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.

The first 30 years of p53: growing ever more complex

Nature Reviews Cancer volume 9, pages 749–758 (2009)Cite this article

Abstract

Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Simplified scheme of the p53 pathway.

References

  1. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).

    Article  CAS  PubMed  Google Scholar 

  3. 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 

  4. 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 

  5. 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 

  6. Melero, J. A., Stitt, D. T., Mangel, W. F. & Carroll, R. B. Identification of new polypeptide species (48–55K) immunoprecipitable by antiserum to purified large T antigen and present in SV40-infected and -transformed cells. Virology 93, 466–480 (1979).

    Article  CAS  PubMed  Google Scholar 

  7. Smith, A. E., Smith, R. & Paucha, E. Characterization of different tumor antigens present in cells transformed by simian virus 40. Cell 18, 335–346 (1979).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. Rotter, V., Witte, O. N., Coffman, R. & Baltimore, D. Abelson murine leukemia virus-induced tumors elicit antibodies against a host cell protein, P50. J. Virol. 36, 547–555 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Linzer, D. I., Maltzman, W. & Levine, A. J. The SV40 A gene product is required for the production of a 54,000 MW cellular tumor antigen. Virology 98, 308–318 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Rotter, V. p53, a transformation-related cellular-encoded protein, can be used as a biochemical marker for the detection of primary mouse tumor cells. Proc. Natl Acad. Sci. USA 80, 2613–2617 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chumakov, P. M., Iotsova, V. S. & Georgiev, G. P. [Isolation of a plasmid clone containing the mRNA sequence for mouse nonviral T-antigen]. Dokl. Akad. Nauk SSSR 267, 1272–1275 (1982).

    CAS  PubMed  Google Scholar 

  14. Oren, M. & Levine, A. J. Molecular cloning of a cDNA specific for the murine p53 cellular tumor antigen. Proc. Natl Acad. Sci. USA 80, 56–59 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Matlashewski, G. et al. Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene. EMBO J. 3, 3257–3262 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Harlow, E., Williamson, N. M., Ralston, R., Helfman, D. M. & Adams, T. E. Molecular cloning and in vitro expression of a cDNA clone for human cellular tumor antigen p53. Mol. Cell. Biol. 5, 1601–1610 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pennica, D. et al. The amino acid sequence of murine p53 determined from a c-DNA clone. Virology 134, 477–482 (1984).

    Article  CAS  PubMed  Google Scholar 

  18. Leppard, K. et al. Purification and partial amino acid sequence analysis of the cellular tumour antigen, p53, from mouse SV40-transformed cells. EMBO J. 2, 1993–1999 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zakut-Houri, R., Bienz-Tadmor, B., Givol, D. & Oren, M. Human p53 cellular tumor antigen: cDNA sequence and expression in COS cells. EMBO J. 4, 1251–1255 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wolf, D., Harris, N., Goldfinger, N. & Rotter, V. Isolation of a full-length mouse cDNA clone coding for an immunologically distinct p53 molecule. Mol. Cell. Biol. 5, 127–132 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  PubMed  Google Scholar 

  22. Jenkins, J. R., Rudge, K. & Currie, G. A. Cellular immortalization by a cDNA clone encoding the transformation-associated phosphoprotein p53. Nature 312, 651–654 (1984).

    Article  CAS  PubMed  Google Scholar 

  23. Parada, L. F., Land, H., Weinberg, R. A., Wolf, D. & Rotter, V. Cooperation between gene encoding p53 tumour antigen and ras in cellular transformation. Nature 312, 649–651 (1984).

    Article  CAS  PubMed  Google Scholar 

  24. Eliyahu, D., Michalovitz, D. & Oren, M. Overproduction of p53 antigen makes established cells highly tumorigenic. Nature 316, 158–160 (1985).

    Article  CAS  PubMed  Google Scholar 

  25. Wolf, D., Harris, N. & Rotter, V. Reconstitution of p53 expression in a nonproducer Ab-MuLV-transformed cell line by transfection of a functional p53 gene. Cell 38, 119–126 (1984).

    Article  CAS  PubMed  Google Scholar 

  26. Wolf, D. & Rotter, V. Inactivation of p53 gene expression by an insertion of Moloney murine leukemia virus-like DNA sequences. Mol. Cell. Biol. 4, 1402–1410 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ben David, Y., Prideaux, V. R., Chow, V., Benchimol, S. & Bernstein, A. Inactivation of the p53 oncogene by internal deletion or retroviral integration in erythroleukemic cell lines induced by Friend leukemia virus. Oncogene 3, 179–185 (1988).

    CAS  PubMed  Google Scholar 

  28. Mowat, M., Cheng, A., Kimura, N., Bernstein, A. & Benchimol, S. Rearrangements of the cellular p53 gene in erythroleukaemic cells transformed by Friend virus. Nature 314, 633–636 (1985).

    Article  CAS  PubMed  Google Scholar 

  29. Wolf, D. & Rotter, V. Major deletions in the gene encoding the p53 tumor antigen cause lack of p53 expression in HL-60 cells. Proc. Natl Acad. Sci. USA 82, 790–794 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eliyahu, D. et al. Meth A fibrosarcoma cells express two transforming mutant p53 species. Oncogene 3, 313–321 (1988).

    CAS  PubMed  Google Scholar 

  31. Finlay, C. A. et al. Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life. Mol. Cell. Biol. 8, 531–539 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Halevy, O., Rodel, J., Peled, A. & Oren, M. Frequent p53 mutations in chemically induced murine fibrosarcoma. Oncogene 6, 1593–1600 (1991).

    CAS  PubMed  Google Scholar 

  33. Baker, S. J. et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244, 217–221 (1989).

    Article  CAS  PubMed  Google Scholar 

  34. Eliyahu, D., Michalovitz, D., Eliyahu, S., Pinhasi-Kimhi, O. & Oren, M. Wild-type p53 can inhibit oncogene-mediated focus formation. Proc. Natl Acad. Sci. USA 86, 8763–8767 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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 

  37. Brosh, R. & Rotter, V. When mutants gain new powers: news from the mutant p53 field. Nature Rev. Cancer 20 Aug 2009 (doi:10.1038/nrc2693).

  38. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Srivastava, S., Zou, Z. Q., Pirollo, K., Blattner, W. & Chang, E. H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature 348, 747–749 (1990).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Donehower, L. A. & Lozano, G. 20 years studying p53 functions in genetically engineered mice. Nature Rev. Cancer (in the press).

  42. DeCaprio, J. A. et al. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell 54, 275–283 (1988).

    Article  CAS  PubMed  Google Scholar 

  43. Shirodkar, S. et al. The transcription factor E2F interacts with the retinoblastoma product and a p107-cyclin A complex in a cell cycle-regulated manner. Cell 68, 157–166 (1992).

    Article  CAS  PubMed  Google Scholar 

  44. Weinberg, R. A. The retinoblastoma protein and cell cycle control. Cell 81, 323–330 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Whyte, P. et al. Association between an oncogene and an anti-oncogene: the adenovirus E1A proteins bind to the retinoblastoma gene product. Nature 334, 124–129 (1988).

    Article  CAS  PubMed  Google Scholar 

  46. Levine, R. L. & Carroll, M. A common genetic mechanism in malignant bone marrow diseases. N. Engl. J. Med. 360, 2355–2357 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  48. Michalovitz, D., Halevy, O. & Oren, M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell 62, 671–680 (1990).

    Article  CAS  PubMed  Google Scholar 

  49. Mercer, W. E. et al. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc. Natl Acad. Sci. USA 87, 6166–6170 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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).

    Article  CAS  PubMed  Google Scholar 

  51. Diller, L. et al. p53 functions as a cell cycle control protein in osteosarcomas. Mol. Cell. Biol. 10, 5772–5781 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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).

    Article  CAS  PubMed  Google Scholar 

  53. Shaw, P. et al. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc. Natl Acad. Sci. USA 89, 4495–4499 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wang, Y., Blandino, G., Oren, M. & Givol, D. Induced p53 expression in lung cancer cell line promotes cell senescence and differentially modifies the cytotoxicity of anti-cancer drugs. Oncogene 17, 1923–1930 (1998).

    Article  CAS  PubMed  Google Scholar 

  55. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Fields, S. & Jang, S. K. Presence of a potent transcription activating sequence in the p53 protein. Science 249, 1046–1049 (1990).

    Article  CAS  PubMed  Google Scholar 

  59. Raycroft, L., Wu, H. Y. & Lozano, G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 249, 1049–1051 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Zhu, J., Zhou, W., Jiang, J. & Chen, X. Identification of a novel p53 functional domain that is necessary for mediating apoptosis. J. Biol. Chem. 273, 13030–13036 (1998).

    Article  CAS  PubMed  Google Scholar 

  61. Bargonetti, J., Friedman, P. N., Kern, S. E., Vogelstein, B. & Prives, C. Wild-type but not mutant p53 immunopurified proteins bind to sequences adjacent to the SV40 origin of replication. Cell 65, 1083–1091 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Kern, S. E. et al. Identification of p53 as a sequence-specific DNA-binding protein. Science 252, 1708–1711 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. el-Deiry, W. S., Kern, S. E., Pietenpol, J. A., Kinzler, K. W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992).

    Article  CAS  PubMed  Google Scholar 

  64. Funk, W. D., Pak, D. T., Karas, R. H., Wright, W. E. & Shay, J. W. A transcriptionally active DNA-binding site for human p53 protein complexes. Mol. Cell. Biol. 12, 2866–2871 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Zauberman, A., Barak, Y., Ragimov, N., Levy, N. & Oren, M. Sequence-specific DNA binding by p53: identification of target sites and lack of binding to p53–MDM2 complexes. EMBO J. 12, 2799–2808 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Farmer, G. et al. Wild-type p53 activates transcription in vitro. Nature 358, 83–86 (1992).

    Article  CAS  PubMed  Google Scholar 

  67. Pietenpol, J. A. et al. Sequence-specific transcriptional activation is essential for growth suppression by p53. Proc. Natl Acad. Sci. USA 91, 1998–2002 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Scharer, E. & Iggo, R. Mammalian p53 can function as a transcription factor in yeast. Nucleic Acids Res. 20, 1539–1545 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chen, X., Farmer, G., Zhu, H., Prywes, R. & Prives, C. Cooperative DNA binding of p53 with TFIID (TBP): a possible mechanism for transcriptional activation. Genes Dev. 7, 1837–1849 (1993).

    Article  CAS  PubMed  Google Scholar 

  70. Menendez, D., Inga, A. & Resnick, M. A. The expanding universe of p53 targets. Nature Rev. Cancer (in the press).

  71. el-Deiry, W. S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).

    Article  CAS  PubMed  Google Scholar 

  72. Miyashita, T. & Reed, J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Zhao, R. et al. Analysis of p53-regulated gene expression patterns using oligonucleotide arrays. Genes Dev. 14, 981–993 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hermeking, H. p53 enters the microRNA world. Cancer Cell 12, 414–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Raver-Shapira, N. & Oren, M. Tiny actors, great roles: microRNAs in p53's service. Cell Cycle 6, 2656–2661 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. He, X., He, L. & Hannon, G. J. The guardian's little helper: microRNAs in the p53 tumor suppressor network. Cancer Res. 67, 11099–11101 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Brosh, R. et al. p53-repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation. Mol. Syst. Biol. 4, 229 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Ginsberg, D., Mechta, F., Yaniv, M. & Oren, M. Wild-type p53 can down-modulate the activity of various promoters. Proc. Natl Acad. Sci. USA 88, 9979–9983 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vaseva, A. V. & Moll, U. M. The mitochondrial p53 pathway. Biochim. Biophys. Acta 1787, 414–420 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. Green, D. R. & Kroemer, G. Cytoplasmic functions of the tumour suppressor p53. Nature 458, 1127–1130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Iwabuchi, K., Bartel, P. L., Li, B., Marraccino, R. & Fields, S. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Natl Acad. Sci. USA 91, 6098–6102 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Momand, J., Zambetti, G. P., Olson, D. C., George, D. & Levine, A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69, 1237–1245 (1992).

    Article  CAS  PubMed  Google Scholar 

  83. Oliner, J. D. et al. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature 362, 857–860 (1993).

    Article  CAS  PubMed  Google Scholar 

  84. Haupt, Y., Maya, R., Kazaz, A. & Oren, M. Mdm2 promotes the rapid degradation of p53. Nature 387, 296–299 (1997).

    Article  CAS  PubMed  Google Scholar 

  85. Honda, R., Tanaka, H. & Yasuda, H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420, 25–27 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. Kubbutat, M. H., Jones, S. N. & Vousden, K. H. Regulation of p53 stability by Mdm2. Nature 387, 299–303 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Barak, Y., Juven, T., Haffner, R. & Oren, M. mdm2 expression is induced by wild type p53 activity. EMBO J. 12, 461–468 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wu, X., Bayle, J. H., Olson, D. & Levine, A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 7, 1126–1132 (1993).

    Article  CAS  PubMed  Google Scholar 

  89. Picksley, S. M. & Lane, D. P. The p53-mdm2 autoregulatory feedback loop: a paradigm for the regulation of growth control by p53? Bioessays 15, 689–690 (1993).

    Article  CAS  PubMed  Google Scholar 

  90. Michael, D. & Oren, M. The p53–Mdm2 module and the ubiquitin system. Semin. Cancer Biol. 13, 49–58 (2003).

    Article  CAS  PubMed  Google Scholar 

  91. Maltzman, W. & Czyzyk, L. UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells. Mol. Cell. Biol. 4, 1689–1694 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kastan, M. B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304–6311 (1991).

    CAS  PubMed  Google Scholar 

  93. Kastan, M. B. et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell 71, 587–597 (1992).

    Article  CAS  PubMed  Google Scholar 

  94. Lane, D. P. p53, guardian of the genome. Nature 358, 15–16 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Kamijo, T. et al. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc. Natl Acad. Sci. USA 95, 8292–8297 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Shvarts, A. et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. EMBO J. 15, 5349–5357 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kostic, M., Matt, T., Martinez-Yamout, M. A., Dyson, H. J. & Wright, P. E. Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53. J. Mol. Biol. 363, 433–450 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Linares, L. K., Hengstermann, A., Ciechanover, A., Muller, S. & Scheffner, M. HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53. Proc. Natl Acad. Sci. USA 100, 12009–12014 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 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 

  100. 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 

  101. 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 

  102. Wade, M. & Wahl, G. M. Targeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry? Mol. Cancer Res. 7, 1–11 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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).

    Article  CAS  PubMed  Google Scholar 

  104. Whibley, C., Pharoah, P. D. & Hollstein, M. p53 polymorphisms: cancer implications. Nature Rev. Cancer 9, 95–107 (2009).

    Article  CAS  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. Lahav, G. et al. Dynamics of the p53-Mdm2 feedback loop in individual cells. Nature Genet. 36, 147–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Roth, J. A. et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nature Med. 2, 985–991 (1996).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  109. Senzer, N. & Nemunaitis, J. A review of contusugene ladenovec (Advexin) p53 therapy. Curr. Opin. Mol. Ther. 11, 54–61 (2009).

    CAS  PubMed  Google Scholar 

  110. Heise, C. et al. ONYX-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Med. 3, 639–45 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Kirn, D., Hermiston, T. & McCormick, F. ONYX-015: clinical data are encouraging. Nature Med. 4, 1341–1342 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Alemany, R. Cancer selective adenoviruses. Mol. Aspects Med. 28, 42–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Yu, W. & Fang, H. Clinical trials with oncolytic adenovirus in China. Curr. Cancer Drug Targets. 7, 141–148 (2007).

    Article  PubMed  Google Scholar 

  114. Zhang, H. et al. Enhanced therapeutic efficacy by simultaneously targeting two genetic defects in tumors. Mol. Ther. 17, 57–64 (2009).

    Article  PubMed  CAS  Google Scholar 

  115. Bykov, V. J. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nature Med. 8, 282–288 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Boeckler, F. M. et al. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl Acad. Sci. USA 105, 10360–10365 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  119. Issaeva, N. et al. Small molecule RITA binds to p53, blocks p53–HDM-2 interaction and activates p53 function in tumors. Nature Med. 10, 1321–1328 (2004).

    Article  CAS  PubMed  Google Scholar 

  120. Grinkevich, V. V. et al. Ablation of key oncogenic pathways by RITA-reactivated p53 is required for efficient apoptosis. Cancer Cell 15, 441–453 (2009).

    Article  CAS  PubMed  Google Scholar 

  121. Yang, Y. et al. Small molecule inhibitors of HDM2 ubiquitin ligase activity stabilize and activate p53 in cells. Cancer Cell 7, 547–559 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Aas, T. et al. Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nature Med. 2, 811–814 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. O'Shea, D. et al. The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival. Blood 112, 3126–3129 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Young, K. H. et al. Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study. Blood 112, 3088–3098 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Tomasini, R. et al. TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes Dev. 22, 2677–2691 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Han, H. S. et al. The estrogen receptor α pathway induces oncogenic Wip1 phosphatase gene expression. Mol. Cancer Res. 7, 713–723 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Lu, X. et al. The Wip1 phosphatase acts as a gatekeeper in the p53-Mdm2 autoregulatory loop. Cancer Cell 12, 342–354 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Shreeram, S. et al. Wip1 phosphatase modulates ATM-dependent signaling pathways. Mol. Cell 23, 757–764 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. 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 

  130. Kang, H. J. et al. Single-nucleotide polymorphisms in the p53 pathway regulate fertility in humans. Proc. Natl Acad. Sci. USA 106, 9761–9766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Vousden, K. H. & Ryan, K. M. p53 and metabolism. Nature Rev. Cancer (in the press).

  132. Stiewe, T. The p53 family in differentiation and tumorigenesis. Nature Rev. Cancer 7, 165–168 (2007).

    Article  CAS  Google Scholar 

  133. Celli, J. et al. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 99, 143–153 (1999).

    Article  CAS  PubMed  Google Scholar 

  134. Yang, A. et al. p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398, 714–718 (1999).

    Article  CAS  PubMed  Google Scholar 

  135. Yang, A. et al. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404, 99–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  136. Finlan, L. E. & Hupp, T. R. p63: the phantom of the tumor suppressor. Cell Cycle 6, 1062–1071 (2007).

    Article  CAS  PubMed  Google Scholar 

  137. Rosenbluth, J. M. & Pietenpol, J. A. The jury is in: p73 is a tumor suppressor after all. Genes Dev. 22, 2591–2595 (2008).

    Article  CAS  PubMed  Google Scholar 

  138. Bourdon, J. C. p53 family isoforms. Curr. Pharm. Biotechnol. 8, 332–336 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Livingstone, L. R. et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).

    Article  CAS  PubMed  Google Scholar 

  140. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & Wahl, G. M. Wild-type p53 restores cell cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).

    Article  CAS  PubMed  Google Scholar 

  141. Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).

    Article  CAS  PubMed  Google Scholar 

  142. 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).

    Article  CAS  PubMed  Google Scholar 

  143. Schmale, H. & Bamberger, C. A novel protein with strong homology to the tumor suppressor p53. Oncogene 15, 1363–1367 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  145. Kamijo, T. et al. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19 ARF. Cell 91, 649–59 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Banin, S. et al. Enhanced phosphorylation of p53 by ATM in response to DNA damage. Science 281, 1674–1677 (1998).

    Article  CAS  PubMed  Google Scholar 

  147. Canman, C. E. et al. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Science 281, 1677–1679 (1998).

    Article  CAS  PubMed  Google Scholar 

  148. Brodsky, M. H. et al. Drosophila p53 binds a damage response element at the reaper locus. Cell 101, 103–113 (2000).

    Article  CAS  PubMed  Google Scholar 

  149. Ollmann, M. et al. Drosophila p53 is a structural and functional homolog of the tumor suppressor p53. Cell 101, 91–101 (2000).

    Article  CAS  PubMed  Google Scholar 

  150. Derry, W. B., Putzke, A. P. & Rothman, J. H. Caenorhabditis elegans p53: role in apoptosis, meiosis, and stress resistance. Science 294, 591–595 (2001).

    Article  CAS  PubMed  Google Scholar 

  151. Schumacher, B., Hofmann, K., Boulton, S. & Gartner, A. The C. elegans homolog of the p53 tumor suppressor is required for DNA damage-induced apoptosis. Curr. Biol. 11, 1722–1727 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  PubMed  Google Scholar 

  153. 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 

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

    Article  CAS  PubMed  Google Scholar 

  155. Bourdon, J. C. et al. p53 isoforms can regulate p53 transcriptional activity. Genes Dev. 19, 2122–2137 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Sablina, A. A. et al. The antioxidant function of the p53 tumor suppressor. Nature Med. 11, 1306–1313 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. Feng, Z., Zhang, H., Levine, A. J. & Jin, S. The coordinate regulation of the p53 and mTOR pathways in cells. Proc. Natl Acad. Sci. USA 102, 8204–8209 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. 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 

  159. 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 

  160. Bommer, G. T. et al. p53-mediated activation of miRNA34 candidate tumor-suppressor genes. Curr. Biol. 17, 1298–1307 (2007).

    Article  CAS  PubMed  Google Scholar 

  161. Chang, T. C. et al. Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. Mol. Cell 26, 745–752 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature 447, 1130–1134 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Raver-Shapira, N. et al. Transcriptional activation of miR-34a contributes to p53-mediated apoptosis. Mol. Cell 26, 731–743 (2007).

    Article  CAS  PubMed  Google Scholar 

  164. Tarasov, V. et al. Differential regulation of microRNAs by p53 revealed by massively parallel sequencing: miR-34a is a p53 target that induces apoptosis and G1-arrest. Cell Cycle 6, 1586–1593 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Tazawa, H., Tsuchiya, N., Izumiya, M. & Nakagama, H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc. Natl Acad. Sci. USA 104, 15472–15477 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. 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).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank the thousands of researchers whose outstanding work over the past 30 years has made p53 research so exciting. We apologize to all our colleagues whose important contributions could not be cited owing to lack of space. Work in the authors' laboratories is supported by grant R37 CA40099 from the National Cancer Institute, USA, a Center of Excellence grant from the Flight Attendant Medical Research Institute, USA, grants from the European Commission (Mutp53, FP6 Contract 502983 and OncomiRs, FP7 Contract 201102) and the Robert Bosch Foundation, Germany, (to M.O.), grant PO1 CA 87497 from the US National Institutes of Health, grant W81XWH-06-1-0514 from the Department of Defense, USA, grants from the Breast Cancer Research Foundation, USA,(to A.J.L.) and general support from the Simons Center for Systems Biology at the Institute for Advanced Study from the Simons Foundation, USA.

Author information

Authors and Affiliations

  1. Arnold J. Levine is at the Institute for Advanced Study, School of Natural Sciences, Einstein Drive, Princeton, New Jersey 08540, USA.,

    Arnold J. Levine

  2. Moshe Oren is at the Weizmann Institute of Science, Molecular Cell Biology, 300 Herzl Street, Rehovot 76100, Israel. alevine@ias.edu; moshe.oren@weizmann.ac.il,

    Moshe Oren

Authors
  1. Arnold J. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Moshe Oren
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Pathway Interaction Database 

p53

FURTHER INFORMATION

Moshe Oren's homepage

Arnold J. Levine's homepage

International Agency for Cancer Research TP53 Mutation Database

p53 Knowledgebase

The TP53 Website

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Levine, A., Oren, M. The first 30 years of p53: growing ever more complex. Nat Rev Cancer 9, 749–758 (2009). https://doi.org/10.1038/nrc2723

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2723

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing