Regulation of the p53 Tumor Suppressor Protein (1999)

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. Mol. Cell. Biol. 1984; 4: 1689-1694Crossref PubMed Scopus (813) Google Scholar, 9Huang L.C. Clarkin K.C. Wahl G.M. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4827-4832Crossref PubMed Scopus (321) Google Scholar) as well as damage to components involved in the proper handling and segregation of the cellular genetic material (e.g. the mitotic spindle (10Cross S.M. Sanchez C.A. Morgan C.A. Schimke M.K. Ramel S. Idzerda R.L. Raskind W.H. Reid B.J. Science. 1995; 267: 1353-1356Crossref PubMed Scopus (675) Google Scholar)), ribonucleotide depletion (11Linke S.P. Clarkin K.C. Di L.A. Tsou A. Wahl G.M. Genes Dev. 1996; 10: 934-947Crossref PubMed Scopus (479) Google Scholar), hypoxia (12Graeber T.G. Osmanian C. Jacks T. Housman D.E. Koch C.J. Lowe S.W. Giaccia A.J. Nature. 1996; 379: 88-91Crossref PubMed Scopus (2160) Google Scholar), heat shock (13Ohnishi T. Wang X.J. Ohnishi K. Matsumoto H. Takahashi A. J. Biol. Chem. 1996; 271: 14510-14513Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar), and exposure to nitric oxide (NO) (14Forrester K. Ambs S. Lupold S.E. Kapust R.B. Spillare E.A. Weinberg W.C. Felleybosco E. Wang X.W. Geller D.A. Tzeng E. Billiar T.R. Harris C.C. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 2442-2447Crossref PubMed Scopus (388) Google Scholar). Accumulation of genomic aberrations is a key carcinogenic mechanism; the rapid induction of p53 activity in response to genomic damage thus serves to ensure that cells carrying such damage are effectively taken care of. Furthermore, p53 may also contribute, directly or indirectly, to particular DNA repair processes (15Smith M.L. Chen I.T. Zhan Q.M. Oconnor P.M. Fornace A.J. Oncogene. 1995; 10: 1053-1059PubMed Google Scholar, 16Offer H. Wolkowicz R. Matas D. Blumenstein S. Livneh Z. Rotter V. FEBS Lett. 1999; 450: 197-204Crossref PubMed Scopus (124) Google Scholar). The pivotal role of p53 in maintaining genomic integrity has earned it the nickname "guardian of the genome" (17Lane D.P. Nature. 1992; 358: 15-16Crossref PubMed Scopus (4436) Google Scholar). In addition, p53 activity is triggered by a variety of oncogenic proteins, including Myc, Ras, adenovirus E1A, and β-catenin (18Hermeking H. Eick D. Science. 1994; 265: 2091-2093Crossref PubMed Scopus (699) Google Scholar, 19Serrano M. Lin A.W. McCurrach M.E. Beach D. Lowe S.W. Cell. 1997; 88: 593-602Abstract Full Text Full Text PDF PubMed Scopus (3887) Google Scholar, 20Debbas M. White E. Gene Dev. 1993; 7: 546-554Crossref PubMed Scopus (831) Google Scholar, 21Damalas A. Ben-Ze'ev A. Simcha I. Shtutman M. Leal J.F. Zhurinsky J. Geiger B. Oren M. EMBO J. 1999; 18: 3054-3063Crossref PubMed Scopus (208) Google Scholar), providing a direct link between oncogenic processes and the tumor suppressor action of p53 (see below).Regulation of p53 Gene ExpressionAs described later, induction of the p53 response upon stress occurs largely through alterations in the p53 protein. Changes in the rate of transcription of the p53 gene play a minor role, if any, in such induction. Consequently, the transcriptional regulation of the p53 gene has received very little attention during recent years. This need not imply that the regulation of p53gene expression is totally irrelevant. In fact, it was observed long ago that p53 mRNA levels rise substantially upon serum stimulation (22Reich N.C. Levine A.J. Nature. 1984; 308: 199-201Crossref PubMed Scopus (376) Google Scholar). This rise may be because of the presence of binding sites for serum-induced factors in the p53 promoter (23Ginsberg D. Oren M. Yaniv M. Piette J. Oncogene. 1990; 5: 1285-1290PubMed Google Scholar) as well as to the ability of the p53 gene to bind the c-Myc protein and to be transcriptionally stimulated by excess c-Myc (24Reisman D. Elkind N.B. Roy B. Beamon J. Rotter V. Cell Growth Differ. 1993; 4: 57-65PubMed Google Scholar). The induction of an anti-proliferative gene, p53, by serum and growth factors may at first glance seem paradoxical. However, it does make good sense. Cells undergoing DNA replication and extensive proliferation are at higher risk of acquiring DNA damage and giving rise to multiple cancer-prone progeny than quiescent cells. Induction of higher p53 mRNA levels under such conditions places the cells in a state of anticipation; as long as there is no DNA damage or other stress, p53 remains latent and does not interfere with normal cellular transactions. However, if conditions emerge that call for a p53 response, the presence of higher levels of p53 mRNA ensures that such a response will be rapid and effective.Activation of p53 by Post-transcriptional MechanismsExposure of cells to p53-activating signals can lead within a relatively short time to a marked elevation in p53 protein. To some extent, this can be achieved by increased translation of the p53 mRNA, probably involving relief of a translational repression mechanism operating through the 3′-untranslated region of this mRNA (25Fu L.N. Minden M.D. Benchimol S. EMBO J. 1996; 15: 4392-4401Crossref PubMed Scopus (131) Google Scholar). There also exists evidence that p53 itself can inhibit p53 synthesis through binding to its own mRNA (26Mosner J. Mummenbrauer T. Bauer C. Sczakiel G. Grosse F. Deppert W. EMBO J. 1995; 14: 4442-4449Crossref PubMed Scopus (266) Google Scholar, 27Fontoura B.M.A. Atienza C.A. Sorokina E.A. Morimoto T. Carroll R.B. Mol. Cell. Biol. 1997; 17: 3146-3154Crossref PubMed Scopus (59) Google Scholar). Yet, it is generally accepted that the accumulation of active p53 in response to stress occurs mainly through post-translational mechanisms. Pivotal is the increase in the protein half-life of p53. p53 is usually a very labile protein, turning over with a half-life sometimes as short as a few minutes (28Rogel A. Popliker M. Webb C.A. Oren M. Mol. Cell. Biol. 1985; 5: 2851-2855Crossref PubMed Scopus (329) Google Scholar). In response to DNA damage and other types of stress, p53 is markedly stabilized (7Kastan M.B. Onyekwere O. Sidransky D. Vogelstein B. Craig R.W. Cancer Res. 1991; 51: 6304-6311PubMed Google Scholar, 8Maltzman W. Czyzyk L. Mol. Cell. Biol. 1984; 4: 1689-1694Crossref PubMed Scopus (813) Google Scholar). A rapid increase in p53 concentration without a need for de novo transcription is particularly advantageous in cells with severely damaged genomes. In addition, there is most probably a qualitative conversion of p53 from latent to active form. The best documented change concerns the sequence-specific DNA binding activity of p53. p53 operates as a gene-specific transcriptional activator, which relies on its ability to bind defined sequence elements within target genes (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). The sequence-specific DNA binding activity of p53 is subject to constitutive negative regulation, primarily through its inhibitory C-terminal domain (29Hupp T.R. Meek D.W. Midgley C.A. Lane D.P. Cell. 1992; 71: 875-886Abstract Full Text PDF PubMed Scopus (859) Google Scholar, 30Bayle J.H. Elenbaas B. Levine A.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5729-5733Crossref PubMed Scopus (115) Google Scholar, 31Wolkowicz R. Peled A. Elkind N.B. Rotter V. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 6842-6846Crossref PubMed Scopus (35) Google Scholar). Relief of this inhibition upon exposure to stress results in increased DNA binding (32Hupp T.R. Lane D.P. J. Biol. Chem. 1995; 270: 18165-18174Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, 33Gu W. Roeder R.G. Cell. 1997; 90: 595-606Abstract Full Text Full Text PDF PubMed Scopus (2152) Google Scholar, 34Waterman M.J. Stavridi E.S. Waterman J.L. Halazonetis T.D. Nat. Genet. 1998; 19: 175-178Crossref PubMed Scopus (402) Google Scholar) and consequently increased biochemical and biological activity. The transcriptional activity of p53 may also be induced by changes in other regions,e.g. modifications within its N-terminal transactivation domain, enabling a more efficient recruitment of components of the transcription machinery (35Lambert P.F. Kashanchi F. Radonovich M.F. Shiekhattar R. Brady J.N. J. Biol. Chem. 1998; 273: 33048-33053Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar). Finally, p53 activation may also involve a change in subcellular localization; whereas latent p53 may often be cytoplasmic, at least during part of the cell cycle (36Shaulsky G. Ben-Zeev A. Rotter V. Oncogene. 1990; 5: 1707-1711PubMed Google Scholar), exposure to stress results in its accumulation in the nucleus, where it is expected to exert its biochemical activities.The p53-Mdm2 LoopA key player in the regulation of p53 is the Mdm2 protein. Mdm2 is the product of an oncogene, whose excess activity facilitates several types of human cancer (for reviews see Refs. 37Lozano G. Montes de Oca Luna R. Biochim. Biophys. Acta. 1998; 1377: M55-M59PubMed Google Scholar, 38Freedman D.A. Wu L. Levine A.J. Cell. Mol. Life Sci. 1999; 55: 96-107Crossref PubMed Scopus (480) Google Scholar, 39Juven-Gershon T. Oren M. Mol. Med. 1999; 5: 71-83Crossref PubMed Google Scholar). Mdm2 exhibits a unique relationship with p53. On the one hand, the Mdm2 protein binds to p53 and inactivates it (40Momand J. Zambetti G.P. Olson D.C. George D. Levine A.J. Cell. 1992; 69: 1237-1245Abstract Full Text PDF PubMed Scopus (2776) Google Scholar, 41Chen J.D. Wu X.W. Lin J.Y. Levine A.J. Mol. Cell. Biol. 1996; 16: 2445-2452Crossref PubMed Scopus (332) Google Scholar, 42Haupt Y. Barak Y. Oren M. EMBO J. 1996; 15: 1596-1606Crossref PubMed Scopus (204) Google Scholar). The binding occurs right within the p53 transactivation domain, interfering with recruitment of basal transcription machinery components (43Thut C.J. Chen J.L. Klemm R. Tjian R. Science. 1995; 267: 100-104Crossref PubMed Scopus (406) Google Scholar, 44Lu H. Levine A.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5154-5158Crossref PubMed Scopus (280) Google Scholar). Moreover, Mdm2 can actively repress transcription when tethered to p53 (45Thut C.J. Goodrich J.A. Tjian R. Gene Dev. 1997; 11: 1974-1986Crossref PubMed Scopus (230) Google Scholar). Importantly, Mdm2 binding can also lead to complete elimination of p53 through proteolytic degradation. On the other hand, p53 binds specifically to the mdm2 gene and stimulates its transcription (46Barak Y. Juven T. Haffner R. Oren M. EMBO J. 1993; 12: 461-468Crossref PubMed Scopus (1167) Google Scholar, 47Wu X.W. Bayle J.H. Olson D. Levine A.J. Genes Dev. 1993; 7: 1126-1132Crossref PubMed Scopus (1621) Google Scholar). This duality defines a negative feedback loop (Fig. 2), which probably serves to keep p53 in tight check and to terminate the p53 signal once the triggering stress has been effectively dealt with. In some situations, mdm2transcription is induced later than that of other p53 target genes (48Perry M.E. Piette J. Zawadzki J.A. Harvey D. Levine A.J. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 11623-11627Crossref PubMed Scopus (239) Google Scholar, 49Wu L. Levine A.J. Mol. Med. 1997; 3: 441-451Crossref PubMed Google Scholar); this may set a time window within which p53 is allowed to exert freely its biochemical and biological effects. The critical importance of the p53-Mdm2 loop is best illustrated by the analysis ofmdm2 knock-out mice. Inactivation of the mdm2gene results in early embryonal lethality, but this is completely prevented by simultaneous inactivation of p53 (50Jones S.N. Roe A.E. Donehower L.A. Bradley A. Nature. 1995; 378: 206-208Crossref PubMed Scopus (1057) Google Scholar, 51Montes de Oca Luna R. Wagner D.S. Lozano G. Nature. 1995; 378: 203-206Crossref PubMed Scopus (1196) Google Scholar). Conceivably, in the absence of functional Mdm2 protein, p53 becomes strongly deregulated to the extent that its excess activity leads to embryonic death. The other side of the coin is revealed in certain human cancers; excessive Mdm2 expression, achieved through mdm2 gene amplification (52Oliner J.D. Kinzler K.W. Meltzer P.S. George D.L. Vogelstein B. Nature. 1992; 358: 80-83Crossref PubMed Scopus (1790) Google Scholar) or other mechanisms (53Landers J.E. Haines D.S. Strauss J.F. George D.L. Oncogene. 1994; 9: 2745-2750PubMed Google Scholar), can lead to constitutive inhibition of p53 and thereby promote cancer without a need to alter the p53 gene itself. It should be kept in mind, however, that excess Mdm2 can also promote cancer independently of p53 (54Lundgren K. Montes de Oca Luna R. McNeill Y.B. Emerick E.P. Spencer B. Barfield C.R. Lozano G. Rosenberg M.P. Finlay C.A. Genes Dev. 1997; 11: 714-725Crossref PubMed Scopus (212) Google Scholar,55Sun P. Dong P. Dai K. Hannon G.J. Beach D. Science. 1998; 282: 2270-2272Crossref PubMed Scopus (184) Google Scholar).FIG. 2The p53-Mdm2 autoregulatory loop. The p53 protein binds to the mdm2 gene and activates its transcription. The resultant Mdm2 protein binds to p53 and blocks its activity.View Large Image Figure ViewerDownload (PPT)Regulation of p53 Protein DegradationMuch of the activation of p53 is achieved through p53 protein stabilization. This realization has markedly accelerated research on p53 degradation. It is now well established that the rapid demise of p53 is achieved largely through the ubiquitin-proteasome pathway (56Maki C.G. Huibregtse J.M. Howley P.M. Cancer Res. 1996; 56: 2649-2654PubMed Google Scholar), although a role for other proteolytic enzymes such as calpain has also been implied (57Kubbutat M.H.G. Vousden K.H. Mol. Cell. Biol. 1997; 17: 460-468Crossref PubMed Scopus (275) Google Scholar). Mdm2 plays a pivotal role here as well. Elevated Mdm2 levels result in rapid p53 degradation, which is dependent on the ability of the two proteins to engage in direct binding (58Haupt Y. Maya R. Kazaz A. Oren M. Nature. 1997; 387: 296-299Crossref PubMed Scopus (3658) Google Scholar, 59Kubbutat M.H.G. Jones S.N. Vousden K.H. Nature. 1997; 387: 299-303Crossref PubMed Scopus (2812) Google Scholar). Furthermore, interference with p53-Mdm2 binding by monoclonal antibodies or competitor peptides results in a dramatic stabilization and accumulation of p53 in non-stressed cells (60Bottger A. Bottger V. Sparks A. Liu W.L. Howard S.F. Lane D.P. Curr. Biol. 1997; 7: 860-869Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar). This strongly argues that the low basal levels of p53 in such cells are due primarily to continuous Mdm2-promoted degradation.How does Mdm2 promote p53 degradation? When the proteolytic activity of the proteasome is blocked by specific inhibitors, excess Mdm2 augments the accumulation of ubiquitinated forms of p53 (58Haupt Y. Maya R. Kazaz A. Oren M. Nature. 1997; 387: 296-299Crossref PubMed Scopus (3658) Google Scholar, 59Kubbutat M.H.G. Jones S.N. Vousden K.H. Nature. 1997; 387: 299-303Crossref PubMed Scopus (2812) Google Scholar), suggesting that Mdm2 facilitates p53 ubiquitination. Strong support for this conclusion was provided by showing that Mdm2 can directly functionin vitro as a p53-specific E3 ubiquitin-protein ligase, which covalently attaches ubiquitin groups to p53 (61Honda R. Tanaka H. Yasuda H. FEBS Lett. 1997; 420: 25-27Crossref PubMed Scopus (1587) Google Scholar, 62Honda R. Yasuda H. EMBO J. 1999; 18: 22-27Crossref PubMed Scopus (612) Google Scholar) (Fig. 3 A). It remains to be determined Mdm2 operates in or is part of a E3 of p53 degradation. The binding of Mdm2 to p53 the of p53 and its by the proteasome DNA damage modifications of p53 and particularly by within the binding can binding and thereby p53 from of Mdm2 within for its biochemical activity will also p53 degradation, if binding is the synthesis of which binds to Mdm2 and its action ubiquitin the and of Large Image Figure ViewerDownload Mdm2 as the key of p53 other mechanisms for p53 and also particular is the role of the c-Jun N-terminal kinase in in that the binding of to p53 results in and proteolytic of p53 V. T. Z. Wu Jones S.N. Z. Genes Dev. 1998; 12: PubMed Scopus (280) Google Scholar). The of between Mdm2 and is however, there are that it changes during the cell cycle V. T. Z. Wu Jones S.N. Z. Genes Dev. 1998; 12: PubMed Scopus (280) Google of post-translational activation of proteins is often achieved through particularly protein It was thus that the rapid stabilization and activation of the p53 protein upon stress also modifications of p53. there is evidence in support of this p53 becomes on multiple sites in in response to various types of stress, and can vitro in Refs. 5Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1225) Google and Z. Oncogene. 1998; 17: PubMed Scopus Google Scholar, D.W. Cell. 1998; 10: PubMed Scopus Google Scholar, A.J. M.B. Genes Dev. 1998; 12: PubMed Scopus Google Scholar, L. C. Cell. Mol. Life Sci. 1999; 55: PubMed Scopus Google Scholar). A of such might be the stabilization of p53 through inhibition of p53 and degradation. The pivotal role of Mdm2 in these processes several likely because the binding of Mdm2 to p53 (58Haupt Y. Maya R. Kazaz A. Oren M. Nature. 1997; 387: 296-299Crossref PubMed Scopus (3658) Google M.H.G. 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This protein through translation of an from tumor suppressor gene T. F. M.F. D.E. G. C.J. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). binds to Mdm2 and to a extent also to p53, and this binding p53 T. J.D. Zambetti G. F. M.F. C.J. Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar, J. N. N. A. L. L. J. Chen K. I. C. Cell. 1998; 92: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Y. Cell. 1998; 92: Full Text Full Text PDF PubMed Scopus Google Scholar), by the E3 activity of Mdm2 R. Yasuda H. EMBO J. 1999; 18: 22-27Crossref PubMed Scopus (612) Google Scholar). The between Mdm2 and is therefore for by stress and particular is the activation of the p53 response by oncogenic stress, such as the deregulated expression of adenovirus E1A, Ras, Myc, and β-catenin (Fig. 1). the importance of this response to tumor is very (Fig. its biochemical has the of and its role in p53 stabilization. has revealed that excess activity of several leads to induction of F. T. J.L. C.J. M.F. Genes Dev. 1998; 12: PubMed Scopus Google Scholar, E. McCurrach M.E. F. G. C. M.F. C.J. Lowe S.W. Genes Dev. 1998; 12: PubMed Scopus Google Scholar, I. C. M. Nature. 1998; PubMed Scopus Google Scholar). This induction is primarily because of at least some of which is through the transcription S. P.A. F. G. R.L. Vousden K.H. Nature. 1998; PubMed Scopus Google Scholar). The induced protein binds to thus p53 and (Fig. 3 the inhibitory effects of p53 are not triggered when or proteins are as part of a growth response, by the binding of a growth to its or such cells not be to a The that to can p53 between such activation of Ras, Myc, or and one that occurs independently of a proper growth signal and may lead to may in the more of the activation in the first However, it is also that when a cell is to a growth one of the response