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The genetics of the p53 pathway, apoptosis and cancer therapy

Nature Reviews Drug Discovery volume 7, pages 979–987 (2008)Cite this article

Abstract

The p53 pathway has been shown to mediate cellular stress responses; p53 can initiate DNA repair, cell-cycle arrest, senescence and, importantly, apoptosis. These responses have been implicated in an individual's ability to suppress tumour formation and to respond to many types of cancer therapy. Here we focus on how best to use knowledge of this pathway to tailor current therapies and develop novel ones. Studies of the genetics of p53 pathway components — in particular p53 itself and its negative regulator MDM2 — in cancer cells has proven useful in the development of targeted therapies. Furthermore, inherited single nucleotide polymorphisms in p53 pathway genes could serve a similar purpose.

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Figure 1: Cancer therapy.
Figure 2: The p53 pathway, somatic genetics and cancer therapeutics.
Figure 3: The p53 pathway, polymorphisms, apoptosis and cancer therapy.
Figure 4: The NCI60 human tumour cell line anticancer drug screen, somatic genetics, SNPs and the p53 pathway: an analysis.

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References

  1. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Riley, T., Sontag, E., Chen, P. & Levine, A. Transcriptional control of human p53-regulated genes. Nature Rev. Mol. Cell Biol. 9, 402–412 (2008).

    CAS  Google Scholar 

  3. Petitjean, A., Achatz, M. I., Borresen-Dale, A. L., Hainaut, P. & Olivier, M. TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26, 2157–2165 (2007).

    CAS  PubMed  Google Scholar 

  4. Soussi, T. & Wiman, K. G. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 12, 303–312 (2007).

    CAS  PubMed  Google Scholar 

  5. Iwakuma, T. & Lozano, G. Crippling p53 activities via knock-in mutations in mouse models. Oncogene 26, 2177–2184 (2007).

    CAS  PubMed  Google Scholar 

  6. Lozano, G. & Zambetti, G. P. What have animal models taught us about the p53 pathway? J. Pathol. 205, 206–220 (2005).

    CAS  PubMed  Google Scholar 

  7. Johnstone, R. W., Ruefli, A. A. & Lowe, S. W. Apoptosis: a link between cancer genetics and chemotherapy. Cell 108, 153–164 (2002).

    CAS  PubMed  Google Scholar 

  8. Yonish-Rouach, E. et al. Wild-type p53 induces apoptosis of myeloid leukaemic cells that is inhibited by interleukin-6. Nature 352, 345–347 (1991).

    CAS  PubMed  Google Scholar 

  9. Meulmeester, E. & Jochemsen, A. G. p53: a guide to apoptosis. Curr. Cancer Drug Targets 8, 87–97 (2008).

    CAS  PubMed  Google Scholar 

  10. Fridman, J. S. & Lowe, S. W. Control of apoptosis by p53. Oncogene 22, 9030–9040 (2003).

    CAS  PubMed  Google Scholar 

  11. Eischen, C. M., Weber, J. D., Roussel, M. F., Sherr, C. J. & Cleveland, J. L. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev. 13, 2658–2669 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schmitt, C. A., McCurrach, M. E., de Stanchina, E., Wallace-Brodeur, R. R. & Lowe, S. W. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53. Genes Dev 13, 2670–2677 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Schmitt, C. A. et al. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 1, 289–298 (2002).

    CAS  PubMed  Google Scholar 

  14. Lowe, S. W. et al. p53 status and the efficacy of cancer therapy in vivo. Science 266, 807–810 (1994).

    CAS  PubMed  Google Scholar 

  15. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007).

    CAS  PubMed  Google Scholar 

  16. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Senzer, N. et al. p53 therapy in a patient with Li-Fraumeni syndrome. Mol. Cancer Ther. 6, 1478–1482 (2007).

    CAS  PubMed  Google Scholar 

  18. Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006).

    CAS  PubMed  Google Scholar 

  19. Dey, A., Verma, C. S. & Lane, D. P. Updates on p53: modulation of p53 degradation as a therapeutic approach. Br. J. Cancer 98, 4–8 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Haupt, S. & Haupt, Y. Importance of p53 for cancer onset and therapy. Anticancer Drugs 17, 725–732 (2006).

    CAS  PubMed  Google Scholar 

  21. Selivanova, G. & Wiman, K. G. Reactivation of mutant p53: molecular mechanisms and therapeutic potential. Oncogene 26, 2243–5224 (2007).

    CAS  PubMed  Google Scholar 

  22. Wang, W. & El-Deiry, W. S. Restoration of p53 to limit tumor growth. Curr. Opin Oncol. 20, 90–96 (2008).

    PubMed  Google Scholar 

  23. Vousden, K. H. & Lu, X. Live or let die: the cell's response to p53. Nature Rev. Cancer 2, 594–604 (2002).

    CAS  Google Scholar 

  24. Snyder, E. L., Meade, B. R., Saenz, C. C. & Dowdy, S. F. Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. PLoS Biol. 2, E36 (2004).

    PubMed  PubMed Central  Google Scholar 

  25. Bond, G. L., Hu, W. & Levine, A. J. MDM2 is a central node in the p53 pathway: 12 years and counting. Curr. Cancer Drug Targets 5, 3–8 (2005).

    CAS  PubMed  Google Scholar 

  26. Freedman, D. A., Wu, L. & Levine, A. J. Functions of the MDM2 oncoprotein. Cell Mol. Life Sci. 55, 96–107 (1999).

    CAS  PubMed  Google Scholar 

  27. Onel, K. & Cordon-Cardo, C. MDM2 and prognosis. Mol. Cancer Res. 2, 1–8 (2004).

    CAS  PubMed  Google Scholar 

  28. Vassilev, L. T. MDM2 inhibitors for cancer therapy. Trends Mol. Med. 13, 23–31 (2007).

    CAS  PubMed  Google Scholar 

  29. Kussie, P. H. et al. Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain. Science 274, 948–953 (1996).

    CAS  PubMed  Google Scholar 

  30. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004).

    CAS  PubMed  Google Scholar 

  31. Tovar, C. et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc. Natl Acad. Sci. USA 103, 1888–1893 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Roth, J. A. Adenovirus p53 gene therapy. Expert Opin Biol. Ther. 6, 55–61 (2006).

    CAS  PubMed  Google Scholar 

  33. Peng, Z. Current status of gendicine in China: recombinant human Ad-p53 agent for treatment of cancers. Hum. Gene Ther. 16, 1016–1027 (2005).

    CAS  PubMed  Google Scholar 

  34. Harris, N. et al. Molecular basis for heterogeneity of the human p53 protein. Mol. Cell Biol. 6, 4650–4656 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Matlashewski, G. J. et al. Primary structure polymorphism at amino acid residue 72 of human p53. Mol. Cell Biol. 7, 961–963 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bond, G. L. et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell 119, 591–602 (2004).

    CAS  PubMed  Google Scholar 

  37. Atwal, G. S. et al. Haplotype structure and selection of the MDM2 oncogene in humans. Proc. Natl Acad. Sci. USA 104, 4524–4529 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bond, G. L. et al. MDM2 SNP309 accelerates tumor formation in a gender-specific and hormone-dependent manner. Cancer Res. 66, 5104–5110 (2006).

    CAS  PubMed  Google Scholar 

  39. Hong, Y. et al. The role of P53 and MDM2 polymorphisms in the risk of esophageal squamous cell carcinoma. Cancer Res. 65, 9582–9587 (2005).

    CAS  PubMed  Google Scholar 

  40. Beckman, G. et al. Is p53 polymorphism maintained by natural selection? Hum. Hered. 44, 266–270 (1994).

    CAS  PubMed  Google Scholar 

  41. Hu, W., Feng, Z., Atwal, G. S. & Levine, A. J. p53: a new player in reproduction. Cell Cycle 7, 848–852 (2008).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  43. Sakamuro, D., Sabbatini, P., White, E. & Prendergast, G. C. The polyproline region of p53 is required to activate apoptosis but not growth arrest. Oncogene 15, 887–898 (1997).

    CAS  PubMed  Google Scholar 

  44. Thomas, M. et al. Two polymorphic variants of wild-type p53 differ biochemically and biologically. Mol. Cell Biol. 19, 1092–1100 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Sullivan, A. et al. Polymorphism in wild-type p53 modulates response to chemotherapy in vitro and in vivo. Oncogene 23, 3328–3337 (2004).

    CAS  PubMed  Google Scholar 

  46. Bergamaschi, D. et al. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nature Genet. 38, 1133–1141 (2006).

    CAS  PubMed  Google Scholar 

  47. Dumont, P., Leu, J. I., Della Pietra, A. C., 3rd, George, D. L. & Murphy, M. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. Nature Genet. 33, 357–365 (2003).

    CAS  PubMed  Google Scholar 

  48. Pim, D. & Banks, L. p53 polymorphic variants at codon 72 exert different effects on cell cycle progression. Int. J. Cancer 108, 196–199 (2004).

    CAS  PubMed  Google Scholar 

  49. Bonafe, M. et al. p53 codon 72 genotype affects apoptosis by cytosine arabinoside in blood leukocytes. Biochem. Biophys. Res. Commun 299, 539–541 (2002).

    CAS  PubMed  Google Scholar 

  50. Bergamaschi, D. et al. p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell 3, 387–402 (2003).

    CAS  PubMed  Google Scholar 

  51. Vikhanskaya, F., Siddique, M. M., Kei Lee, M., Broggini, M. & Sabapathy, K. Evaluation of the combined effect of p53 codon 72 polymorphism and hotspot mutations in response to anticancer drugs. Clin. Cancer Res. 11, 4348–4356 (2005).

    CAS  PubMed  Google Scholar 

  52. Marin, M. C. et al. A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nature Genet. 25, 47–54 (2000).

    CAS  PubMed  Google Scholar 

  53. Arva, N. C. et al. A chromatin-associated and transcriptionally inactive p53-Mdm2 complex occurs in mdm2 SNP309 homozygous cells. J. Biol. Chem. 280, 26776–26787 (2005).

    CAS  PubMed  Google Scholar 

  54. Hu, W. et al. A single nucleotide polymorphism in the MDM2 gene disrupts the oscillation of p53 and MDM2 levels in cells. Cancer Res. 67, 2757–2765 (2007).

    CAS  PubMed  Google Scholar 

  55. Hirata, H. et al. MDM2 SNP309 polymorphism as risk factor for susceptibility and poor prognosis in renal cell carcinoma. Clin. Cancer Res. 13, 4123–4129 (2007).

    CAS  PubMed  Google Scholar 

  56. Gryshchenko, I. et al. MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J. Clin. Oncol. 26, 2252–2257 (2008).

    CAS  PubMed  Google Scholar 

  57. Nayak, M. S., Yang, J. M. & Hait, W. N. Effect of a single nucleotide polymorphism in the murine double minute 2 promoter (SNP309) on the sensitivity to topoisomerase II-targeting drugs. Cancer Res. 67, 5831–5839 (2007).

    CAS  PubMed  Google Scholar 

  58. Ohkubo, S., Tanaka, T., Taya, Y., Kitazato, K. & Prives, C. Excess HDM2 impacts cell cycle and apoptosis and has a selective effect on p53-dependent transcription. J. Biol. Chem. 281, 16943–16950 (2006).

    CAS  PubMed  Google Scholar 

  59. Asomaning, K. et al. MDM2 promoter polymorphism and pancreatic cancer risk and prognosis. Clin. Cancer Res. 14, 4010–4015 (2008).

    CAS  PubMed  Google Scholar 

  60. Cattelani, S. et al. Impact of a single nucleotide polymorphism in the MDM2 gene on neuroblastoma development and aggressiveness: results of a pilot study on 239 patients. Clin. Cancer Res. 14, 3248–3253 (2008).

    CAS  PubMed  Google Scholar 

  61. Heist, R. S. et al. MDM2 polymorphism, survival, and histology in early-stage non-small-cell lung cancer. J. Clin. Oncol. 25, 2243–2247 (2007).

    CAS  PubMed  Google Scholar 

  62. Ohmiya, N. et al. MDM2 promoter polymorphism is associated with both an increased susceptibility to gastric carcinoma and poor prognosis. J. Clin. Oncol. 24, 4434–4440 (2006).

    CAS  PubMed  Google Scholar 

  63. Tu, H. F. et al. MDM2 SNP 309 and p53 codon 72 polymorphisms are associated with the outcome of oral carcinoma patients receiving postoperative irradiation. Radiother. Oncol. 87, 243–252 (2008).

    CAS  PubMed  Google Scholar 

  64. Han, J. Y., Lee, G. K., Jang, D. H., Lee, S. Y. & Lee, J. S. Association of p53 codon 72 polymorphism and MDM2 SNP309 with clinical outcome of advanced non small cell lung cancer. Cancer 113, 799–807 (2008).

    CAS  PubMed  Google Scholar 

  65. Seyfried, I., Hofbauer, S., Stoecher, M., Greil, R. & Tinhofer, I. SNP309 as predictor for sensitivity of CLL cells to the MDM2 inhibitor nutlin-3a. Blood 112, 2168; author reply 2169 (2008).

    CAS  PubMed  Google Scholar 

  66. Shoemaker, R. H. The NCI60 human tumour cell line anticancer drug screen. Nature Rev. Cancer 6, 813–823 (2006).

    CAS  Google Scholar 

  67. Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005).

    CAS  PubMed  Google Scholar 

  68. Ikediobi, O. N. et al. Mutation analysis of 24 known cancer genes in the NCI-60 cell line set. Mol. Cancer Ther. 5, 2606–2612 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. O'Connor, P. M. et al. Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res. 57, 4285–4300 (1997).

    CAS  PubMed  Google Scholar 

  70. Olivier, M. et al. The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin. Cancer Res. 12, 1157–1167 (2006).

    CAS  PubMed  Google Scholar 

  71. Kahyo, T., Nishida, T. & Yasuda, H. Involvement of PIAS1 in the sumoylation of tumor suppressor p53. Mol. Cell 8, 713–718 (2001).

    CAS  PubMed  Google Scholar 

  72. Okubo, S. et al. NMR structure of the N-terminal domain of SUMO ligase PIAS1 and its interaction with tumor suppressor p53 and A/T-rich DNA oligomers. J. Biol. Chem. 279, 31455–31461 (2004).

    CAS  PubMed  Google Scholar 

  73. Stavridi, E. S., Chehab, N. H., Malikzay, A. & Halazonetis, T. D. Substitutions that compromise the ionizing radiation-induced association of p53 with 14-3-3 proteins also compromise the ability of p53 to induce cell cycle arrest. Cancer Res. 61, 7030–7033 (2001).

    CAS  PubMed  Google Scholar 

  74. Megidish, T., Xu, J. H. & Xu, C. W. Activation of p53 by protein inhibitor of activated Stat1 (PIAS1). J. Biol. Chem. 277, 8255–8259 (2002).

    CAS  PubMed  Google Scholar 

  75. Schmidt, D. & Muller, S. Members of the PIAS family act as SUMO ligases for c-Jun and p53 and repress p53 activity. Proc. Natl Acad. Sci. USA 99, 2872–2877 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Waterman, M. J., Stavridi, E. S., Waterman, J. L. & Halazonetis, T. D. ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins. Nature Genet. 19, 175–178 (1998).

    CAS  PubMed  Google Scholar 

  77. Dohoney, K. M. et al. Phosphorylation of p53 at serine 37 is important for transcriptional activity and regulation in response to DNA damage. Oncogene 23, 49–57 (2004).

    CAS  PubMed  Google Scholar 

  78. Kimura, S. H. & Nojima, H. Cyclin G1 associates with MDM2 and regulates accumulation and degradation of p53 protein. Genes Cells 7, 869–880 (2002).

    CAS  PubMed  Google Scholar 

  79. Li, H. H., Cai, X., Shouse, G. P., Piluso, L. G. & Liu, X. A specific PP2A regulatory subunit, B56gamma, mediates DNA damage-induced dephosphorylation of p53 at Thr55. Embo J. 26, 402–411 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Moule, M. G., Collins, C. H., McCormick, F. & Fried, M. Role for PP2A in ARF signaling to p53. Proc. Natl Acad. Sci. USA 101, 14063–14066 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Okamoto, K. et al. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol. Cell 9, 761–771 (2002).

    CAS  PubMed  Google Scholar 

  82. Feng, Z. et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res. 67, 3043–3053 (2007).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  84. Welch, W. J. Construction of permutation tests. J. Am. Stat. Assoc. 85, 693–698 (1990).

    Google Scholar 

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Acknowledgements

The authors would like to acknowledge the NCI-DCTD Repository Molecular Characterization Program for the development of the 60 cell line screening panel, their molecular characterization and the generous contribution of genomic DNA from the NCI60 panel of cell lines.

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Authors and Affiliations

  1. Alexei Vazquez and Arnold J. Levine are at The Institute for Advanced Study, Einstein Drive, Princeton, New Jersey, 08540, USA.,

    Alexei Vazquez & Arnold J. Levine

  2. Arnold J. Levine is at The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey, 08903, USA.,

    Arnold J. Levine

  3. Elisabeth E. Bond and Gareth L. Bond are at The Ludwig Institute of Cancer Research, University of Oxford, Old Road Campus, Oxford, OX3 7DQ, United Kingdom.,

    Elisabeth E. Bond & Gareth L. Bond

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  1. Alexei Vazquez
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  2. Elisabeth E. Bond
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Corresponding author

Correspondence to Gareth L. Bond.

Supplementary information

Supplementary information S1 (table)

p53 stress response genes (PDF 365 kb)

Supplementary information S2 (table)

Six SNPs with allelic differences in p53-dependent drug responses (PDF 156 kb)

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Developmental Therapeutics Program NCI/NIH

NCI60 database

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Vazquez, A., Bond, E., Levine, A. et al. The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 7, 979–987 (2008). https://doi.org/10.1038/nrd2656

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