Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

p53 alterations in human cancer: more questions than answers

Oncogene volume 26, pages 2145–2156 (2007)Cite this article

Abstract

The strongest and undisputed fact about p53 is the high frequency of p53 alterations in human cancer and that mutant p53 proteins constitute a complex family of several hundred proteins with heterogeneous properties. Beyond these observations, the p53 pathway and its regulation in a normal cell is like a desert trail, always moving with the wind of novel findings. The field is full of black boxes that are often ignored for sake of simplicity or because they do not fit with the current dominant view. Mutant p53 protein accumulation in tumours is the best example of a preconceived idea, as there is no experimental evidence to explain this observation. In this review, we will discuss several questions concerning the activity or selection of p53 mutations. The central domain of the p53 protein targeted by 80% of p53 mutations is associated with the DNA-binding activity of the p53 protein, but it is also the binding site for several proteins that play a key role in p53 regulation such as ASPP proteins or BclxL. The role of impaired DNA binding and/or protein interactions in tumour development has not been fully elucidated. Similarly, novel animal models carrying either missense p53 mutations or inducible p53 have provided abundant observations, some of which could challenge our view on p53 function as a tumour suppressor gene. Finally, the possible clinical applications of p53 will be discussed.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Aas T, Borresen AL, Geisler S, Smithsorensen B, Johnsen H, Varhaug JE et al. (1996). Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2: 811–814.

    CAS  PubMed  Google Scholar 

  • Appella E, Anderson CW . (2001). Post-translational modifications and activation of p53 by genotoxic stresses. Eur J Biochem 268: 2764–2772.

    Article  CAS  Google Scholar 

  • Bader S, Walker M, Hendrich B, Bird A, Bird C, Hooper M et al. (1999). Somatic frameshift mutations in the MBD4 gene of sporadic colon cancers with mismatch repair deficiency. Oncogene 18: 8044–8047.

    Article  CAS  Google Scholar 

  • Baylin SB, Belinsky SA, Herman JG . (2000). Aberrant methylation of gene promoters in cancer – concepts, misconcepts, and promise. J Natl Cancer Inst 92: 1460–1461.

    Article  CAS  Google Scholar 

  • Bergamaschi D, Gasco M, Hiller L, Sullivan A, Syed N, Trigiante G et al. (2003). p53 polymorphism influences response in cancer chemotherapy via modulation of p73-dependent apoptosis. Cancer Cell 3: 387–402.

    Article  CAS  Google Scholar 

  • Blagosklonny MV . (2000). p53 from complexity to simplicity: mutant p53 stabilization, gain-of-function, and dominant-negative effect [In Process Citation]. FASEB J 14: 1901–1907.

    Article  CAS  Google Scholar 

  • Blandino G, Levine AJ, Oren M . (1999). Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy. Oncogene 18: 477–485.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Brash DE . (1996). Cellular proofreading. Nat Med 2: 525–526.

    Article  CAS  Google Scholar 

  • Bruins W, Zwart E, Attardi LD, Iwakuma T, Hoogervorst EM, Beems RB et al. (2004). Increased Sensitivity to UV Radiation in Mice with a p53 Point Mutation at Ser389. Mol Cell Biol 24: 8884–8894.

    Article  CAS  Google Scholar 

  • Chipuk JE, Green DR . (2003). p53's believe it or not: lessons on transcription-independent death. J Clin Immunol 23: 355–361.

    Article  CAS  Google Scholar 

  • Cho YJ, Gorina S, Jeffrey PD, Pavletich NP . (1994). Crystal structure of a p53 tumor suppressor DNA complex: understanding tumorigenic mutations. Science 265: 346–355.

    Article  CAS  Google Scholar 

  • Christophorou MA, Ringshausen I, Finch AJ, Swigart LB, Evan GI . (2006). The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443: 214–217.

    Article  CAS  Google Scholar 

  • Denissenko MF, Chen JX, Tang MS, Pfeifer GP . (1997). Cytosine methylation determines hot spots of DNA damage in the human P53 gene. Proc Natl Acad Sci USA 94: 3893–3898.

    Article  CAS  Google Scholar 

  • Deppert W, Gohler T, Koga H, Kim E . (2000). Mutant p53: ‘gain of function’ through perturbation of nuclear structure and function? J Cell Biochem Suppl 35: 115–122.

    Article  Google Scholar 

  • DiComo CJ, Gaiddon C, Prives C . (1999). p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol Cell Biol 19: 1438–1449.

    Article  CAS  Google Scholar 

  • Dittmer D, Pati S, Zambetti G, Chu S, Teresky AK, Moore M et al. (1993). Gain of function mutations in p53. Nat Genet 4: 42–46.

    Article  CAS  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery CAJ, Butel JS et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.

    Article  CAS  Google Scholar 

  • Dowell SP, Wilson POG, Derias NW, Lane DP, Hall PA . (1994). Clinical utility of the immunocytochemical detection of p53 protein in cytological specimens. Cancer Res 54: 2914–2918.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Fan S, Yuan R, Ma YX, Meng Q, Goldberg ID, Rosen EM . (2001). Mutant BRCA1 genes antagonize phenotype of wild-type BRCA1. Oncogene 20: 8215–8235.

    Article  CAS  Google Scholar 

  • Fei P, Bernhard EJ, El-Deiry WS . (2002). Tissue-specific induction of p53 targets in vivo. Cancer Res 62: 7316–7327.

    CAS  PubMed  Google Scholar 

  • Freedman DA, Wu L, Levine AJ . (1999). Functions of the MDM2 oncoprotein. Cell Mol Life Sci 55: 96–107.

    Article  CAS  Google Scholar 

  • Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C . (2001). A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol 21: 1874–1887.

    Article  CAS  Google Scholar 

  • Gatz SA, Wiesmuller L . (2006). p53 in recombination and repair. Cell Death Differ 13: 1003–1016.

    Article  CAS  Google Scholar 

  • Gorina S, Pavletich NP . (1996). Structure of the p53 tumor suppressor bound to the ankyrin and SH3 domains of 53BP2. Science 274: 1001–1005.

    Article  CAS  Google Scholar 

  • Gottlieb E, Haffner R, King A, Asher G, Gruss P, Lonai P et al. (1997). Transgenic mouse model for studying the transcriptional activity of the p53 protein: Age- and tissue-dependent changes in radiation-induced activation during embryogenesis. EMBO J 16: 1381–1390.

    Article  CAS  Google Scholar 

  • Gudkov AV . (2002). Converting p53 from a killer into a healer. Nat Med 8: 1196–1198.

    Article  CAS  Google Scholar 

  • Halevy O, Michalovitz D, Oren M . (1990). Different tumor-derived p53 mutants exhibit distinct biological activities. Science 250: 113–116.

    Article  CAS  Google Scholar 

  • Hall PA, Lane DP . (1994). P53 in tumour pathology – can we trust immunohistochemistry – revisited. J Pathol 172: 1–4.

    Article  CAS  Google Scholar 

  • Helton ES, Chen X . (2006). p53 modulation of the DNA damage response. J Cell Biochem; Published online 9 October 2006.

  • Irwin MS, Kondo K, Marin MC, Cheng LS, Hahn WC, Kaelin WG . (2003). Chemosensitivity linked to p73 function. Cancer Cell 3: 403–410.

    Article  CAS  Google Scholar 

  • Jenkins JR, Chumakov P, Addison C, Stürzbzecher HW, Wade-Evans A . (1988). Two distinct regions of the murine p53 primary amino acid sequence are implicated in stable complex formation with simian virus 40T antigen. J Virol 62: 3902–3906.

    Google Scholar 

  • Johnson TM, Attardi LD . (2006). Dissecting p53 tumor suppressor function in vivo through the analysis of genetically modified mice. Cell Death Differ 13: 902–908.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Krummel KA, Lee CJ, Toledo F, Wahl GM . (2005). 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.

    Article  CAS  Google Scholar 

  • Lane DP, Benchimol S . (1990). p53: oncogene or anti-oncogene? Genes Dev 4: 1–8.

    Article  CAS  Google Scholar 

  • Lang GA, Iwakuma T, Suh YA, Liu G, Rao VA, Parant JM et al. (2004). Gain of Function of a p53 Hot Spot Mutation in a Mouse Model of Li-Fraumeni Syndrome. Cell 119: 861–872.

    Article  CAS  Google Scholar 

  • Lavigueur A, Maltby V, Mock D, Rossant J, Pawson T, Bernstein A . (1989). High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol Cell Biol 9: 3982–3991.

    Article  CAS  Google Scholar 

  • Levine AJ, Hu W, Feng Z . (2006). The P53 pathway: what questions remain to be explored? Cell Death Differ 13: 1027–1036.

    Article  CAS  Google Scholar 

  • Lilyestrom W, Klein MG, Zhang R, Joachimiak A, Chen XS . (2006). Crystal structure of SV40 large T-antigen bound to p53: interplay between a viral oncoprotein and a cellular tumor suppressor. Genes Dev 20: 2373–2382.

    Article  CAS  Google Scholar 

  • Liu G, Parant JM, Lang G, Chau P, Chavez-Reye A, El-Naggar AK et al. (2004). Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice. Nat Genet 36: 63–68.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • MacPherson D, Kim J, Kim T, Rhee BK, Van Oostrom CT, DiTullio RA et al. (2004). Defective apoptosis and B-cell lymphomas in mice with p53 point mutation at Ser 23. EMBO J 23: 3689–3699.

    Article  CAS  Google Scholar 

  • Marin MC, Jost CA, Brooks LA, Irwin MS, O’Nions J, Tidy JA et al. (2000). A common polymorphism acts as an intragenic modifier of mutant p53 behaviour. Nat Genet 25: 47–54.

    Article  CAS  Google Scholar 

  • Melino G, De Laurenzi V, Vousden KH . (2002). p73: Friend or foe in tumorigenesis. Nat Rev Cancer 2: 605–615.

    Article  CAS  Google Scholar 

  • Midgley CA, Owens B, Briscoe CV, Thomas DB, Lane DP, Hall PA . (1995). Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo. J Cell Sci 108: 1843–1848.

    CAS  PubMed  Google Scholar 

  • Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P et al. (2003). p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11: 577–590.

    Article  CAS  Google Scholar 

  • Milner J . (1995). Flexibility: the key to p53 function? Trends Biochem Sci 20: 49–51.

    Article  CAS  Google Scholar 

  • Mummenbrauer T, Janus F, Muller B, Wiesmuller L, Deppert W, Grosse F . (1996). p53 protein exhibits 3′-to-5′ exonuclease activity. Cell 85: 1089–1099.

    Article  CAS  Google Scholar 

  • Norimura T, Nomoto S, Katsuki M, Gondo Y, Kondo S . (1996). p53-dependent apoptosis suppresses radiation-induced teratogenesis. Nat Med 2: 577–580.

    Article  CAS  Google Scholar 

  • Olive KP, Tuveson DA, Ruhe ZC, Yin B, Willis NA, Bronson RT et al. (2004). Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119: 847–860.

    Article  CAS  Google Scholar 

  • Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . (1997). A model for p53-induced apoptosis. Nature 389: 300–305.

    Article  CAS  Google Scholar 

  • Prives C, Manfredi JJ . (2005). The continuing saga of p53 – more sleepless nights ahead. Mol Cell 19: 719–721.

    Article  CAS  Google Scholar 

  • Resnick MA, Inga A . (2003). Functional mutants of the sequence-specific transcription factor p53 and implications for master genes of diversity. Proc Natl Acad Sci USA 100: 9934–9939.

    Article  CAS  Google Scholar 

  • Rohaly G, Chemnitz J, Dehde S, Nunez AM, Heukeshoven J, Deppert W et al. (2005). A novel human p53 isoform is an essential element of the ATR-intra-S phase checkpoint. Cell 122: 21–32.

    Article  CAS  Google Scholar 

  • Rowan AJ, Lamlum H, Ilyas M, Wheeler J, Straub J, Papadopoulou A et al. (2000). APC mutations in sporadic colorectal tumors: a mutational ‘hotspot’ and interdependence of the ‘two hits’. Proc Natl Acad Sci USA 97: 3352–3357.

    Article  CAS  Google Scholar 

  • Sablina AA, Budanov AV, Ilyinskaya GV, Agapova LS, Kravchenko JE, Chumakov PM . (2005). The antioxidant function of the p53 tumor suppressor. Nat Med 11: 1306–1313.

    Article  CAS  Google Scholar 

  • Samuels-Lev Y, O’Connor DJ, Bergamaschi D, Trigiante G, Hsieh JK, Zhong S et al. (2001). ASPP proteins specifically stimulate the apoptotic function of p53. Mol Cell 8: 781–794.

    Article  CAS  Google Scholar 

  • Sengupta S, Harris CC . (2005). p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol 6: 44–55.

    Article  CAS  Google Scholar 

  • Seo YR, Kelley MR, Smith ML . (2002). Selenomethionine regulation of p53 by a ref1-dependent redox mechanism. Proc Natl Acad Sci USA 99: 14548–14553.

    Article  CAS  Google Scholar 

  • Sigal A, Rotter V . (2000). Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. [In Process Citation]. Cancer Res 60: 6788–6793.

    CAS  PubMed  Google Scholar 

  • Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314: 268–274.

    Article  Google Scholar 

  • Sluss HK, Armata H, Gallant J, Jones SN . (2004). Phosphorylation of serine 18 regulates distinct p53 functions in mice. Mol Cell Biol 24: 976–984.

    Article  CAS  Google Scholar 

  • Soussi T, Béroud C . (2001). Assessing TP53 status in human tumours to evaluate clinical outcome. Nat Rev Cancer 1: 233–240.

    Article  CAS  Google Scholar 

  • Soussi T, Béroud C . (2003). Significance of TP53 mutations in human cancer: A critical analysis of mutations at CpG dinucleotides. Hum Mutat 21: 192–200.

    Article  CAS  Google Scholar 

  • Soussi T, Lozano G . (2005). p53 mutation heterogeneity in cancer. Biochem Biophys Res Commun 331: 834–842.

    Article  CAS  Google Scholar 

  • Soussi T, Caron de Fromentel C, Stürzbecher HW, Ullrich S, Jenkins J, May P . (1989). Evolutionary conservation of the biochemical properties of p53 – specific interaction of xenopus-laevis p53 with simian virus 40 large T-antigen and mammalian heat shock proteins-70. J Virol 63: 3894–3901.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Soussi T, Kato S, Levy PP, Ishioka C . (2005). Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. Hum Mutat 25: 6–17.

    Article  CAS  Google Scholar 

  • Soussi T . (2005). A critical analysis of p53 gene alterations in cancer. In: Wiman K, Hainaut P (eds). 25 Years of p53 Research. Springer: Berlin. pp 225–292.

    Google Scholar 

  • Strano S, Munarriz E, Rossi M, Cristofanelli B, Shaul Y, Castagnoli L et al. (2000). Physical and functional interaction between p53 mutants and different isoforms of p73. J Biol Chem 275: 29503–29512.

    Article  CAS  Google Scholar 

  • Takagi M, Absalon MJ, McLure KG, Kastan MB . (2005). Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin. Cell 123: 49–63.

    Article  CAS  Google Scholar 

  • Tidow H, Veprintsev DB, Freund SM, Fersht AR . (2006). Effects of oncogenic mutations and DNA response elements on the binding of p53 to p53-binding protein 2 (53BP2). J Biol Chem 281: 32526–32533.

    Article  CAS  Google Scholar 

  • Tomita Y, Marchenko N, Erster S, Nemajerova A, Dehner A, Klein C et al. (2006). WT p53, but not tumor-derived mutants, bind to Bcl2 via the DNA binding domain and induce mitochondrial permeabilization. J Biol Chem 281: 8600–8606.

    Article  CAS  Google Scholar 

  • Tornaletti S, Pfeifer GP . (1995). Complete and tissue-independent methylation of CpG sites in the p53 gene: implications for mutations in human cancers. Oncogene 10: 1493–1499.

    CAS  PubMed  Google Scholar 

  • Tyner SD, Venkatachalam S, Choi J, Jones S, Ghebranious N, Igelmann H et al. (2002). p53 mutant mice that display early ageing-associated phenotypes. Nature 415: 45–53.

    Article  CAS  Google Scholar 

  • Vogelstein B, Kinzler KW . (2004). Cancer genes and the pathways they control. Nat Med 10: 789–799.

    Article  CAS  Google Scholar 

  • Wong KB, DeDecker BS, Freund SMV, Proctor MR, Bycroft M, Fersht AR . (1999). Hot-spot mutants of p53 core domain evince characteristic local structural changes. Proc Nat Acad Sci USA 96: 8438–8442.

    Article  CAS  Google Scholar 

  • Yang A, Kaghad M, Caput D, McKeon F . (2002). On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet 18: 90–95.

    Article  Google Scholar 

  • You YH, Li C, Pfeifer GP . (1999). Involvement of 5-methylcytosine in sunlight-induced mutagenesis. J Mol Biol 293: 493–503.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The author is grateful to the Dpt of Oncology Pathology at CCK for its hospitality and to G Klein, G Salivanova and K Wiman for continuous enlightening discussions.

Author information

Authors and Affiliations

  1. Department of Life Sciences, Université Pierre et Marie Curie-Paris, Paris, France

    T Soussi

  2. Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institute, Stockholm, Sweden

    T Soussi

Authors
  1. T Soussi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Soussi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Soussi, T. p53 alterations in human cancer: more questions than answers. Oncogene 26, 2145–2156 (2007). https://doi.org/10.1038/sj.onc.1210280

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210280

Keywords

This article is cited by

Search

Advanced search

Quick links