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A complex barcode underlies the heterogeneous response of p53 to stress

Key Points

  • The tumour suppressor p53 is a master sensor of stress and integrates incoming signals to prevent malignant progression by inducing cellular responses such as apoptosis and senescence.

  • The response to p53 activation is heterogeneous and depends on the nature and intensity of the activating stress and on the cell or tissue type in which the stress is encountered.

  • Different stimuli induce p53 with different kinetics, which is reflected in the diversity of responses to p53.

  • Variation is coordinated by post-translational modifications of p53 and the availability of cofactors that together determine the appropriate cellular fate.

  • These variables dictate the level, subcellular localization and activities of p53, whether its actions are dependent or independent of transcription, and the array of genes the expression of which are altered.

  • Several new interacting partners of p53 have been identified, and we must now begin to understand how these partners affect p53 activity in tissue- and stress-specific contexts.

Abstract

The tumour suppressor p53 is activated following stress and initiates a heterogeneous response in a cell-, tissue- and stress-dependent manner. This heterogeneity is reflected in the different physiological outcomes that follow p53 activation. One mechanism that may contribute to this variability is the promoter selectivity of p53 target genes. p53 is at the hub of numerous signalling pathways that are triggered in response to particular stresses, all of which can leave their mark on p53 by way of post-translational modifications and interactions with cofactors. The precise combination of these marks, much like the bars in a barcode, dictates the behaviour of p53 in any given situation.

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Figure 1: Classification of tissues based on the heterogeneous p53 response.
Figure 2: Kinetics of the p53 response.
Figure 3: The p53 barcode.
Figure 4: The p53–MDM2 feedback loop.
Figure 5: Post-translational modifications and interactions with protein cofactors can regulate the subcellular localization of p53.
Figure 6: Residues that directly influence p53 promoter selectivity following post-translational modification.
Figure 7: Protein interactions that directly affect p53 promoter selectivity.
Figure 8: Cofactors that indirectly affect p53 activity.

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References

  1. Lane, D. P. & Crawford, L. V. T antigen is bound to a host protein in SV40-transformed cells. Nature 278, 261–263 (1979).

    Article  CAS  PubMed  Google Scholar 

  2. Linzer, 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 17, 43–52 (1979).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Rubbi, C. P. & Milner, J. Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J. 22, 6068–6077 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Crighton, D. et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126, 121–134 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Amaravadi, R. K. et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Invest. 117, 326–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Roger, L., Gadea, G. & Roux., P. Control of cell migration: a tumour suppressor function for p53? Biol. Cell 98, 141–152 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Hu, W., Feng, Z., Teresky, A. K. & Levine, A. J. p53 regulates maternal reproduction through LIF. Nature 450, 721–724 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Bensaad, K. et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell 126, 107–120 (2006).

    Article  CAS  PubMed  Google Scholar 

  11. Jones, R. G. et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol. Cell 18, 283–293 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Matoba, S. et al. p53 regulates mitochondrial respiration. Science 312, 1650–1653 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Bensaad, K. & Vousden, K. H. p53: new roles in metabolism. Trends Cell Biol. 17, 286–291 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Teodoro, J. G., Parker, A. E., Zhu, X. & Green, M. R. p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase. Science 313, 968–971 (2006).

    Article  CAS  PubMed  Google Scholar 

  15. Woods, Y. L. & Lane, D. P. Exploiting the p53 pathway for cancer diagnosis and therapy. Hematol. J. 4, 233–247 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. MacCallum, D. E. et al. The p53 response to ionising radiation in adult and developing murine tissues. Oncogene 13, 2575–2587 (1996). One of the first reports that showed that the p53 response in vivo is tissue dependent.

    CAS  PubMed  Google Scholar 

  17. Komarova, E. A., Christov, K., Faerman, A. I. & Gudkov, A. V. Different impact of p53 and p21 on the radiation response of mouse tissues. Oncogene 19, 3791–3798 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Fei, P., Bernhard, E. J. & El-Deiry, W. S. Tissue-specific induction of p53 targets in vivo. Cancer Res. 62, 7316–7327 (2002). One of the first reports to examine the differential induction of p53 target genes in vivo and link selective target-gene induction to differences in tissue response.

    CAS  PubMed  Google Scholar 

  19. Bouvard, V. et al. Tissue and cell-specific expression of the p53-target genes: Bax, Fas, Mdm2 and Waf1/p21, before and following ionising irradiation in mice. Oncogene 19, 649–660 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Villunger, A. et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins Puma and Noxa. Science 302, 1036–1038 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Jeffers, J. R. et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways. Cancer Cell 4, 321–328 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Lu, X. & Lane, D. P. Differential induction of transcriptionally active p53 following UV or ionizing radiation: defects in chromosome instability syndromes? Cell 75, 765–778 (1993). One of the first reports that determined the kinetics of p53 induction and found that the kinetics of the response of p53 will be different depending on the activating stress.

    Article  CAS  PubMed  Google Scholar 

  23. Graeber, T. G. et al. Hypoxia induces accumulation of p53 protein, but activation of a G1-phase checkpoint by low-oxygen conditions is independent of p53 status. Mol. Cell. Biol. 14, 6264–6277 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Erster, S., Mihara, M., Kim, R. H., Petrenko, O. & Moll, U. M. In vivo mitochondrial p53 translocation triggers a rapid first wave of cell death in response to DNA damage that can precede p53 target gene activation. Mol. Cell. Biol. 24, 6728–6741 (2004). The first article to show in vivo that, in response to γ-irradiation, the first wave of p53-dependent apoptosis is independent of transcription.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao, R. et al. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14, 981–993 (2000). A comprehensive comparison of the kinetics of p53 target-gene induction in response to three different ways of activating p53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Alvarez, S. et al. A comprehensive study of p53 transcriptional activity in thymus and spleen of γ-irradiated mouse: high sensitivity of genes involved in the two main apoptotic pathways. Int. J. Radiat. Biol. 82, 761–770 (2006). Showed the different sensitivities and kinetics of p53 target genes in vivo in response to γ-irradiation.

    Article  CAS  PubMed  Google Scholar 

  27. Toledo, F. & Wahl, G. M. Regulating the p53 pathway: in vitro hypotheses, in vivo veritas. Nature Rev. Cancer 6, 909–923 (2006).

    Article  CAS  Google Scholar 

  28. Takaoka, A. et al. Integration of interferon-α /β signalling to p53 responses in tumour suppression and antiviral defence. Nature 424, 516–523 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Takagi, M., Absalon, M. J., McLure, K. G. & Kastan, M. B. Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 123, 49–63 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Galban, S. et al. Influence of the RNA-binding protein HuR in pVHL-regulated p53 expression in renal carcinoma cells. Mol. Cell. Biol. 23, 7083–7095 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Mazan-Mamczarz, K. et al. RNA-binding protein HuR enhances p53 translation in response to ultraviolet light irradiation. Proc. Natl Acad. Sci. USA 100, 8354–8359 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Fu, L. & Benchimol, S. Participation of the human p53 3′ UTR in translational repression and activation following γ-irradiation. EMBO J. 16, 4117–4125 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Brooks, C. L. & Gu, W. p53 ubiquitination: Mdm2 and beyond. Mol. Cell 21, 307–315 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Marine, J. C. et al. Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Cell Death Differ. 13, 927–934 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Jones, S. N., Roe, A. E., Donehower, L. A. & Bradley, A. Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature 378, 206–208 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Montes de Oca Luna, R., Wagner, D. S. & Lozano, G. Rescue of early embryonic lethality in Mdm2-deficient mice by deletion of p53. Nature 378, 203–206 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Parant, J. et al. Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53. Nature Genet. 29, 92–95 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Uldrijan, S., Pannekoek, W. J. & Vousden, K. H. An essential function of the extreme C-terminus of MDM2 can be provided by MDMX. EMBO J. 26, 102–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  39. Itahana, K. et al. Targeted inactivation of Mdm2 RING finger E3 ubiquitin ligase activity in the mouse reveals mechanistic insights into p53 regulation. Cancer Cell 12, 355–366 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Li, M. et al. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature 416, 648–653 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Cummins, J. M. et al. Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature 428, (2004).

  42. Li, M., Brooks, C. L., Kon, N. & Gu, W. A dynamic role of HAUSP in the p53–Mdm2 pathway. Mol. Cell 13, 879–886 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Leng, R. P. et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 112, 779–791 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Dornan, D. et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 429, 86–92 (2004).

    Article  CAS  PubMed  Google Scholar 

  45. Yang, W. et al. CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation. J. Biol. Chem. 282, 3273–3281 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Olsson, A., Manzl, C., Strasser, A. & Villunger, A. How important are post-translational modifications in p53 for selectivity in target-gene transcription and tumour suppression? Cell Death Differ. 14, 1561–1575 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Feng, L., Lin, T., Uranishi, H., Gu, W. & Xu, Y. Functional analysis of the roles of posttranslational modifications at the p53 C terminus in regulating p53 stability and activity. Mol. Cell. Biol. 25, 5389–5395 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Krummel, K. A., Lee, C. J., Toledo, F. & Wahl, G. M. The C-terminal lysines fine-tune p53 stress responses in a mouse model but are not required for stability control or transactivation. Proc. Natl Acad. Sci. USA 102, 10188–10193 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Huang, J. et al. Repression of p53 activity by Smyd2-mediated methylation. Nature 444, 629–632 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Xirodimas, D. P., Saville, M. K., Bourdon, J. C., Hay, R. T. & Lane, D. P. MDM2-mediated NEDD8 conjugation of p53 inhibits its transcriptional activity. Cell 118, 83–97 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Rodriguez, M. S., Desterro, J. M., Lain, S., Lane, D. P. & Hay, R. T. Multiple C-terminal lysine residues target p53 for ubiquitin-proteasome-mediated degradation. Mol. Cell. Biol. 20, 8458–8467 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Huang, J. et al. p53 is regulated by the lysine demethylase LSD1. Nature 449, 105–108 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. O'Brate, A. & Giannakakou, P. The importance of p53 location: nuclear or cytoplasmic zip code? Drug Resist. Update 6, 313–322 (2003).

    Article  CAS  Google Scholar 

  54. Le Cam, L. et al. E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell 127, 775–788 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Kanai, M. et al. Inhibition of Crm1–p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nature Cell Biol. 9, 1175–1183 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Stommel, J. M. et al. A leucine-rich nuclear export signal in the p53 tetramerization domain: regulation of subcellular localization and p53 activity by NES masking. EMBO J. 18, 1660–1672 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fogal, V. et al. ASPP1 and ASPP2 are new transcriptional targets of E2F. Cell Death Differ. 12, 369–376 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Hsieh, J. K. et al. Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage. Mol. Cell. Biol. 22, 78–93 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sarnow, P., Ho, Y. S., Williams, J. & Levine, A. J. Adenovirus E1b-58kd 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).

    Article  CAS  PubMed  Google Scholar 

  60. Zantema, A. et al. Localization of the E1B proteins of adenovirus 5 in transformed cells, as revealed by interaction with monoclonal antibodies. Virology 142, 44–58 (1985).

    Article  CAS  PubMed  Google Scholar 

  61. Elmore, L. W. et al. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc. Natl Acad. Sci. USA 94, 14707–14712 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Takada, S., Kaneniwa, N., Tsuchida, N. & Koike, K. Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells. Oncogene 15, 1895–1901 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Li, M. et al. Mono- versus polyubiquitination: differential control of p53 fate by Mdm2. Science 302, 1972–1975 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Wang, Y. V. et al. Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation. Proc. Natl Acad. Sci. USA 104, 12365–12370 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Carter, S., Bischof, O., Dejean, A. & Vousden, K. H. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nature Cell Biol. 9, 428–435 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Andrews, P., He, Y. J. & Xiong, Y. Cytoplasmic localized ubiquitin ligase cullin 7 binds to p53 and promotes cell growth by antagonizing p53 function. Oncogene 25, 4534–4548 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Nikolaev, A. Y., Li, M., Puskas, N., Qin, J. & Gu, W. Parc: a cytoplasmic anchor for p53. Cell 112, 29–40 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Laine, A. & Ronai, Z. Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 26, 1477–1483 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Marchenko, N. D., Wolff, S., Erster, S., Becker, K. & Moll, U. M. Monoubiquitylation promotes mitochondrial p53 translocation. EMBO J. 26, 923–934 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tasdemir, E. et al. Regulation of autophagy by cytoplasmic p53. Nature Cell Biol. 10, 676–687 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577–590 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Leu, J. I., Dumont, P., Hafey, M., Murphy, M. E. & George, D. L. Mitochondrial p53 activates Bak and causes disruption of a Bak–Mcl1 complex. Nature Cell Biol. 6, 443–450 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Chipuk, J. E. et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303, 1010–1014 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Talos, F., Petrenko, O., Mena, P. & Moll, U. M. Mitochondrially targeted p53 has tumor suppressor activities in vivo. Cancer Res. 65, 9971–9981 (2005).

    Article  CAS  PubMed  Google Scholar 

  75. Leu, J. I. & George, D. L. Hepatic IGFBP1 is a prosurvival factor that binds to BAK, protects the liver from apoptosis, and antagonizes the proapoptotic actions of p53 at mitochondria. Genes Dev. 21, 3095–3109 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chen, X., Ko, L. J., Jayaraman, L. & Prives, C. p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev. 10, 2438–2451 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Weinberg, R. L., Veprintsev, D. B., Bycroft, M. & Fersht, A. R. Comparative binding of p53 to its promoter and DNA recognition elements. J. Mol. Biol. 348, 589–596 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Hofmann, T. G. et al. Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2. Nature Cell Biol. 4, 1–10 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. D'Orazi, G. et al. Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser46 and mediates apoptosis. Nature Cell Biol. 4, 11–19 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Taira, N., Nihira, K., Yamaguchi, T., Miki, Y. & Yoshida, K. DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage. Mol. Cell 25, 725–738 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Oda, K. et al. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell 102, 849–862 (2000). One of the first reports to identify that post-translational modification of a single residue in p53 can direct promoter selectivity.

    Article  CAS  PubMed  Google Scholar 

  82. Sykes, S. M. et al. Acetylation of the p53 DNA-binding domain regulates apoptosis induction. Mol. Cell 24, 841–851 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Tang, Y., Luo, J., Zhang, W. & Gu, W. Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis. Mol. Cell 24, 827–839 (2006). This article, together with reference 82, recently identified a single residue in the binding domain of p53 that is acetylated, resulting in promoter selectivity and induction of apoptosis.

    Article  CAS  PubMed  Google Scholar 

  84. Knights, C. D. et al. Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate. J. Cell Biol. 173, 533–544 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Di Giovanni, S. et al. The tumor suppressor protein p53 is required for neurite outgrowth and axon regeneration. EMBO J. 25, 4084–4096 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001). One of the first articles to identify a family of cofactors that can regulate the promoter selectivity of p53.

    Article  CAS  PubMed  Google Scholar 

  87. Bergamaschi, D. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genet. 33, 162–167 (2003).

    Article  CAS  PubMed  Google Scholar 

  88. Flores, E. R. et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 416, 560–564 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Das, S. et al. Hzf determines cell survival upon genotoxic stress by modulating p53 transactivation. Cell 130, 624–637 (2007). Identifies a new cofactor of p53 that specifically enhances p53 promoter selectivity of cell-cycle-arrest genes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Budhram-Mahadeo, V. S. et al. Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of Bax expression. Nucleic Acids Res. 34, 6640–6652 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Budram-Mahadeo, V., Morris, P. J. & Latchman, D. S. The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1). Oncogene 21, 6123–6131 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Fogal, V. et al. Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J. 19, 6185–6195 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zacchi, P. et al. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 419, 853–857 (2002).

    Article  CAS  PubMed  Google Scholar 

  94. Zheng, H. et al. The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response. Nature 419, 849–853 (2002).

    Article  CAS  PubMed  Google Scholar 

  95. Mantovani, F. et al. The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nature Struct. Mol. Biol. 14, 912–920 (2007).

    Article  CAS  Google Scholar 

  96. Toledo, F. et al. Mouse mutants reveal that putative protein interaction sites in the p53 proline-rich domain are dispensable for tumor suppression. Mol. Cell. Biol. 27, 1425–1432 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Ludwig, R. L., Bates, S. & Vousden, K. H. Differential activation of target cellular promoters by p53 mutants with impaired apoptotic function. Mol. Cell. Biol. 16, 4952–4960 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Crook, T., Marston, N. J., Sara, E. A. & Vousden, K. H. Transcriptional activation by p53 correlates with suppression of growth but not transformation. Cell 79, 817–827 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Rowan, S. et al. Specific loss of apoptotic but not cell-cycle arrest function in a human tumor derived p53 mutant. EMBO J. 15, 827–838 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Shikama, N. et al. A novel cofactor for p300 that regulates the p53 response. Mol. Cell 4, 365–376 (1999). Identifies a novel p53 cofactor, which was one of the first to be identified that specifically enhances the apoptotic function of p53.

    Article  CAS  PubMed  Google Scholar 

  101. Demonacos, C. et al. A new effector pathway links ATM kinase with the DNA damage response. Nature Cell Biol. 6, 968–976 (2004).

    Article  CAS  PubMed  Google Scholar 

  102. Demonacos, C., Krstic-Demonacos, M. & La Thangue, N. B. A TPR motif cofactor contributes to p300 activity in the p53 response. Mol. Cell 8, 71–84 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Kitagawa, M., Lee, S. H. & McCormick, F. Skp2 suppresses p53-dependent apoptosis by inhibiting p300. Mol. Cell 29, 217–231 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Tanaka, T., Ohkubo, S., Tatsuno, I. & Prives, C. hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes. Cell 130, 638–650 (2007). Identifies a new p53 cofactor that enhances p53-dependent transactivation, even though it binds chromatin independently of p53.

    Article  CAS  PubMed  Google Scholar 

  105. Donner, A. J., Szostek, S., Hoover, J. M. & Espinosa, J. M. CDK8 is a stimulus-specific positive coregulator of p53 target genes. Mol. Cell 27, 121–133 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Espinosa, J. M. & Emerson, B. M. Transcriptional regulation by p53 through intrinsic DNA/chromatin binding and site-directed cofactor recruitment. Mol. Cell 8, 57–69 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Ludwig Institute for Cancer Research, the Association for International Cancer Research and the European Union for funding, and G. Bond for critical reading of the manuscript.

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Correspondence to Xin Lu.

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Some of the data discussed in this article are the subject of various patent applications filed by the Ludwig Institute of Cancer Research.

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Glossary

Senescence

The irreversible arrest of cell growth. This process limits the lifespan of mammalian cells and prevents the growth of cells that are at risk of neoplastic transformation.

Missense mutation

A genetic mutation whereby a single nucleotide is substituted, which changes a codon so that it codes for a different amino acid. This change in one amino acid can alter the activity of the protein.

Telomere erosion

The shortening of the ends of telomeres due to incomplete replication of the lagging strand of DNA. The shortening of telomeres can happen in the early stages of cancer, leading to short dysfunctional telomeres.

γ-radiation

A type of electromagnetic radiation that is generally characterized by having high frequency and energy, but short wavelength. γ-radiation is often used to kill living cells, such as in the sterilization of medical equipment, in a process called irradiation.

Poly-ubiquitylation

The addition of multiple ubiquitin molecules to a target protein. The process usually involves the addition of a chain of ubiquitin to a target Lys residue (or residues) on the target protein.

E3 ligase

The third enzyme in a series (after E1 and E2) of enzymes that mediate the ubiquitylation of target proteins. E3 ligases recruit E2 ligases and the specific substrate, and aid in the transfer of ubiquitin to the target protein.

Co-activator

A protein that enhances gene expression by binding (directly or indirectly) to a transcription factor.

Mono-ubiquitylation

The addition of a single ubiquitin molecule to a target Lys residue on the substrate protein.

Poly(ADP-ribosyl)ation

The covalent or non-covalent attachment of polymers of ADP-ribose units to proteins. Poly(ADP-ribose) polymerase-1 (PARP1) catalyses the covalent poly(ADP-ribosyl)ation of p53

Prolyl isomerase

A molecule that mediates the interconversion of Pro residues in specific amino-acid motifs from the cis to the trans conformation, and vice versa.

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Murray-Zmijewski, F., Slee, E. & Lu, X. A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol 9, 702–712 (2008). https://doi.org/10.1038/nrm2451

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