Regulation of the p53 Tumor Suppressor Protein

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 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 Cell. Biol. PubMed Scopus Google Scholar). rapid in p53 a for is in cells with is most probably a of p53 from to The the DNA activity of p53 a which on to within target 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 DNA activity of p53 is subject to primarily through C.A. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, B. A.J. A. PubMed Scopus Google Scholar, R. A. Rotter V. A. PubMed Scopus Google Scholar). of this to in DNA J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, W. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Genet. 1998; PubMed Scopus Google and and The activity of p53 may also be in within N-terminal a of of the R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). p53 may also a in p53 may be at least of the cell cycle A. Rotter V. Google Scholar), to in in the it is to in the of p53 is the is the of activity types of human cancer (for reviews see Refs. R. Biochim. Biophys. Acta. 1998; Google Scholar, A.J. Cell. 1999; PubMed Scopus Google Scholar, Oren M. 1999; PubMed Google Scholar). a with the the to p53 and it J. D. A.J. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, A.J. Cell. Biol. PubMed Scopus Google Scholar, Oren M. J. PubMed Scopus Google Scholar). The within the p53 with of R. R. PubMed Scopus Google Scholar, A.J. A. PubMed Scopus Google Scholar). Moreover, can when to p53 R. Dev. 1997; PubMed Scopus Google Scholar). can also lead to elimination of p53 through the p53 to the gene and R. Oren M. J. PubMed Scopus Google Scholar, D. A.J. Dev. 7: PubMed Scopus Google Scholar). a (Fig. which probably to p53 in tight and to the p53 the some is that of p53 target J. Harvey D. A.J. A. PubMed Scopus Google Scholar, A.J. 1997; PubMed Google this may a within which p53 is to and The of the is the knock-out of the in this is of p53 L.A. Bradley A. Nature. PubMed Scopus Google Scholar, R. Nature. PubMed Scopus Google Scholar). in the of protein, p53 to the that activity to The of the is in human through gene Vogelstein B. Nature. 1992; PubMed Scopus Google mechanisms Google Scholar), can lead to of p53 and cancer a to the p53 gene be kept in that can also cancer of p53 R. B. C.A. Dev. 1997; PubMed Scopus Google D. 1998; PubMed Scopus Google The p53 to the gene and The to p53 and of p53 of the of p53 is through p53 on p53 is that the rapid of p53 is through the Cancer Res. Google Scholar), although a for such also Cell. Biol. 1997; PubMed Scopus Google Scholar). a levels in rapid p53 which is on the of the proteins to in direct R. A. Oren M. Nature. 1997; PubMed Scopus Google Scholar, Nature. 1997; PubMed Scopus Google Scholar). with in a and of p53 in cells A. V. A. Curr. Biol. 1997; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). that the low levels of p53 in such cells are primarily to does p53 the activity of the is the of forms of p53 R. A. Oren M. Nature. 1997; PubMed Scopus Google Scholar, Nature. 1997; PubMed Scopus Google Scholar), suggesting that p53 for this that can a which to p53 R. 1997; PubMed Scopus Google Scholar, R. J. 1999; PubMed Scopus Google (Fig. to be in is of a of p53 The of to p53 the of p53 and the DNA damage of p53 and within the can and p53 from of within for activity also p53 if is the of which to and the and of the of p53 mechanisms for p53 and also is the of the c-Jun N-terminal kinase in in that the of to p53 in and of p53 V. Dev. 1998; PubMed Scopus Google Scholar). The of and is are that it the cell cycle V. Dev. 1998; PubMed Scopus Google of of proteins is through that the rapid and of the p53 also of is in of this p53 on in in to various types of stress, and can in Refs. 5Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1225) Google and 1998; PubMed Scopus Google Scholar, Cell. 1998; PubMed Scopus Google Scholar, A.J. M.B. Dev. 1998; PubMed Scopus Google Scholar, C. Cell. 1999; PubMed Scopus Google Scholar). of such might be the of p53 through of p53 and The of in these likely the of to p53 R. A. Oren M. Nature. 1997; PubMed Scopus Google Nature. 1997; PubMed Scopus Google Scholar), of within the of may interfere with and lead to p53 (Fig. the of within which are in to DNA damage and the of p53 for M. C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, C. J. 1999; PubMed Scopus Google Scholar, M. R. Oren M. J. 1999; PubMed Scopus Google Scholar). are and and of human all within very to the of it is the of p53 the kinase C. 1998; PubMed Scopus Google Scholar, M.B. 1998; PubMed Scopus Google Scholar), activity is for p53 in to and some types of DNA damage M.B. Vogelstein B. A.J. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, J. R. Google Scholar). be that although the that such are for p53 is very the in of this M. Cell. Biol. 1999; PubMed Scopus Google Scholar, C. M. 1999; PubMed Scopus Google Scholar). the of p53 on may on the and on the of mechanisms for p53 of p53 might be not only p53 also a may become in a that with p53 (Fig. a within Cancer Res. 1997; Google Scholar). may p53 become with to activity (Fig. may to the of to be for p53 R. 1997; PubMed Scopus Google Scholar, A.J. 1999; Google p53 and may also be subject to types of of to DNA W. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. A. Dev. 1998; PubMed Scopus Google Scholar). p53 also and it may DNA J. R. R. Google Scholar). The of in p53 a very of to also a in cellular p53 levels and Such and are the subject of and it is to The is to recent reviews C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1225) Google Scholar, C. Cell. 1999; PubMed Scopus Google 1999; PubMed Scopus Google of to p53 can be not only also the of The most and most is the through of from tumor suppressor gene Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). to and to a also to and this p53 A. 1998; PubMed Scopus Google Scholar, J. N. N. A. J. C. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), the activity of R. J. 1999; PubMed Scopus Google Scholar). The and is therefore for and is the of the p53 oncogenic stress, such the of and (Fig. 1). the of this to tumor is very (Fig. the of and in p53 that activity of to induction of Dev. 1998; PubMed Scopus Google Scholar, C. Dev. 1998; PubMed Scopus Google Scholar, C. M. Nature. 1998; PubMed Scopus Google Scholar). induction is primarily of at least some of which is through the P.A. Nature. 1998; PubMed Scopus Google Scholar). The to p53 and (Fig. the effects of p53 are not when proteins are of a the of a to such cells not be to a The that to can p53 such of and that of a proper and may lead to may in the of the in the However, it is also that when a cell is to a of the the of p53 with the of and the for this from the that such and and p53 activity D. O. A. A. Oren M. 1997; PubMed Scopus Google Scholar, A. J. A. J. Pathol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). also contribute to the of these signals may of p53 to cellular effects on p53 of p53 on the of the activity of proteins in when oncogenic mutations occur in the p53 in arrest and the of such cancer-prone cells. these proteins are of the normal to of the this may the of p53 to and cell p53 can to a of is through which it to from very 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 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 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 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 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 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 Cell. Biol. PubMed Scopus Google Scholar). rapid in p53 a for is in cells with is most probably a of p53 from to The the DNA activity of p53 a which on to within target 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 DNA activity of p53 is subject to primarily through C.A. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, B. A.J. A. PubMed Scopus Google Scholar, R. A. Rotter V. A. PubMed Scopus Google Scholar). of this to in DNA J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, W. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Genet. 1998; PubMed Scopus Google and and The activity of p53 may also be in within N-terminal a of of the R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). p53 may also a in p53 may be at least of the cell cycle A. Rotter V. Google Scholar), to in in the it is to 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 Cell. Biol. PubMed Scopus Google Scholar). rapid in p53 a for is in cells with is most probably a of p53 from to The the DNA activity of p53 a which on to within target 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 DNA activity of p53 is subject to primarily through C.A. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, B. A.J. A. PubMed Scopus Google Scholar, R. A. Rotter V. A. PubMed Scopus Google Scholar). of this to in DNA J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, W. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M.J. Genet. 1998; PubMed Scopus Google and and The activity of p53 may also be in within N-terminal a of of the R. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). p53 may also a in p53 may be at least of the cell cycle A. Rotter V. Google Scholar), to in in the it is to The in the of p53 is the is the of activity types of human cancer (for reviews see Refs. R. Biochim. Biophys. Acta. 1998; Google Scholar, A.J. Cell. 1999; PubMed Scopus Google Scholar, Oren M. 1999; PubMed Google Scholar). a with the the to p53 and it J. D. A.J. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, A.J. Cell. Biol. PubMed Scopus Google Scholar, Oren M. J. PubMed Scopus Google Scholar). The within the p53 with of R. R. PubMed Scopus Google Scholar, A.J. A. PubMed Scopus Google Scholar). Moreover, can when to p53 R. Dev. 1997; PubMed Scopus Google Scholar). can also lead to elimination of p53 through the p53 to the gene and R. Oren M. J. PubMed Scopus Google Scholar, D. A.J. Dev. 7: PubMed Scopus Google Scholar). a (Fig. which probably to p53 in tight and to the p53 the some is that of p53 target J. Harvey D. A.J. A. PubMed Scopus Google Scholar, A.J. 1997; PubMed Google this may a within which p53 is to and The of the is the knock-out of the in this is of p53 L.A. Bradley A. Nature. PubMed Scopus Google Scholar, R. Nature. PubMed Scopus Google Scholar). in the of protein, p53 to the that activity to The of the is in human through gene Vogelstein B. Nature. 1992; PubMed Scopus Google mechanisms Google Scholar), can lead to of p53 and cancer a to the p53 gene be kept in that can also cancer of p53 R. B. C.A. Dev. 1997; PubMed Scopus Google D. 1998; PubMed Scopus Google Scholar). in the of p53 is the is the of activity types of human cancer (for reviews see Refs. R. Biochim. Biophys. Acta. 1998; Google Scholar, A.J. Cell. 1999; PubMed Scopus Google Scholar, Oren M. 1999; PubMed Google Scholar). a with the the to p53 and it J. D. A.J. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar, A.J. Cell. Biol. PubMed Scopus Google Scholar, Oren M. J. PubMed Scopus Google Scholar). The within the p53 with of R. R. PubMed Scopus Google Scholar, A.J. A. PubMed Scopus Google Scholar). Moreover, can when to p53 R. Dev. 1997; PubMed Scopus Google Scholar). can also lead to elimination of p53 through the p53 to the gene and R. Oren M. J. PubMed Scopus Google Scholar, D. A.J. Dev. 7: PubMed Scopus Google Scholar). a (Fig. which probably to p53 in tight and to the p53 the some is that of p53 target J. Harvey D. A.J. A. PubMed Scopus Google Scholar, A.J. 1997; PubMed Google this may a within which p53 is to and The of the is the knock-out of the in this is of p53 L.A. Bradley A. Nature. PubMed Scopus Google Scholar, R. Nature. PubMed Scopus Google Scholar). in the of protein, p53 to the that activity to The of the is in human through gene Vogelstein B. Nature. 1992; PubMed Scopus Google mechanisms Google Scholar), can lead to of p53 and cancer a to the p53 gene be kept in that can also cancer of p53 R. B. C.A. Dev. 1997; PubMed Scopus Google D. 1998; PubMed Scopus Google Scholar). of p53 of the of p53 is through p53 on p53 is that the rapid of p53 is through the Cancer Res. Google Scholar), although a for such also Cell. Biol. 1997; PubMed Scopus Google Scholar). a levels in rapid p53 which is on the of the proteins to in direct R. A. Oren M. Nature. 1997; PubMed Scopus Google Scholar, Nature. 1997; PubMed Scopus Google Scholar). with in a and of p53 in cells A. V. A. Curr. Biol. 1997; 7: Full Text Full Text PDF PubMed Scopus Google Scholar). that the low levels of p53 in such cells are primarily to does p53 the activity of the is the of forms of p53 R. A. Oren M. Nature. 1997; PubMed Scopus Google Scholar, Nature. 1997; PubMed Scopus Google Scholar), suggesting that p53 for this that can a which to p53 R. 1997; PubMed Scopus Google Scholar, R. J. 1999; PubMed Scopus Google (Fig. to be in is of a the of p53 mechanisms for p53 and also is the of the c-Jun N-terminal kinase in in that the of to p53 in and of p53 V. Dev. 1998; PubMed Scopus Google Scholar). The of and is are that it the cell cycle V. Dev. 1998; PubMed Scopus Google Scholar). of the of p53 is through p53 on p53 is that the rapid of p53 is through the Cancer Res. Google Scholar), although a for such also Cell. Biol. 1997; PubMed Scopus Google Scholar). a levels