Regulation of the p53 Tumor Suppressor Protein

Abstract

c-Jun N-terminal kinase Mutations in the p53 tumor suppressor gene occur in about 50% of all human tumors, making it the most frequent target for genetic alterations in cancer (for recent reviews on p53 see Refs. 1Hansen R. Oren M. Curr. Opin. Genet. Dev. 1997; 7: 46-51Crossref PubMed Scopus (206) Google Scholar, 2Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6697) Google Scholar, 3Agarwal M.L. Taylor W.R. Chernov M.V. Chernova O.B. Stark G.R. J. Biol. Chem. 1998; 273: 1-4Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 4Almog N. Rotter V. Biochim. Biophys. Acta. 1998; 1378: R43-R54PubMed Google Scholar, 5Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1225) Google Scholar). Such mutations probably facilitate carcinogenesis primarily through abrogating the tumor suppressor activities of the wild type p53 protein, although at least some forms of tumor-associated mutant p53 proteins may also contribute overt oncogenic activities (gain of function). Excessive wild type p53 activity gives rise to a variety of cellular outcomes, most notably cell cycle arrest and apoptosis. These cellular effects of wild type p53 can reduce cancer incidence through elimination of cancer-prone cells from the replicative pool. However, such effects might become very undesirable if occurring in a normal, unperturbed cell. p53 activity must therefore be kept under tight control, being unleashed only when a cell accumulates lesions that may otherwise drive it into a cancerous state. The signals and mechanisms that regulate p53 activity, maintaining it at low levels under normal conditions and turning it on in cancer-prone cells, are the subject of this review.p53-activating SignalsUnder normal conditions, p53 is most probably latent. Consequently, it does not interfere with cell cycle progression and cell survival. Moreover, p53 knock-out mice appear in most cases to undergo proper development and maturation (6Donehower L.A. Harvey M. Slagle B.L. Mcarthur M.J. Montgomery C.A. Butel J.S. Bradley A. Nature. 1992; 356: 215-221Crossref PubMed Scopus (4009) Google Scholar), suggesting that p53 is not essential for the normal performance of cells within the body. However, a variety of conditions can lead to rapid induction of p53 activity (Fig. 1). The common denominator of these conditions is that they represent various types of stress, which are likely to favor the emergence of cancer-bound cells. Such conditions include direct DNA damage (7Kastan M.B. Onyekwere O. Sidransky D. Vogelstein B. Craig R.W. Cancer Res. 1991; 51: 6304-6311PubMed Google Scholar, 8Maltzman W. Czyzyk L. Cell. Biol. PubMed Scopus Google Scholar, A. PubMed Scopus Google damage to in the proper and of the cellular genetic the C.A. C.A. PubMed Scopus Google L.A. A. Dev. PubMed Scopus Google Scholar), C. A.J. Nature. PubMed Scopus Google Scholar), A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), and to A. PubMed Scopus Google Scholar). of is a the rapid induction of p53 activity in to damage to that cells such damage are p53 may also to DNA M.L. A.J. Google Scholar, R. D. Rotter V. 1999; PubMed Scopus Google Scholar). The of p53 in maintaining it the of the Nature. 1992; PubMed Scopus Google Scholar). p53 activity is a variety of oncogenic and D. PubMed Scopus Google Scholar, M. D. Cell. 1997; 88: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Dev. 7: PubMed Scopus Google Scholar, A. A. M. J. B. Oren M. J. 1999; PubMed Scopus Google Scholar), a direct oncogenic and the tumor suppressor of p53 of p53 induction of the p53 through alterations in the p53 in the of of the p53 gene a if in such Consequently, the of the p53 gene very recent not that the of is it that p53 levels rise A.J. Nature. PubMed Scopus Google Scholar). rise may be of the of for in the p53 D. Oren M. M. J. Google to the of the p53 gene to the and to be D. B. J. Rotter V. Google Scholar). The induction of and may at However, it does DNA and are at of DNA damage and rise to cancer-prone cells. of p53 levels under such conditions the cells in a of is DNA damage stress, p53 and does not interfere with normal cellular However, if conditions that for a p53 the of levels of p53 that such a be rapid and of p53 of cells to signals can lead within a to a in p53 some this can be of the p53 probably of a through the of this J. PubMed Scopus Google Scholar). also that p53 can p53 through to J. C. W. J. PubMed Scopus Google Scholar, C.A. Cell. Biol. 1997; PubMed Scopus Google Scholar). it is that the of p53 in to through is the in the of p53 is a very protein, turning with a a A. M. C.A. Oren M. Cell. Biol. PubMed Scopus Google Scholar). to DNA damage and types of stress, p53 is (7Kastan M.B. Onyekwere O. Sidransky D. Vogelstein B. Craig R.W. Cancer Res. 1991; 51: 6304-6311PubMed Google Scholar, 8Maltzman W. Czyzyk L. Cell. Biol. PubMed Scopus Google Scholar). rapid in p53 a for is in cells with is mos