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Recent advances in p53 research: an interdisciplinary perspective

Cancer Gene Therapy volume 16, pages 1–12 (2009)Cite this article

Abstract

The TP53 gene is one of the most studied genes in human cancer. In recent years, considerable interest was focused on mutant p53, the abnormal protein product of TP53 somatic or germline alleles with missense mutations that often accumulate in cancer cells. There is now compelling experimental evidence that many mutations can exert mutant-specific, gain-of-function effects by perturbing the regulation of expression of multiple genes. This notion is supported by the observation that targeted mutant p53 expression enhances the formation of specific cancers in the mouse even in the absence of wild-type p53 expression. In addition, clinical studies are producing a wealth of functional pathway data demonstrating correlations between specific TP53 mutations and gene expression patterns identified by transcriptome studies. These correlations imply that alteration of p53 function is critical in shaping gene expression patterns in cancer. Finally, progress is being made in the development of new therapeutic approaches targeting p53 alterations. Key advances regarding the structural, biochemical and functional properties of normal and mutant p53 proteins, their abnormal regulation and distribution in human cancers, and their associations with clinical and pathological cancer characteristics are reviewed. New opportunities for translational research for improving cancer detection, prognosis, prevention and therapy based upon the integration of this knowledge are described.

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References

  1. Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M . TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 2007; 26: 2157–2165.

    Article  CAS  PubMed  Google Scholar 

  2. Jegga AG, Inga A, Menendez D, Aronow BJ, Resnick MA . Functional evolution of the p53 regulatory network through its target response elements. Proc Natl Acad Sci USA 2008; 105: 944–949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Menendez D, Inga A, Snipe J, Krysiak O, Schonfelder G, Resnick MA . A single-nucleotide polymorphism in a half-binding site creates p53 and estrogen receptor control of vascular endothelial growth factor receptor 1. Mol Cell Biol 2007; 27: 2590–2600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Resnick MA . Noncanonical sequence motifs as targets for transactivation by WT and mutant p53. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 6.

  5. Milner J . Reciprocal regulation between p53 and SIRT1. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 11.

  6. Vousden KH . Role of p53 in apoptosis and autophagy. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 12.

  7. Bensaad K, Vousden KH . p53: new roles in metabolism. Trends Cell Biol 2007; 17: 286–291.

    Article  CAS  PubMed  Google Scholar 

  8. Yee KS, Vousden KH . Contribution of membrane localization to the apoptotic activity of PUMA. Apoptosis 2008; 13: 87–95.

    Article  PubMed  Google Scholar 

  9. Moore L, Lu X, Ghebranious N, Tyner S, Donehower LA . Aging-associated truncated form of p53 interacts with wild-type p53 and alters p53 stability, localization, and activity. Mech Ageing Dev 2007; 128: 717–730.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hinkal G . The cellular and molecular characterization of a p53 mutant mouse model of accelerated aging. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Short presentation 5.

  11. Perwez HS, Harris CC . Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 2007; 121: 2373–2380.

    Article  Google Scholar 

  12. Harris CC . Inflammation and cancer: interactions of the microRNA, p53 and cytokine pathways. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 1.

  13. Gadea G, Lapasset L, Gauthier-Rouviere C, Roux P . Regulation of Cdc42-mediated morphological effects: a novel function for p53. EMBO J 2002; 21: 2373–2382.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gadea G, de Toledo M, Anguille C, Roux P . Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J Cell Biol 2007; 178: 23–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Joerger AC, Allen MD, Fersht AR . Crystal structure of a superstable mutant of human p53 core domain. Insights into the mechanism of rescuing oncogenic mutations. J Biol Chem 2004; 279: 1291–1296.

    Article  CAS  PubMed  Google Scholar 

  16. Joerger AC, Ang HC, Fersht AR . Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci USA 2006; 103: 15056–15061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Veprintsev DB, Freund SM, Andreeva A, Rutledge SE, Tidow H, Canadillas JM et al. Core domain interactions in full-length p53 in solution. Proc Natl Acad Sci USA 2006; 103: 2115–2119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kato S, Han SY, Liu W, Otsuka K, Shibata H, Kanamaru R et al. Understanding the function–structure and function–mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA 2003; 100: 8424–8429.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Scian MJ, Stagliano KE, Anderson MA, Hassan S, Bowman M, Miles MF et al. Tumor-derived p53 mutants induce NF-kappaB2 gene expression. Mol Cell Biol 2005; 25: 10097–10110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Blandino G . Mutant p53: an oncogenic transcription factor. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 16.

  21. Oren M . Modulation of the vitamin D3 response by cancer associated mutant p53. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 15.

  22. Kalo E, Buganim Y, Shapira KE, Besserglick H, Goldfinger N, Weisz L et al. Mutant p53 attenuates the SMAD-dependent transforming growth factor beta1 (TGF-beta1) signaling pathway by repressing the expression of TGF-beta receptor type II. Mol Cell Biol 2007; 27: 8228–8242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Heinlein C, Krepulat F, Lohler J, Speidel D, Deppert W, Tolstonog GV . Mutant p53(R270H) gain of function phenotype in a mouse model for oncogene-induced mammary carcinogenesis. Int J Cancer 2008; 122: 1701–1709.

    Article  CAS  PubMed  Google Scholar 

  24. Krepulat F, Lohler J, Heinlein C, Hermannstadter A, Tolstonog GV, Deppert W . Epigenetic mechanisms affect mutant p53 transgene expression in WAP-mutp53 transgenic mice. Oncogene 2005; 24: 4645–4659.

    Article  CAS  PubMed  Google Scholar 

  25. Bossi G, Lapi E, Strano S, Rinaldo C, Blandino G, Sacchi A . Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 2006; 25: 304–309.

    Article  CAS  PubMed  Google Scholar 

  26. Bougeard G, Brugieres L, Chompret A, Gesta P, Charbonnier F, Valent A et al. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene 2003; 22: 840–846.

    Article  CAS  PubMed  Google Scholar 

  27. Lozano G . From bad to worse: p53 loss versus missense mutations. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 21.

  28. Jochemsen AG . Oncogenic functions of MDMX (MDM4), an essential regulator of p53 activity. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 14.

  29. Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C et al. Inactivation of the p53 pathway in retinoblastoma. Nature 2006; 444: 61–66.

    Article  CAS  PubMed  Google Scholar 

  30. Wang YV, Wade M, Wong E, Li YC, Rodewald LW, Wahl GM . Quantitative analyses reveal the importance of regulated Hdmx degradation for p53 activation. Proc Natl Acad Sci USA 2007; 104: 12365–12370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zacchi P, Gostissa M, Uchida T, Salvagno C, Avolio F, Volinia S et al. The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults. Nature 2002; 419: 853–857.

    Article  CAS  PubMed  Google Scholar 

  32. Mantovani F, Tocco F, Girardini J, Smith P, Gasco M, Lu X et al. The prolyl isomerase Pin1 orchestrates p53 acetylation and dissociation from the apoptosis inhibitor iASPP. Nat Struct Mol Biol 2007; 14: 912–920.

    Article  CAS  PubMed  Google Scholar 

  33. Del Sal G . Characterization of the role of PIN1 as a regulator of p53 function and dysfunction. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 7.

  34. Sheich-Bartok O, Haupt S, kalay-Snir I, Saito S, Appella E, Haupt Y . PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 2008; 27: 3653–3661.

    Article  Google Scholar 

  35. Moll U . Regulated nuclear import of p53 by binding to importin alpha 3 contributes to stress-mediated nuclear accumulation. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 18.

  36. Beckerman R, Prives C . New findings on the impact of c-terminal lysines on p53 transactivation and cellular outcomes. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Short communication 8.

  37. Le CL, Linares LK, Paul C, Julien E, Lacroix M, Hatchi E et al. E4F1 is an atypical ubiquitin ligase that modulates p53 effector functions independently of degradation. Cell 2006; 127: 775–788.

    Article  Google Scholar 

  38. Puisieux A, Valsesia-Wittmann S, Ansieau S . A twist for survival and cancer progression. Br J Cancer 2006; 94: 13–17.

    Article  CAS  PubMed  Google Scholar 

  39. Puisieux A . Inactivation of failsafe programs by twist oncoproteins. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 19.

  40. Bourdon JC, Fernandes K, Murray-Zmijewski F, Liu G, Diot A, Xirodimas DP et al. p53 isoforms can regulate p53 transcriptional activity. Genes Dev 2005; 19: 2122–2137.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bourdon JC . p53 isoform expression may abrogate p53 mutation and is associated with good prognosis in breast cancer. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 4.

  42. Kim E . Splice isoform p53-beta has anti-apoptotic activity and antagonizes apoptotic signaling mediated by p53. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Short communication 2.

  43. Olivier M, Hussain SP, Caron de FC, Hainaut P, Harris CC . TP53 mutation spectra and load: a tool for generating hypotheses on the etiology of cancer. IARC Sci Publ 2004; 157: 247–270.

    Google Scholar 

  44. Hainaut P . Revisiting ‘initiation’ in carcinogenesis: place of TP53 mutations in early steps of cancer. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 2.

  45. Roman S, Petre A, Thepot A, Hautefeuille A, Scoazec JY, Mion F et al. Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol 2007; 293: G45–G53.

    Article  CAS  PubMed  Google Scholar 

  46. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA 2001; 98: 10869–10874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA 2003; 100: 8418–8423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Langerod A, Zhao H, Borgan O, Nesland JM, Bukholm IR, Ikdahl T et al. TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 2007; 9: R30.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Bartek J, Bartkova J, Lukas J . DNA damage signalling guards against activated oncogenes and tumour progression. Oncogene 2007; 26: 7773–7779.

    Article  CAS  PubMed  Google Scholar 

  50. Bartek J . Tumor suppressors in DNA-damage checkpoints pathways. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 9.

  51. Reinbold M, Luo JL, Nedelko T, Jerchow B, Murphy ME, Whibley C et al. Common tumour p53 mutations in immortalized cells from Hupki mice heterozygous at codon 72. Oncogene 2008; 27: 2788–2794.

    Article  CAS  PubMed  Google Scholar 

  52. Lawrence HJ . Detection of p53 mutations in cancer by the Amplichip p53 test, a microarray-based resequencing assay. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 10.

  53. Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J et al. The clinical value of somatic TP53 gene mutations in 1794 patients with breast cancer. Clin Cancer Res 2006; 12: 1157–1167.

    Article  CAS  PubMed  Google Scholar 

  54. Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 2002; 8: 282–288.

    Article  CAS  PubMed  Google Scholar 

  55. Issaeva N, Bozko P, Enge M, Protopopova M, Verhoef LG, Masucci M et al. Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors. Nat Med 2004; 10: 1321–1328.

    Article  CAS  PubMed  Google Scholar 

  56. Wiman KG . Mechanisms of prima-1-mediated mutant p53 reactivation and apoptosis. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 27.

  57. Selivanova G . Molecular mechanisms of preferential induction of apoptosis and downregulation of oncogenic pathways by pharmacological reactivation of p53. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 26.

  58. Fersht AR . The structure of p53. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 3.

  59. Theobald M . Targeting p53 by T cells. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 25.

  60. Senzer N, Nemunaitis J, Nemunaitis M, Lamont J, Gore M, Gabra H et al. p53 therapy in a patient with Li-Fraumeni syndrome. Mol Cancer Ther 2007; 6: 1478–1482.

    Article  CAS  PubMed  Google Scholar 

  61. Sobol RE . Clinical efficacy and safety of adenoviral p53 (advexin) in the treatment of tumors with inherited and acquired p53 abnormalities. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 29.

  62. Li FP, Fraumeni Jr JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988; 48: 5358–5362.

    CAS  PubMed  Google Scholar 

  63. Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250: 1233–1238.

    Article  CAS  PubMed  Google Scholar 

  64. Birch J . Genotype & phenotype in families with Li-Fraumeni & Li-Fraumeni-like syndromes. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 28.

  65. Frebourg T . Molecular basis of the Li-Fraumeni syndrome (LFS): an update from the french LFS families. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 30.

  66. Bougeard G, Brugieres L, Chompret A, Gesta P, Charbonnier F, Valent A et al. Screening for TP53 rearrangements in families with the Li-Fraumeni syndrome reveals a complete deletion of the TP53 gene. Oncogene 2003; 22: 840–846.

    Article  CAS  PubMed  Google Scholar 

  67. Achatz MI, Olivier M, Le CF, Martel-Planche G, Lopes A, Rossi BM et al. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 2007; 245: 96–102.

    Article  CAS  PubMed  Google Scholar 

  68. Ribeiro RC, Sandrini F, Figueiredo B, Zambetti GP, Michalkiewicz E, Lafferty AR et al. An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma. Proc Natl Acad Sci USA 2001; 98: 9330–9335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Achatz MI, Ashton-Prolla P . High population impact of a low penetrance tp53 germline mutation causes high incidence of lfl families in southern Brazil. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 34.

  70. Olivier M . IARC database of Li-Fraumeni syndrome: a resource for the exploration of genotype–phenotype relationships. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 31.

  71. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 2007; 28: 622–629.

    Article  CAS  PubMed  Google Scholar 

  72. Garber JE, Syngal S . Support for potential surveillance strategies for members of lfs kindreds. Third International Workshop on Mutant p53 and Li Fraumeni Symposium 2007: Lecture 33.

  73. Wong P, Verselis SJ, Garber JE, Schneider K, DiGianni L, Stockwell DH et al. Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. Gastroenterology 2006; 130: 73–79.

    Article  PubMed  Google Scholar 

  74. Rahman N . Fraumeni syndrome—a new look at old problems. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007.

  75. Strong LC . Li-fraumeni syndrome: cancer risk and risk modifiers. Third International Workshop on Mutant p53 and Li-Fraumeni Symposium 2007: Lecture 23.

  76. Bougeard G, Baert-Desurmont S, Tournier I, Vasseur S, Martin C, Brugieres L et al. Impact of the MDM2 SNP309 and p53 Arg72Pro polymorphism on age of tumour onset in Li-Fraumeni syndrome. J Med Genet 2006; 43: 531–533.

    Article  CAS  PubMed  Google Scholar 

  77. Tabori U, Nanda S, Druker H, Lees J, Malkin D . Younger age of cancer initiation is associated with shorter telomere length in Li-Fraumeni syndrome. Cancer Res 2007; 67: 1415–1418.

    Article  CAS  PubMed  Google Scholar 

  78. Fujiwara T, Grimm EA, Mukhopadhyay T, Cai DW, Owen-Schaub LB, Roth JA . A retroviral wild-type p53 expression vector penetrates human lung cancer spheroids and inhibits growth by inducing apoptosis. Cancer Res 1993; 53: 4129–4133.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank all speakers for their participation at the p53 Marathon Meeting 2007 and their stimulating scientific contributions. The meeting was funded by IARC and EC FP6 and with support received from CLARA, Roche Molecular Systems Inc. and Introgen Therapeutics Inc. This publication reflects the author's views and not necessarily those of the EC. The community is not liable for any use that may be made of the information contained herein. V Marcel is supported by a fellowship of Ligue Nationale contre le Cancer, France. We thank Michelle Wrisez, Dominique Bouchard and all members of the Group of Molecular Carcinogenesis and Biomarkers at IARC for their help with logistics and organization. Links: IARC TP53 database: http://www-p53.iarc.fr/; Abstracts of International Workshop on Mutant p53: http://www.p53.iarc.fr/P53meeting2007/P53meeting2007.html; p53 Gateway: http://www.p53gateway.org/

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Authors and Affiliations

  1. Group of Molecular Carcinogenesis and Biomarkers, International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France

    M Olivier, A Petitjean, V Marcel, A Pétré, M Mounawar, A Plymoth & P Hainaut

  2. INSERM UMR590, Unité d’Oncogenèse et de Progression Tumorale,

    C C de Fromentel

  3. Université Lyon-1, Centre Léon Bérard, Lyon, France

    C C de Fromentel

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  1. M Olivier
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Correspondence to M Olivier.

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Olivier, M., Petitjean, A., Marcel, V. et al. Recent advances in p53 research: an interdisciplinary perspective. Cancer Gene Ther 16, 1–12 (2009). https://doi.org/10.1038/cgt.2008.69

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