics of p53 in single cells. Mol. Syst. Biol. 7, 488 (2011).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Kadowaki, H. & Nishitoh, H. Signaling pathways from the endoplasmic reticulum and their roles in disease. Genes 4, 306–333 (2013).

    PubMed  PubMed Central  Google Scholar 

  104. 104.

    Lowe, S. & Lin, A. W. Apoptosis and cancer. Carcinogenesis 21, 485–495 (2000).

    CAS  PubMed  Google Scholar 

  105. 105.

    Li, J. et al. Ferroptosis: past, present and future. Cell Death Dis. 11, 88–101 (2020).

    PubMed  PubMed Central  Google Scholar 

  106. 106.

    Dhuriya, V. K. & Sharma, D. Necroptosis a regulated inflammatory mode of cell death. J. Neuroinflamation 15, 199–206 (2018).

    Google Scholar 

  107. 107.

    Boyle, E. A., Li, Y. I. & Prichard, J. K. An expanded view of complex traits: from pylogenic to omnigenic. Cell 169, 1177–1186 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Surget, S., Khoury, M. P. & Bourdon, J.-C. Uncovering the role of p53 splice varients in human malignancy: a clinical perspective. Oncotargets Ther. 7, 57–68 (2014).

    Google Scholar 

  109. 109.

    Horikawa, I. et al. Autophagic degradation of inhibitory p53 isoform Δ133p53α as a regulatory mechanism for p53 mediated senescense. Nat. Commun. 5, 4706 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Mello, S. S. & Attardi, L. D. Not all gain of function mutants are created equal. Cell Death Differ. 20, 855–857 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author thanks S. Christian, N. Jenkins and N. Copeland for discussions and advice in developing this manuscript and A. Puzio-Kuter for the figures. The work presented here was supported by a programme project grant from the NIH, NCI (P01CA087497-18).

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Correspondence to Arnold J. Levine.

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A.J.L. is the founder of a Biotech company, PMV Pharmaceuticals, which designs and produces small molecules that functionally reactivate mutant missense proteins in cancers. A.J.L. also chairs the scientific advisory board of Janssen Pharmaceuticals.

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Levine, A.J. p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer 20, 471–480 (2020). https://doi.org/10.1038/s41568-020-0262-1

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