Phosphorylation of p53 Serine 15 Increases Interaction with CBP

p53 exerts its cell cycle regulatory effects through its ability to function as a sequence-specific DNA binding transcription factor. CREB-binding protein (CBP)/p300, through its interaction with the N terminus of p53, acts as a coactivator for p53 and increases the sequence-specific DNA-binding activity of p53 by acetylating its C terminus. The same N-terminal domain of p53 has recently been shown to be phosphorylated at Ser15 in response to γ-irradiation. Remarkably, we now demonstrate that phosphorylation of p53 at Ser15 increases its ability to recruit CBP/p300. The increase in CBP/p300 binding was followed by an increase in the overall level of acetylation of the C terminus of p53. These results provide a mechanism for the activation of p53-regulated genes following DNA damage, through a signaling pathway linking p53 N-terminal kinase and C-terminal acetyltransferase activities. p53 exerts its cell cycle regulatory effects through its ability to function as a sequence-specific DNA binding transcription factor. CREB-binding protein (CBP)/p300, through its interaction with the N terminus of p53, acts as a coactivator for p53 and increases the sequence-specific DNA-binding activity of p53 by acetylating its C terminus. The same N-terminal domain of p53 has recently been shown to be phosphorylated at Ser15 in response to γ-irradiation. Remarkably, we now demonstrate that phosphorylation of p53 at Ser15 increases its ability to recruit CBP/p300. The increase in CBP/p300 binding was followed by an increase in the overall level of acetylation of the C terminus of p53. These results provide a mechanism for the activation of p53-regulated genes following DNA damage, through a signaling pathway linking p53 N-terminal kinase and C-terminal acetyltransferase activities. CREB-binding protein glutathione S-transferase DNA-dependent protein kinase polyacrylamide gel electrophoresis. p53, which mediates cell cycle arrest and apoptosis in response to DNA damage, is inactivated in approximately 60% of all human cancers (1Bates S. Vousden K.H. Curr. Opin. Genet. Dev. 1996; 6: 12-18Crossref PubMed Scopus (338) Google Scholar, 2Kastan M.B. Canman C.E. Leonard C.J. Cancer Metastasis Rev. 1995; 14: 3-15Crossref PubMed Scopus (440) Google Scholar, 3Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google Scholar, 4Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar). Regulation of the cell cycle and apoptosis is achieved through the function of p53 as a transcription factor, regulating transcription of genes including p21/waf1, GADD45, mdm2, cyclin G, and bax. The structure of p53 can be divided into three main domains: an N-terminal activation domain, a central, sequence-specific DNA-binding domain, and a C-terminal domain, which mediates tetramerization and regulates sequence-specific and nonspecific DNA binding (1Bates S. Vousden K.H. Curr. Opin. Genet. Dev. 1996; 6: 12-18Crossref PubMed Scopus (338) Google Scholar, 2Kastan M.B. Canman C.E. Leonard C.J. Cancer Metastasis Rev. 1995; 14: 3-15Crossref PubMed Scopus (440) Google Scholar, 3Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google Scholar, 4Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar). The N-terminal region interacts with a number of proteins, including MDM2 (5Momand 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), TBP (6Truant R. Xiao H. Ingles C.J. Greenblatt J. J. Biol. Chem. 1993; 268: 2284-2287Abstract Full Text PDF PubMed Google Scholar), dTAFII40 and dTAFII60 (7Thut C.J. Chen J.L. Klemm R. Tjian R. Science. 1995; 267: 100-104Crossref PubMed Scopus (406) Google Scholar), hTAFII31 (8Lu H. Levine A.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5154-5158Crossref PubMed Scopus (280) Google Scholar), CBP1 (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar), the p62 subunit of TFIIH (11Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar), and the adenovirus E1B 55-kDa protein (12Teodoro J.G. Branton P.E. J. Virol. 1997; 71: 3620-3627Crossref PubMed Google Scholar). It also contains a number of sites that are phosphorylated in vitroby casein kinase I (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar), DNA-dependent protein kinase S.J. E. Mol. Cell. Biol. 1992; PubMed Scopus Google Scholar), and N-terminal kinase D.M. Campbell Campbell J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the which is a kinase was also shown to human p53 L.J. Chen L. Prives C. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). Ser15 has been shown to be phosphorylated in in response to Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google and is in human E. J. Virol. PubMed Google Scholar). of Ser15 has been shown to binding of in E. J. Virol. PubMed Google Scholar), and phosphorylation has been shown to with MDM2 binding Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google coactivator and activation through a number of transcription including and R.G. Nature. 1994; PubMed Scopus Google Scholar, Nature. 1993; PubMed Scopus Google Scholar, A.J. S. Shi Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, H. C. S. Genes Dev. 1996; 10: PubMed Scopus Google Scholar, D. M.C. H. Nature. 1996; PubMed Scopus Google Scholar). and also been shown to with p53 in and in and to with p53 in of a the The interaction of the N terminus of p53 with the C-terminal region of is to be for activity (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google Scholar). and acetyltransferase activity A.J. Nature. 1996; PubMed Scopus Google Scholar, Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the acetyltransferase activity of has been shown to the C-terminal region of p53 as a and the acetylation of regulatory region by increases the sequence-specific binding of p53 in W. Roeder R.G. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google that phosphorylation of p53 in its N-terminal domain increases the of p53 and CBP/p300 in and that is a increase in the acetylation of p53. Ser15 to be for the interaction of p53 and CBP/p300. These results provide a mechanism linking phosphorylation and acetylation in the of the p53 response to is a protein in the response of a cell to DNA It is in the cell cycle arrest that DNA to and in the of apoptosis the be to The activation activity of the N-terminal domain of p53 is for L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar, J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is that phosphorylation of in the N terminus regulates the activity of the phosphorylation of Ser15 and by in the binding of MDM2 Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google and phosphorylation of Ser15 binding E. J. Virol. PubMed Google Scholar). Ser15 phosphorylation with a in MDM2 binding by p53 in cell Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), the of p53 the effects of MDM2 J. J. Levine A.J. Mol. 1995; PubMed Google Scholar, J. J. Levine A.J. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, Vousden K.H. Nature. 1997; 387: PubMed Scopus Google Scholar). the same the increase in the ability of p53 to recruit CBP/p300 following phosphorylation as shown in a mechanism for its It be of to the increase in interaction an increase in binding binding with p53 in and in W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google in with p53 in activation of a (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google the D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar). is for p53 of the A. E. Genes Dev. PubMed Scopus Google Scholar). binding of CBP/p300 by p53 transcription by by of the coactivator into the and by the DNA binding activity of p53 following acetylation of the C terminus W. Roeder R.G. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). It be of to the of CBP/p300 activation domain and acetyltransferase activation of Ser15 following DNA by and of to with the cell of p53 S.J. D. E. 1993; Google Scholar). in the of DNA can through its DNA-binding and be an for the DNA p53, to the cell cycle arrest pathway W. S. Mol. Cell. Biol. 10: PubMed Scopus Google Scholar, Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, Chen Mol. Cell. Biol. 10: PubMed Scopus Google Scholar). The that which are in the subunit of arrest in and C.J. 1996; PubMed Scopus Google Scholar, Cancer Res. 1997; 57: Google with has been that p53 Ser15 Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and of activity been in R. Nature. PubMed Scopus Google Scholar). R. Nature. PubMed Scopus Google recently that is for the of DNA binding in response to DNA is acts p53 in and is to that R. Nature. PubMed Scopus Google that in to a in was for the of the DNA binding activity of in are also These also are to and are to be The kinase is a of the and which to be in the response of the cell to in Cancer 1997; Google can also p53 at Ser15 S. L. L. Prives C. Science. PubMed Scopus Google Scholar, C.E. E. Science. PubMed Scopus Google and also be for CBP/p300 to p53. kinase activity is following of to S. L. L. Prives C. Science. PubMed Scopus Google Scholar, C.E. E. Science. PubMed Scopus Google Scholar), and has been shown that for the and phosphorylation of p53 Ser15 following to Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar). we as a for the phosphorylation of regulatory is that a kinase is for the phosphorylation in is that phosphorylation be to the cell and of phosphorylation is for of the The in the of the p53 N terminus and its is the phosphorylation to with to (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar, Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, D. Cancer Biol. 1994; Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), has activation the and the in J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. D.M. Halazonetis T.D. Berger S.L. 1997; PubMed Scopus Google Scholar). that the activation of of p53 The domain has been in apoptosis J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the p53 N terminus be to protein regulating transcription of genes and a and for the response of the cell to DNA the of p53 phosphorylation in response to (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar, Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, D. Cancer Biol. 1994; Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), be of to which p53 response the of p53 with CBP/p300. a response be to of that phosphorylation of p53 that phosphorylation Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the that the response to including p53 binding by the response to including phosphorylation of its human These also the of the of p53, with the of MDM2 p53 and of the cell p53, which mediates cell cycle arrest and apoptosis in response to DNA damage, is inactivated in approximately 60% of all human cancers (1Bates S. Vousden K.H. Curr. Opin. Genet. Dev. 1996; 6: 12-18Crossref PubMed Scopus (338) Google Scholar, 2Kastan M.B. Canman C.E. Leonard C.J. Cancer Metastasis Rev. 1995; 14: 3-15Crossref PubMed Scopus (440) Google Scholar, 3Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google Scholar, 4Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar). Regulation of the cell cycle and apoptosis is achieved through the function of p53 as a transcription factor, regulating transcription of genes including p21/waf1, GADD45, mdm2, cyclin G, and bax. The structure of p53 can be divided into three main domains: an N-terminal activation domain, a central, sequence-specific DNA-binding domain, and a C-terminal domain, which mediates tetramerization and regulates sequence-specific and nonspecific DNA binding (1Bates S. Vousden K.H. Curr. Opin. Genet. Dev. 1996; 6: 12-18Crossref PubMed Scopus (338) Google Scholar, 2Kastan M.B. Canman C.E. Leonard C.J. Cancer Metastasis Rev. 1995; 14: 3-15Crossref PubMed Scopus (440) Google Scholar, 3Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google Scholar, 4Levine A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar). The N-terminal region interacts with a number of proteins, including MDM2 (5Momand 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), TBP (6Truant R. Xiao H. Ingles C.J. Greenblatt J. J. Biol. Chem. 1993; 268: 2284-2287Abstract Full Text PDF PubMed Google Scholar), dTAFII40 and dTAFII60 (7Thut C.J. Chen J.L. Klemm R. Tjian R. Science. 1995; 267: 100-104Crossref PubMed Scopus (406) Google Scholar), hTAFII31 (8Lu H. Levine A.J. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 5154-5158Crossref PubMed Scopus (280) Google Scholar), CBP1 (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar), the p62 subunit of TFIIH (11Xiao H. Pearson A. Coulombe B. Truant R. Zhang S. Regier J.L. Triezenberg S.J. Reinberg D. Flores O. Ingles C.J. Greenblatt J. Mol. Cell. Biol. 1994; 14: 7013-7024Crossref PubMed Scopus (327) Google Scholar), and the adenovirus E1B 55-kDa protein (12Teodoro J.G. Branton P.E. J. Virol. 1997; 71: 3620-3627Crossref PubMed Google Scholar). It also contains a number of sites that are phosphorylated in vitroby casein kinase I (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar), DNA-dependent protein kinase S.J. E. Mol. Cell. Biol. 1992; PubMed Scopus Google Scholar), and N-terminal kinase D.M. Campbell Campbell J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the which is a kinase was also shown to human p53 L.J. Chen L. Prives C. Mol. Cell. Biol. 1997; PubMed Scopus Google Scholar). Ser15 has been shown to be phosphorylated in in response to Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google and is in human E. J. Virol. PubMed Google Scholar). of Ser15 has been shown to binding of in E. J. Virol. PubMed Google Scholar), and phosphorylation has been shown to with MDM2 binding Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). The coactivator and activation through a number of transcription including and R.G. Nature. 1994; PubMed Scopus Google Scholar, Nature. 1993; PubMed Scopus Google Scholar, A.J. S. Shi Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, H. C. S. Genes Dev. 1996; 10: PubMed Scopus Google Scholar, D. M.C. H. Nature. 1996; PubMed Scopus Google Scholar). and also been shown to with p53 in and in and to with p53 in of a the The interaction of the N terminus of p53 with the C-terminal region of is to be for activity (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google Scholar). and acetyltransferase activity A.J. Nature. 1996; PubMed Scopus Google Scholar, Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). the acetyltransferase activity of has been shown to the C-terminal region of p53 as a and the acetylation of regulatory region by increases the sequence-specific binding of p53 in W. Roeder R.G. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). that phosphorylation of p53 in its N-terminal domain increases the of p53 and CBP/p300 in and that is a increase in the acetylation of p53. Ser15 to be for the interaction of p53 and CBP/p300. These results provide a mechanism linking phosphorylation and acetylation in the of the p53 response to is a protein in the response of a cell to DNA It is in the cell cycle arrest that DNA to and in the of apoptosis the be to The activation activity of the N-terminal domain of p53 is for L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar, J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is that phosphorylation of in the N terminus regulates the activity of the phosphorylation of Ser15 and by in the binding of MDM2 Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google and phosphorylation of Ser15 binding E. J. Virol. PubMed Google Scholar). Ser15 phosphorylation with a in MDM2 binding by p53 in cell Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), the of p53 the effects of MDM2 J. J. Levine A.J. Mol. 1995; PubMed Google Scholar, J. J. Levine A.J. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, Vousden K.H. Nature. 1997; 387: PubMed Scopus Google Scholar). the same the increase in the ability of p53 to recruit CBP/p300 following phosphorylation as shown in a mechanism for its It be of to the increase in interaction an increase in binding binding with p53 in and in W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google in with p53 in activation of a (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google the D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar). is for p53 of the A. E. Genes Dev. PubMed Scopus Google Scholar). binding of CBP/p300 by p53 transcription by by of the coactivator into the and by the DNA binding activity of p53 following acetylation of the C terminus W. Roeder R.G. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). It be of to the of CBP/p300 activation domain and acetyltransferase activation of Ser15 following DNA by and of to with the cell of p53 S.J. D. E. 1993; Google Scholar). in the of DNA can through its DNA-binding and be an for the DNA p53, to the cell cycle arrest pathway W. S. Mol. Cell. Biol. 10: PubMed Scopus Google Scholar, Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, Chen Mol. Cell. Biol. 10: PubMed Scopus Google Scholar). The that which are in the subunit of arrest in and C.J. 1996; PubMed Scopus Google Scholar, Cancer Res. 1997; 57: Google with has been that p53 Ser15 Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and of activity been in R. Nature. PubMed Scopus Google Scholar). R. Nature. PubMed Scopus Google recently that is for the of DNA binding in response to DNA is acts p53 in and is to that R. Nature. PubMed Scopus Google that in to a in was for the of the DNA binding activity of in are also These also are to and are to be The kinase is a of the and which to be in the response of the cell to in Cancer 1997; Google can also p53 at Ser15 S. L. L. Prives C. Science. PubMed Scopus Google Scholar, C.E. E. Science. PubMed Scopus Google and also be for CBP/p300 to p53. kinase activity is following of to S. L. L. Prives C. Science. PubMed Scopus Google Scholar, C.E. E. Science. PubMed Scopus Google Scholar), and has been shown that for the and phosphorylation of p53 Ser15 following to Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar). we as a for the phosphorylation of regulatory is that a kinase is for the phosphorylation in is that phosphorylation be to the cell and of phosphorylation is for of the The in the of the p53 N terminus and its is the phosphorylation to with to (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar, Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, D. Cancer Biol. 1994; Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), has activation the and the in J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. D.M. Halazonetis T.D. Berger S.L. 1997; PubMed Scopus Google Scholar). that the activation of of p53 The domain has been in apoptosis J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the p53 N terminus be to protein regulating transcription of genes and a and for the response of the cell to DNA the of p53 phosphorylation in response to (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar, Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, D. Cancer Biol. 1994; Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), be of to which p53 response the of p53 with CBP/p300. a response be to of that phosphorylation of p53 that phosphorylation Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). the that the response to including p53 binding by the response to including phosphorylation of its human These also the of the of p53, with the of MDM2 p53 and of the cell p53 is a protein in the response of a cell to DNA It is in the cell cycle arrest that DNA to and in the of apoptosis the be to The activation activity of the N-terminal domain of p53 is for L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2282) Google A.J. Cell. 1997; 88: 323-331Abstract Full Text Full Text PDF PubMed Scopus (6695) Google Scholar, J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is that phosphorylation of in the N terminus regulates the activity of the phosphorylation of Ser15 and by in the binding of MDM2 Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google and phosphorylation of Ser15 binding E. J. Virol. PubMed Google Scholar). Ser15 phosphorylation with a in MDM2 binding by p53 in cell Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), the of p53 the effects of MDM2 J. J. Levine A.J. Mol. 1995; PubMed Google Scholar, J. J. Levine A.J. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, Vousden K.H. Nature. 1997; 387: PubMed Scopus Google Scholar). the same the increase in the ability of p53 to recruit CBP/p300 following phosphorylation as shown in a mechanism for its It be of to the increase in interaction an increase in binding binding CBP/p300 with p53 in and in W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, 10Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google in with p53 in activation of a (9Gu W. Shi X.L. Roeder R.G. Nature. 1997; 387: 819-823Crossref PubMed Scopus (520) Google Scholar, A. Levine Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, D. J. D.M. Nature. 1997; 387: PubMed Scopus Google the D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Halazonetis T.D. Cancer Res. 1997; 57: 3693-3696PubMed Google Scholar). is for p53 of the A. E. Genes Dev. PubMed Scopus Google Scholar). binding of CBP/p300 by p53 transcription by by of the coactivator into the and by the DNA binding activity of p53 following acetylation of the C terminus W. Roeder R.G. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). It be of to the of CBP/p300 activation domain and acetyltransferase activation of Ser15 following DNA by and of to with the cell of p53 S.J. D. E. 1993; Google Scholar). in the of DNA can through its DNA-binding and be an for the DNA p53, to the cell cycle arrest pathway W. S. Mol. Cell. Biol. 10: PubMed Scopus Google Scholar, Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, Chen Mol. Cell. Biol. 10: PubMed Scopus Google Scholar). The that which are in the subunit of arrest in and C.J. 1996; PubMed Scopus Google Scholar, Cancer Res. 1997; 57: Google with has been that p53 Ser15 Prives C. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), and of activity been in R. Nature. PubMed Scopus Google Scholar). R. Nature. PubMed Scopus Google recently that is for the of DNA binding in response to DNA is acts p53 in and is to that R. Nature. PubMed Scopus Google that in to a in was for the of the DNA binding activity of in are also These also are to and are to be The kinase is a of the and which to be in the response of the cell to in Cancer 1997; Google can also p53 at Ser15 S. L. L. Prives C. Science. PubMed Scopus Google Scholar, C.E. E. Science. PubMed Scopus Google and also be for CBP/p300 to p53. kinase activity is following of to S. L. L. Prives C. Science. PubMed Scopus Google Scholar, C.E. E. Science. PubMed Scopus Google Scholar), and has been shown that for the and phosphorylation of p53 Ser15 following to Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar). we as a for the phosphorylation of regulatory is that a kinase is for the phosphorylation in is that phosphorylation be to the cell and The of phosphorylation is for of the The in the of the p53 N terminus and its is the phosphorylation to with to (13Knippschild U. Milne D.M. Campbell A.J. E. 1997; PubMed Scopus Google Scholar, Campbell L.J. U. L. Milne D.M. 1997; PubMed Scopus Google Scholar, Canman C.E. E. M.B. Genes Dev. 1997; PubMed Scopus Google Scholar, D. Cancer Biol. 1994; Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), has activation the and the in J. W. J. Chen J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R. D.M. Halazonetis T.D. 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