Key points are not available for this paper at this time.
The p53 transcription factor contains two separate tandem activation domains (AD1 and AD2), a proline-rich domain (PRD), and a C-terminal basic domain (BD). Previously, we have shown that these domains are necessary for transcriptional activity. To further characterize the role of these domains in transactivation, we analyzed the regulation of p21, a well characterized p53 target gene, by various p53 mutants deficient in one or more of these domains. We found that the induction of endogenous p21 is compromised by AD1-deficient p53 (p53(AD1−)), AD2-deficient p53 (p53(AD2−)), both AD1- and AD2-deficient p53 (p53(AD1−AD2−)), p53(ΔPRD), which lacks PRD, and p53(ΔBD), which lacks BD. However, p53(AD2−), p53(ΔPRD), and p53(ΔBD) are still capable of activating exogenous p21 promoter to an extent comparable with that by wild-type p53. Thus, we performed chromatin immunoprecipitation assay to measure the DNA binding ability of various p53 mutants in vivo. We found that like wild-type p53, these p53 mutants are capable of binding to the p53 response elements in the p21 promoter. In contrast, we found that the extent of acetylated histones on the p21 promoter, especially the proximal promoter, and the amount of interaction with p300/CREB-binding protein, which contain histone acetyltransferase activity, directly correlate with the activity of p53 to induce endogenous p21. Furthermore, we showed that down-regulation of p300/CBP by short interference RNA markedly decreases the ability of p53 to induce endogenous p21. These data lead us to hypothesize that when p53 binds to the responsive element(s) of a target gene, its ability to interact with histone acetyltransferase-containing proteins and subsequently the acetylation of histones bound to the proximal promoter dictate the induction level of a target gene. The p53 transcription factor contains two separate tandem activation domains (AD1 and AD2), a proline-rich domain (PRD), and a C-terminal basic domain (BD). Previously, we have shown that these domains are necessary for transcriptional activity. To further characterize the role of these domains in transactivation, we analyzed the regulation of p21, a well characterized p53 target gene, by various p53 mutants deficient in one or more of these domains. We found that the induction of endogenous p21 is compromised by AD1-deficient p53 (p53(AD1−)), AD2-deficient p53 (p53(AD2−)), both AD1- and AD2-deficient p53 (p53(AD1−AD2−)), p53(ΔPRD), which lacks PRD, and p53(ΔBD), which lacks BD. However, p53(AD2−), p53(ΔPRD), and p53(ΔBD) are still capable of activating exogenous p21 promoter to an extent comparable with that by wild-type p53. Thus, we performed chromatin immunoprecipitation assay to measure the DNA binding ability of various p53 mutants in vivo. We found that like wild-type p53, these p53 mutants are capable of binding to the p53 response elements in the p21 promoter. In contrast, we found that the extent of acetylated histones on the p21 promoter, especially the proximal promoter, and the amount of interaction with p300/CREB-binding protein, which contain histone acetyltransferase activity, directly correlate with the activity of p53 to induce endogenous p21. Furthermore, we showed that down-regulation of p300/CBP by short interference RNA markedly decreases the ability of p53 to induce endogenous p21. These data lead us to hypothesize that when p53 binds to the responsive element(s) of a target gene, its ability to interact with histone acetyltransferase-containing proteins and subsequently the acetylation of histones bound to the proximal promoter dictate the induction level of a target gene. cAMP-response element-binding protein (CREB)-binding protein activation domain proline-rich domain C-terminal basic domain hemagglutinin chromatin immunoprecipitation assay responsive element short interference RNA polyclonal antibody p300- and CBP-associated factor p53 up-regulated modulator of apoptosis In the eukaryotic nucleus, DNA exists in a highly organized chromatin. The basic structural unit is the nucleosome, consisting of DNA wrapped around an octamer of histones (two each of H2A, H2B, H3, and H4). The packaged nucleosome is the natural barrier to most regulatory proteins due to restriction of access to DNA (1Cosma M. Mol. Cell. 2002; 10: 227-236Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 2Emerson B.M. Cell. 2002; 109: 267-270Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 3Kadam S. Emerson B.M. Curr. Opin. Cell Biol. 2002; 14: 262-268Crossref PubMed Scopus (58) Google Scholar, 4Featherstone M. Curr. Opin. Genet. Dev. 2002; 12: 149-155Crossref PubMed Scopus (71) Google Scholar, 5Woychik N.A. Hampsey M. Cell. 2002; 108: 453-463Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Therefore, activation of transcription requires disruption of the highly dense structure of chromatin to increase the accessibility of DNA to transcription factors. It is believed that disruption of chromatin structure depends on chromatin-modifying complexes, which include two major groups, the ATP-dependent remodeling complexes and the histone modification enzymes. Histone acetyltransferase is one of the well characterized histone modification enzymes that acetylates histone tails and introduces negative charge to histones, thereby reducing the interaction between histones and DNA and promoting accessibility of DNA to the transcriptional machinery (3Kadam S. Emerson B.M. Curr. Opin. Cell Biol. 2002; 14: 262-268Crossref PubMed Scopus (58) Google Scholar, 6Cheung P. Allis C.D. Sassone-Corsi P. Cell. 2000; 103: 263-271Abstract Full Text Full Text PDF PubMed Scopus (828) Google Scholar). Therefore, increased acetylation of histones on promoters often leads to transcriptional activation. In mammalian cells the histone acetyltransferase-containing transcription co-activators p300/CBP1 and PCAF acetylate histones after being recruited by sequence-specific DNA binding transcription factors (7Vo N. Goodman R.H. J. Biol. Chem. 2001; 276: 13505-13508Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar). This is underscored by evidence that p300/CBP can interact with many transcription factors, such as c-Jun, JunB, JunD, MyoD, STATs (signal transducers and activators of transcription), and p53, and increase the transcriptional activity of these proteins (7Vo N. Goodman R.H. J. Biol. Chem. 2001; 276: 13505-13508Abstract Full Text Full Text PDF PubMed Scopus (708) Google Scholar). The p53 tumor suppressor gene is the most frequent target for genetic alterations in human cancers, with mutations occurring in almost 507 of all human tumors (8Hollstein M. Rice K. Greenblatt M.S. Soussi T. Fuchs R. Sorlie T. Hovig E. Smith-Sorensen B. Montesano R. Harris C.C. Nucleic Acids Res. 1994; 22: 3551-3555PubMed Google Scholar, 9Hollstein M. Sidransky D. Vogelstein B. Harris C.C. Science. 1991; 253: 49-53Crossref PubMed Scopus (7479) Google Scholar). In response to environmental and intracellular stresses, including DNA damage, ionizing irradiation, and hypoxia, p53 is rapidly stabilized and accumulated (10Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2294) Google Scholar). The activated p53 induces many target genes, including p21, Bax, PUMA, and MCG10, which mediate p53-dependent cell cycle arrest and/or apoptosis (11el-Deiry W.S. Tokino T. Velculescu V.E. Levy D.B. Parsons R. Trent J.M. Lin D. Mercer W.E. Kinzler K.W. Vogelstein B. Cell. 1993; 75: 817-825Abstract Full Text PDF PubMed Scopus (7957) Google Scholar, 12Miyashita T. Reed J.C. Cell. 1995; 80: 293-299Abstract Full Text PDF PubMed Scopus (305) Google Scholar, 13Zhu J. Chen X. Mol. Cell. Biol. 2000; 20: 5602-5618Crossref PubMed Scopus (92) Google Scholar, 14Nakano K. Vousden K.H. Mol. Cell. 2001; 7: 683-694Abstract Full Text Full Text PDF PubMed Scopus (1894) Google Scholar, 15Yu J. Zhang L. Hwang P.M. Kinzler K.W. Vogelstein B. Mol. Cell. 2001; 7: 673-682Abstract Full Text Full Text PDF PubMed Scopus (1100) Google Scholar). The p53 protein consists of two N-terminal activation domains (AD1 within residues 1–42 and AD2 within residues 43–63), a proline-rich domain (PRD, within residues 64–93), a sequence-specific DNA binding domain (within residues 102–292), and an extreme C-terminal basic domain (BD within residues 364–393) (16Chen X. Mol. Med. Today. 1999; 5: 387-392Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). The transcription co-activators p300/CBP have been found to interact with p53 activation domains and enhance the ability of p53 to activate p21 or mdm2 (17Avantaggiati M.L. Ogryzko V. Gardner K. Giordano A. Levine A.S. Kelly K. Cell. 1997; 89: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 18Dickman S. Science. 1997; 277: 1605-1606Crossref PubMed Scopus (30) Google Scholar, 19Gu W. Roeder R.G. Cell. 1997; 90: 595-606Abstract Full Text Full Text PDF PubMed Scopus (2189) Google Scholar, 20Lill N.L. Grossman S.R. Ginsberg D. DeCaprio J. Livingston D.M. Nature. 1997; 387: 823-827Crossref PubMed Scopus (596) Google Scholar, 21Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar). can the p53-dependent induction of p21 D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar). p53 with a in and each of which is deficient in transactivation, is to interact with in D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar). In the p53-dependent induction of p21, disruption of the interaction between and p53 N.L. Grossman S.R. Ginsberg D. DeCaprio J. Livingston D.M. Nature. 1997; 387: 823-827Crossref PubMed Scopus (596) Google Scholar). evidence that the transcriptional activity of p53 depends on its interaction with The of p53 been shown to a role in regulation of p53 the DNA binding ability of p53 is increased after of the C-terminal of residues in or binding of an antibody to domain (10Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2294) Google Scholar). that p300/CBP and PCAF can acetylate residues within the C-terminal domain in response to N.A. L. Chehab N.H. K. Harris Berger S.L. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, W. Roeder R.G. Nature. 1997; 387: PubMed Scopus Google Scholar, K. S. T. M. A. E. Genes Dev. 12: PubMed Scopus Google Scholar, L. D.M. Zhang R. Berger S.L. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, A. X. S. E. J. 2001; 20: PubMed Scopus Google Scholar). p53 a DNA binding to short a p53 binding the p21 W. Roeder R.G. Nature. 1997; 387: PubMed Scopus Google Scholar, K. S. T. M. A. E. Genes Dev. 12: PubMed Scopus Google to a DNA J.M. Emerson B.M. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). In we cell to regulation of p21 by wild-type p53 or various We showed that all of the p53 mutants in assay are compromised in endogenous p21 gene, both wild-type p53 and various p53 mutants have an sequence-specific DNA binding We found that the ability of p53 mutants to increase acetylation of histones and is We found that the compromised transcriptional activity of p53 mutants with the acetylation level of histones and on the proximal to the We the RNA interference to and the that p300/CBP is for the transcriptional activity of wild-type p53. Furthermore, we evidence that compromised transcriptional activity of various p53 mutants with interaction with Therefore, data that the amount of p300/CBP recruited by p53 and the extent of acetylated histones bound to the proximal promoter can in the transcriptional activity wild-type p53 and various p53 cell which can to wild-type p53, p53(AD2−), p53(ΔBD), and p53(ΔPRD), J. J. W. K. Chen X. 1999; PubMed Scopus Google Scholar, J. W. J. Chen X. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and wild-type p53 and the mutants are with an the RNA performed as M. Zhang S. Chen X. 2001; 20: PubMed Scopus Google Scholar). The p21 and as M. J. Chen X. 2001; 20: PubMed Scopus Google Scholar). The the of the p21 promoter with two elements R. Med. 1997; PubMed Scopus Google Scholar). of the cells with of or a wild-type p53, p53(AD2−), p53(ΔBD), or an of performed in to the of which for RNA or with Chen X. 2002; PubMed Scopus Google Scholar). by The level of wild-type p53, p53(AD2−), p53(ΔBD), and in cell or cells by antibody and by and to an which and to p53, p53(AD2−), p53(ΔBD), or p53(ΔPRD), with DNA and proteins by the of directly and for The cells on with and by The cells by with of and to DNA by the with a and with histone H3, and histone The by protein with The that various with and The with the for the The by for DNA by and by and in of of DNA as a for To the element and and the proximal to in the p21 promoter, performed with the of p53 and p53 and p21 and The RNA promoter of N. Cell. Full Text PDF PubMed Scopus Google The the promoter the of to and a The promoter with and and The as and for of vivo. of both and and and the as and The in in the gene to and The in the gene to and The in the gene to and The in the gene to and cells with the of of each of and or with of cells with of or or with of The cell on the after The level of p53, and p21 by and and to an cells to wild-type p53, p53(AD2−), p53(ΔBD), or with and by The cells in of and on for to cell to the of Cell on for the cell in of and and The by for p53, p53(AD2−), p53(ΔBD), and by with of by of and protein The with and p53 of for The amount of or with p53 or various mutants by In the of p53 we a of cell that to wild-type p53 or various p53 We found that the level of p21 by p53 in these cell J. J. W. K. Chen X. 1999; PubMed Scopus Google Scholar, J. W. J. Chen X. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Zhang S. J. Chen X. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). To the induction of p21 in these cell we performed and the level of p21 We found that p21 in the of wild-type p53. In contrast, which is in the DNA binding in of p21 with the W. J. J. J. Chen X. 1999; PubMed Scopus Google Scholar). We found that induction of p21 by of activation domain or activation domain that both and AD2 are necessary the transcriptional activity of p53. This further by the evidence that mutations in both and AD2 the induction of p21 In p53(ΔBD), which lacks the C-terminal basic and p53(ΔPRD), which lacks the proline-rich a activity in p21 both mutants are capable of cell cycle arrest J. W. J. Chen X. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Zhang S. J. Chen X. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). To the that transcriptional activity of wild-type p53 and various p53 mutants on p21 due to level of p53 in these cell we performed and found that the level of these p53 mutants comparable with that of wild-type p53 The activity of the of a responsive element of a transcription factor been to measure the transcriptional activity S. Chen X. 2002; PubMed Scopus Google Scholar). we a the of the p21 promoter two elements to the transcriptional activity of wild-type p53 and various p53 We found that and and showed a transcriptional activity on the p21 promoter However, activated the p21 promoter which is the by we found that p53(ΔBD) and transcriptional activity on the p21 promoter with wild-type p53 both mutants endogenous p21 wild-type p53 p21 the assay the transcriptional activity of p53 and various mutants in the endogenous p21 gene. This is a promoter is more to an the endogenous promoter. To an level of wild-type p53 and various p53 we performed and found that comparable Furthermore, we the level of endogenous p21 by wild-type p53 and various mutants p21 We found that p21 highly by wild-type p53, by p53(AD2−), and p21 by p53(ΔBD), the level of its induction by p53(ΔBD) by wild-type p53. This is with the data in the cell the all of the mutants in have an DNA binding the DNA binding ability of p53 is necessary and p53 transcriptional activity (10Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2294) Google Scholar, X. Mol. Med. Today. 1999; 5: 387-392Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, B. Kinzler K.W. Cell. Full Text PDF PubMed Scopus Google is that p53 mutants have an DNA binding which leads to induction of endogenous p21. To we to the ability of wild-type p53 and various mutants to the elements in the p21 promoter. two elements and in the p21 promoter we two of to We found that and to both and in the p21 promoter when wild-type p53 However, by a antibody that wild-type p53 binds both and We found that p53(AD2−), and an ability to and with wild-type p53 These are mutations in or AD2 the DNA binding ability of p53. Furthermore, both p53(ΔBD) and an ability to both and as wild-type p53 ability to induce p21 In we antibody to in the and which a in the p53 DNA binding of binding or transcription factors to within a promoter, often a with histone acetyltransferase activity to the promoter, to acetylation of the N-terminal tails of histones and can the interaction of histones with thereby the accessibility of the promoter to the transcriptional machinery and the of transcription (3Kadam S. Emerson B.M. Curr. Opin. Cell Biol. 2002; 14: 262-268Crossref PubMed Scopus (58) Google Scholar, 4Featherstone M. Curr. Opin. Genet. Dev. 2002; 12: 149-155Crossref PubMed Scopus (71) Google Scholar). the ability of p53 mutants to both and in the p21 promoter we to wild-type p53 and various mutants can increase the acetylation of histones on the and shown in and acetylation of histones and on both and increased when wild-type p53 that wild-type p53 can histone to and However, the ability of p53(AD2−), or to increase acetylation of histones and on both and compromised with wild-type p53 This that these mutants histone acetyltransferase activity to and wild-type p53 DNA binding ability as wild-type p53. This is further by that the ability of p53(ΔBD) or to increase acetylation of histones and on both and to a extent that of p53(AD2−), or p53 binds to its responsive histones bound on the the responsive element for we that histone acetylated to a extent histone of wild-type p53 or various mutants and histones and The of the proximal promoter, including the to the transcriptional machinery is a for transcriptional B.M. Cell. 2002; 109: 267-270Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 5Woychik N.A. Hampsey M. Cell. 2002; 108: 453-463Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). of the of chromatin structural disruption is acetylation of histones on the proximal promoter the p53 such as deficient in endogenous p21 still showed activity to increase the acetylation of histones on and we these p53 mutants are capable of acetylation of histones on the proximal to the shown in acetylation of both histones and on the proximal p21 promoter increased when wild-type p53 of histone increased induction of p53(ΔBD) or to a extent that after induction of wild-type p53. However, increase in histone or acetylation found when p53(AD2−), or Thus, p53 the extent of histone acetylation on the proximal p21 promoter with the of induction of the endogenous p21 gene. and two histone acetyltransferase-containing have been found to interact with p53 and increase the ability of p53 to induce endogenous p21 or activate promoters of p53 target (17Avantaggiati M.L. Ogryzko V. Gardner K. Giordano A. Levine A.S. Kelly K. Cell. 1997; 89: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 19Gu W. Roeder R.G. Cell. 1997; 90: 595-606Abstract Full Text Full Text PDF PubMed Scopus (2189) Google Scholar, 20Lill N.L. Grossman S.R. Ginsberg D. DeCaprio J. Livingston D.M. Nature. 1997; 387: 823-827Crossref PubMed Scopus (596) Google Scholar). showed that the amount of p300/CBP binding to the p21 promoter with the level of acetylation of histones and N.A. L. Chehab N.H. K. Harris Berger S.L. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google that the of p300/CBP to the p21 promoter by p53 is for histone acetylation and activation of p21. To p300/CBP in the p53-dependent induction of p21, we the p300/CBP We found that p300/CBP of p300/CBP and a we found that the ability of wild-type p53 to induce p21 in cells p300/CBP in cells Thus, data are and the that the decreases the induction of endogenous p21 by p53 D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar). showed that down-regulation of p300/CBP the induction of endogenous p21 by wild-type p53 we showed that p53 which are compromised in p21, are compromised in the acetylation of histones on the p21 promoter These us to the compromised ability of various p53 mutants to increase the acetylation of histones on the p21 promoter and to induce p21 is due to interaction with To we performed immunoprecipitation with or to complexes and with and to the amount of p300/CBP in the p53 We found that wild-type p53 and p300/CBP in with the (17Avantaggiati M.L. Ogryzko V. Gardner K. Giordano A. Levine A.S. Kelly K. Cell. 1997; 89: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 20Lill N.L. Grossman S.R. Ginsberg D. DeCaprio J. Livingston D.M. Nature. 1997; 387: 823-827Crossref PubMed Scopus (596) Google D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar, W. Roeder R.G. Nature. 1997; 387: PubMed Scopus Google Scholar). In we found that p53(ΔBD) and capable of with p300/CBP However, the amount of p300/CBP with these two mutants that with wild-type p53 and the amount of wild-type p53 and various p53 mutants in the comparable In contrast, p53(AD2−), and showed almost interaction with p300/CBP and This that mutations in and AD2 and of and the interaction between p53 and such mutations and with the sequence-specific DNA binding ability of p53. We like to that the amount of which with wild-type p53 and various is to the extent of histone acetylation on the proximal p21 promoter with The transcriptional activity of p53 is by various domains in p53 (10Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2294) Google Scholar, X. Mol. Med. Today. 1999; 5: 387-392Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, J. J. W. K. Chen X. 1999; PubMed Scopus Google Scholar, J. W. J. Chen X. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Zhang S. J. Chen X. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, B. D. Levine Nature. 2000; PubMed Scopus Google Scholar). most p53 mutants have a in the DNA binding domain that leads to p53 (10Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2294) Google Scholar, Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Cell. Full Text PDF PubMed Scopus Google many have on various domains in p53 the sequence-specific DNA binding activity of the DNA binding have shown that the extreme C-terminal basic domain the activity of the DNA binding domain in the DNA binding activity is increased when the basic domain is or bound by a or an antibody (10Ko L.J. Prives C. Genes Dev. 1996; 10: 1054-1072Crossref PubMed Scopus (2294) Google Scholar, 19Gu W. Roeder R.G. Cell. 1997; 90: 595-606Abstract Full Text Full Text PDF PubMed Scopus (2189) Google Scholar). These data lead to a that p53 exists in two and J. Prives C. Biol. 2001; PubMed Scopus Google Scholar). However, a that both and of p53 are in A. Biol. 2001; PubMed Scopus Google that the basic domain have on the DNA binding In we directly the DNA binding activity in and showed that the DNA binding activity is by the basic domain In we found that p53(ΔPRD), p53(AD2−), and all of which contain an DNA binding have an DNA binding ability these p53 mutants are compromised in the transcriptional activity, especially in endogenous p21, the is of is for of the dense chromatin structure by chromatin remodeling complexes is a for transcriptional activation (1Cosma M. Mol. Cell. 2002; 10: 227-236Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 2Emerson B.M. Cell. 2002; 109: 267-270Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar, 5Woychik N.A. Hampsey M. Cell. 2002; 108: 453-463Abstract Full Text Full Text PDF PubMed Scopus (208) Google Scholar). Histone acetyltransferase complexes, which are well chromatin remodeling complexes, acetylate the of histones and the promoter to the transcriptional machinery (3Kadam S. Emerson B.M. Curr. Opin. Cell Biol. 2002; 14: 262-268Crossref PubMed Scopus (58) Google Scholar, 6Cheung P. Allis C.D. Sassone-Corsi P. Cell. 2000; 103: 263-271Abstract Full Text Full Text PDF PubMed Scopus (828) Google Scholar). that p53 with p300/CBP both in and in and of p300/CBP can p53 to activate the p21 promoter (17Avantaggiati M.L. Ogryzko V. Gardner K. Giordano A. Levine A.S. Kelly K. Cell. 1997; 89: 1175-1184Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar, 20Lill N.L. Grossman S.R. Ginsberg D. DeCaprio J. Livingston D.M. Nature. 1997; 387: 823-827Crossref PubMed Scopus (596) Google Scholar, 21Scolnick D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar, W. Roeder R.G. Nature. 1997; 387: PubMed Scopus Google Scholar). is to the p53-dependent induction of endogenous p21 D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar). In a in the activation domain or the activation domain which the transcriptional activity of p53, the interaction of p53 with in D.M. Chehab N.H. Stavridi E.S. Lien M.C. Caruso L. Moran E. Berger S.L. Res. 1997; Google Scholar, W. Roeder R.G. Nature. 1997; 387: PubMed Scopus Google Scholar). Therefore, we have analyzed histone acetylation on the p21 promoter of p53 in vivo. We found that when p53 binds to the responsive elements in the p21 promoter, histone acetylation on the proximal to the p21 promoter is to the extent of p21 induction by wild-type p53 and various Furthermore, we found that the extent of histone acetylation on the proximal p21 promoter is to the amount of p300/CBP that with wild-type p53 and various we found that down-regulation of p300/CBP can lead to of p53-dependent induction of endogenous p21. Thus, data the and for the that both activation domains in p53 are necessary for with p300/CBP in histone acetylation on the proximal p21 promoter, and the promoter Furthermore, we found that the basic domain and the proline-rich domain are for the interaction between p53 and both domains the extent of interaction in histone acetylation and the promoter We that histone acetylation on the the elements in the p21 promoter is increased by the is almost deficient in p21 and in with p300/CBP These data that binds to the the chromatin structure of these which for access of histone acetyltransferase-containing and the acetylation of histones in these However, these histone acetyltransferase-containing proteins are to the acetylation to the proximal to the p21 promoter. the proximal promoter is the to which the transcriptional machinery of chromatin remodeling and of accessibility the proximal p21 promoter are for the of to induce endogenous p21. We Chen for the and for a
Liu et al. (Thu,) studied this question.