Negative Regulation of p53 Functions by Daxx and the Involvement of MDM2

In normal cells p53 activity is tightly controlled and MDM2 is a known negative regulator. Here we show that via its acidic domain, Daxx binds to the COOH-terminal domain of p53, whose positive charges are critical for this interaction, as Lys to Arg mutations preserved, but Lys to Ala or Ser to Glu mutations abolished Daxx-p53 interaction. These results thus implicate acetylation and phosphorylation of p53 in regulating its binding to Daxx. Interestingly, whereas Daxx did not bind to p53 in cells as assessed by immunoprecipitation, MDM2 expression restored p53-Daxx interaction, and this correlated with deacetylation of p53. In p53/MDM2-null mouse embryonic fibroblasts (DKO MEF), Daxx repressed p53 target promoters whose p53-binding elements were required for the repression. Coexpression of Daxx and MDM2 led to further repression. p53 expression in DKO MEF induced apoptosis and Daxx expression relieved this effect. Similarly, in HCT116 cells, Daxx conferred striking resistance to 5-fluorouracil-induced apoptosis. As p53 is required for 5-fluorouracil-induced cell death, our data show that Daxx can suppress cell death induced by p53 overexpression and p53-dependent stress response. Collectively, our data reveal Daxx as a novel negative regulator of p53. Importantly, posttranslational modifications of p53 inhibit Daxx-p53 interaction, thereby relieving negative regulation of p53 by Daxx. In normal cells p53 activity is tightly controlled and MDM2 is a known negative regulator. Here we show that via its acidic domain, Daxx binds to the COOH-terminal domain of p53, whose positive charges are critical for this interaction, as Lys to Arg mutations preserved, but Lys to Ala or Ser to Glu mutations abolished Daxx-p53 interaction. These results thus implicate acetylation and phosphorylation of p53 in regulating its binding to Daxx. Interestingly, whereas Daxx did not bind to p53 in cells as assessed by immunoprecipitation, MDM2 expression restored p53-Daxx interaction, and this correlated with deacetylation of p53. In p53/MDM2-null mouse embryonic fibroblasts (DKO MEF), Daxx repressed p53 target promoters whose p53-binding elements were required for the repression. Coexpression of Daxx and MDM2 led to further repression. p53 expression in DKO MEF induced apoptosis and Daxx expression relieved this effect. Similarly, in HCT116 cells, Daxx conferred striking resistance to 5-fluorouracil-induced apoptosis. As p53 is required for 5-fluorouracil-induced cell death, our data show that Daxx can suppress cell death induced by p53 overexpression and p53-dependent stress response. Collectively, our data reveal Daxx as a novel negative regulator of p53. Importantly, posttranslational modifications of p53 inhibit Daxx-p53 interaction, thereby relieving negative regulation of p53 by Daxx. The critical role of p53 in tumor suppression is manifested in frequent mutations of the p53 gene in cancers (∼50% of all human cancers) and in its inactivation in many other cancers by cellular or viral oncogenes and other epigenetic alterations (1Vogelstein B. Lane D. Levine A.J. Nature. 2000; 408: 307-310Crossref PubMed Scopus (5904) Google Scholar). p53-deficient mice develop normally, although such mice exhibit higher incidence of tumors than their wild-type counterparts, demonstrating a critical role for p53 in suppressing tumors (2Donehower L.A. Harvey M. Slagle B.L. McArthur M.J. Montgomery Jr., C.A. Butel J.S. Bradley A. Nature. 1992; 356: 215-221Crossref PubMed Scopus (4082) Google Scholar). p53 exerts its tumor suppression function by activating expression of genes involved in growth arrest and apoptosis (3Vousden K.H. Biochim. Biophys. Acta. 2002; 1602: 47-59Crossref PubMed Scopus (305) Google Scholar, 4Prives C. Hall P.A. J. Pathol. 1999; 187: 112-126Crossref PubMed Scopus (1243) Google Scholar), and it can also induce apoptosis directly by binding to Bcl-2 family proteins and triggering cytochrome c release (5Mihara M. Erster S. Zaika A. Petrenko O. Chittenden T. Pancoska P. Moll U.M. Mol. Cell. 2003; 11: 577-590Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar). Inducing growth arrest and cell death by p53 can impact negatively on normal cell growth and organismal development. Indeed, deletion of the mdm2 gene, whose product is a negative regulator of p53, results in embryonic lethality, but deletion of both p53 and mdm2 simultaneously completely rescues such lethal phenotype (6Jones S.N. Roe A.E. Donehower L.A. Bradley A. Nature. 1995; 378: 206-208Crossref PubMed Scopus (1078) Google Scholar, 7Montes de Oca Luna R. Wagner D.S. Lozano G. Nature. 1995; 378: 203-206Crossref PubMed Scopus (1217) Google Scholar). Thus, p53 activity must be tightly controlled under physiological conditions. In addition to MDM2, numerous cellular and viral proteins interact with p53 and these proteins can positively or negatively modulate p53-mediated biological effects. Recently, we and others demonstrated that the transcriptional corepressor Daxx interacts with p53 (8Zhao L.Y. Colosimo A.L. Liu Y. Wan Y. Liao D. J. Virol. 2003; 77: 11809-11821Crossref PubMed Scopus (47) Google Scholar, 9Kim E.J. Park J.S. Um S.J. Nucleic Acids Res. 2003; 31: 5356-5367Crossref PubMed Scopus (62) Google Scholar, 10Ohiro Y. Usheva A. Kobayashi S. Duffy S.L. Nantz R. Gius D. Horikoshi N. Mol. Cell. Biol. 2003; 23: 322-334Crossref PubMed Scopus (29) Google Scholar), but the biological significance of this interaction remains to be explored. Daxx was initially identified as a binding protein of Fas death domain and was shown to potentiate Fas-mediated apoptosis (11Yang X. Khosravi-Far R. Chang H.Y. Baltimore D. Cell. 1997; 89: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar). Subsequent studies implicate Daxx in promoting apoptosis in diverse stress conditions (12Zhong S. Salomoni P. Ronchetti S. Guo A. Ruggero D. Pandolfi P.P. J. Exp. Med. 2000; 191: 631-640Crossref PubMed Scopus (195) Google Scholar, 13Torii S. Egan D.A. Evans R.A. Reed J.C. EMBO J. 1999; 18: 6037-6049Crossref PubMed Scopus (236) Google Scholar, 14Perlman R. Schiemann W.P. Brooks M.W. Lodish H.F. Weinberg R.A. Nat. Cell Biol. 2001; 3: 708-714Crossref PubMed Scopus (307) Google Scholar, 15Gongora R. Stephan R.P. Zhang Z. Cooper M.D. Immunity. 2001; 14: 727-737Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). deletion of the Daxx gene in mice results in embryonic and apoptosis was in and cells J.S. D. C. P. 1999; PubMed Scopus Google Scholar), that Daxx function and is critical for organismal development. The of Daxx was in a Daxx expression by apoptosis by death L.Y. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar). Daxx as a regulator that can or G. EMBO J. 1999; 18: PubMed Scopus Google Scholar, C. J. X. J. Park E.J. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, R. 2000; PubMed Scopus Google Scholar, J. Biol. 2002; 77: Full Text Full Text PDF Scopus Google Scholar). Thus, Daxx cellular by of genes under conditions. Daxx to in that and DKO mouse embryonic cell E.J. R. G. J. Cell 2002; PubMed Google and a that protein and Y. R. Z. D. S. J. S. D. S. A. 2003; PubMed Scopus Google Scholar, J. S. Liu R. R. X. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). As Daxx directly with a of and G. EMBO J. 1999; 18: PubMed Scopus Google Scholar, J. Biol. 2002; 77: Full Text Full Text PDF Scopus Google Scholar), R. 2000; PubMed Scopus Google Scholar), and p53 and its family and (8Zhao L.Y. Colosimo A.L. Liu Y. Wan Y. Liao D. J. Virol. 2003; 77: 11809-11821Crossref PubMed Scopus (47) Google Scholar, 9Kim E.J. Park J.S. Um S.J. Nucleic Acids Res. 2003; 31: 5356-5367Crossref PubMed Scopus (62) Google Scholar, 10Ohiro Y. Usheva A. Kobayashi S. Duffy S.L. Nantz R. Gius D. Horikoshi N. Mol. Cell. Biol. 2003; 23: 322-334Crossref PubMed Scopus (29) Google Scholar), it is that Daxx a and this a for the of Daxx in apoptosis and other cellular it remains the biological significance of Daxx-p53 interaction. In it was shown that p53 but not the wild-type with Daxx Y. Usheva A. Kobayashi S. Duffy S.L. Nantz R. Gius D. Horikoshi N. Mol. Cell. Biol. 2003; 23: 322-334Crossref PubMed Scopus (29) Google Scholar). that both wild-type p53 and its with Daxx in Daxx-p53 interaction was by posttranslational modifications of the p53 COOH-terminal MDM2 Daxx-p53 interaction in also that Daxx both p53 transcriptional and of the Daxx were to the domain in or to domain in Similarly, and p53 were with were as Y. Colosimo A.L. Liao D. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). Cell and tumor cell HCT116 A. C. T. S. B. PubMed Scopus Google Scholar), and the p53 and MDM2 mouse embryonic (DKO de Oca Luna R. Wagner D.S. Lozano G. Nature. 1995; 378: 203-206Crossref PubMed Scopus (1217) Google were in with were with the of Daxx in was the of Daxx was the to the as Y. Colosimo A.L. Liao D. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar). cells were with Daxx and Daxx with the was the cells with binding and and was with were and in with of of of of of Cell was and Cell were by for The was with for and with by a with The were with and with and in In proteins were to and the proteins were were (8Zhao L.Y. Colosimo A.L. Liu Y. Wan Y. Liao D. J. Virol. 2003; 77: 11809-11821Crossref PubMed Scopus (47) Google Scholar, L.Y. Liao D. J. Virol. 2003; 77: PubMed Scopus Google Scholar). DKO MEF cells on were with the and were with for and with in The were with and in with or or all the cells were with and with with The cells were and in MEF and cells were in a The and were L.Y. Liu Y. Liao D. 2003; PubMed Scopus Google Scholar). the p53 elements the of the human gene as T. C. T. T. Y. Y. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The the gene the were cells or with other as in the cells were and for activity was the cells on were with of expression for and The of in was with expression Cell were with or The cells were with and on were under a and were or that also and as by the under a were The cells and cells were and of cells was and cells were with expression or cells were and under and were as C. Liao D. 1999; PubMed Scopus Google Scholar). were and with or and were and with The cells in were by of for with for the The cells were by for and in a with and for The cells were with for in the were with a Daxx to p53 in we identified interaction Daxx and and that Daxx and p53 in the in cells (8Zhao L.Y. Colosimo A.L. Liu Y. Wan Y. Liao D. J. Virol. 2003; 77: 11809-11821Crossref PubMed Scopus (47) Google Scholar), we Daxx also bind directly to p53. a interaction Daxx and p53, we their interaction in the of cells Daxx was with p53, Daxx was with p53 in p53 was the were to the required for Daxx-p53 As shown in Daxx and Daxx the and and with p53, but not other Daxx and not of the acidic domain Daxx abolished its interaction with p53 Thus, Daxx and the acidic domain is required for binding to p53 in p53 with the to were to bind to Daxx in deletion the abolished p53-Daxx interaction and These deletion were all in p53 and the did not interact with Daxx not mutations in the p53 and did not Daxx-p53 interaction and mutations in the domain of and did not binding of p53 to Daxx These p53 were in The results that a that but not wild-type p53, with Daxx Y. Usheva A. Kobayashi S. Duffy S.L. Nantz R. Gius D. Horikoshi N. Mol. Cell. Biol. 2003; 23: 322-334Crossref PubMed Scopus (29) Google Scholar). COOH-terminal of p53 abolished p53-Daxx interaction and the p53 COOH-terminal domain is required for binding to and mutations in the or domain not binding of p53 to Daxx in The data also that of the of p53 also be involved in binding to as the to in this of the and of the COOH-terminal domain of p53. In the of the p53 it is that this the of the COOH-terminal domain that Daxx can bind to p53. of the COOH-terminal of p53 for Daxx-p53 of p53 is in regulating p53 was shown that this domain negatively the p53 function J. C. Nat. Biol. 2001; PubMed Scopus Google Scholar). In it of acetylation by and as as phosphorylation J. 2001; PubMed Scopus Google Scholar, Cell Biol. 2003; PubMed Scopus Google Scholar). of acetylation and phosphorylation in regulating Daxx-p53 interaction, we known and acetylation and phosphorylation the of p53 and the interaction of Daxx with such p53 As shown in COOH-terminal abolished Daxx-p53 interaction, whereas were for binding in of of and and acetylation Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Zhang R. S.L. Mol. Cell. Biol. 1999; PubMed Scopus Google Scholar, S. T. M. A. PubMed Scopus Google positively did not interaction and all and were p53-Daxx interaction was Daxx-p53 interaction was abolished of were and of negatively also abolished Daxx-p53 interaction and of the phosphorylation did not Daxx-p53 interaction in of to that the Daxx-p53 interaction and whereas did not p53-Daxx interaction and are phosphorylation of p53 J. 2001; PubMed Scopus Google of the p53 shown in interaction with in not In we expression of these p53 in and that were all Thus, negative interaction results of p53 were of not of protein in Collectively, these results that positive charges in the p53 a critical role in Daxx-p53 interaction, but is for this that Daxx-p53 interaction is and is not by of or acetylation is to inhibit Daxx-p53 interaction, acetylation by the binding of Daxx to p53. In phosphorylation the of p53 also inhibit binding of Daxx to p53. both acetylation and phosphorylation Daxx p53. MDM2 Daxx-p53 in the by and others to Daxx-p53 interaction in cell by were Y. Usheva A. Kobayashi S. Duffy S.L. Nantz R. Gius D. Horikoshi N. Mol. Cell. Biol. 2003; 23: 322-334Crossref PubMed Scopus (29) Google Scholar). Y. J. G. S. Y. Y. and D. Daxx-p53 interaction was Daxx and p53 cells as as in p53 in the cell p53 binding to Daxx. Indeed, Daxx cells not bind to p53 human cells not acetylation of p53 Daxx-p53 interaction, overexpression of proteins that acetylation of p53 binding of Daxx to p53. to p53 J. D. A. Nature. 2000; 408: PubMed Scopus Google Scholar). MDM2 p53 acetylation Y. J. Biol. 2002; Google and also deacetylation of p53 A. Y. Y. EMBO J. 2002; PubMed Scopus Google Scholar). these proteins Daxx-p53 interaction, was p53-deficient HCT116 cells with of p53, MDM2, and of p53, and MDM2 in cells was by The cell were to in the of MDM2 was Daxx-p53 interaction restored and the of p53 acetylation in cell of p53 protein was and the that p53 and was to p53. As shown in the of MDM2 in deacetylation of p53 and with other that MDM2 Daxx-p53 interaction in by p53 of Daxx-p53 in the shown that MDM2 is critical for Daxx-p53 interaction in the we to of Daxx are required for binding to p53 in Daxx with the were with for p53 and MDM2 HCT116 cells and expression of these proteins in the cells was The cell were to with and the proteins were Daxx led to p53 and Daxx and a with deletion of G. EMBO J. 1999; 18: PubMed Scopus Google to p53 than wild-type Daxx and In the Daxx with a deletion and binding to p53 The Daxx domain and the COOH-terminal and did not bind to p53. These results that the acidic domain of Daxx is required for binding to p53, with the results MDM2 was in the the shown in was and with MDM2 was with Daxx and its and and MDM2 was with Daxx than with the Daxx in with the of p53. Interestingly, although p53 was with Daxx and MDM2 was with and These results that MDM2 in Daxx-p53 and the Daxx-p53 and modifications of p53, thereby Daxx-p53 interaction. MDM2 the of Daxx to its p53-binding domain, or Daxx in Daxx-p53 interaction in the of MDM2 and in and that p53 that or p53 abolished binding of p53 to Daxx in these results also in human cells, was with p53 and the cell were to Daxx was with p53 and to a with p53 and p53 Daxx was with p53 and In the of p53, Daxx was not p53 not bind to MDM2 J. J. B. Levine A.J. PubMed Scopus Google Scholar), the that it also to bind to Daxx in HCT116 cells MDM2 is required for the Daxx-p53 MDM2 deacetylation of the p53 and Daxx not bind to this the p53 was not and not of of the interaction by the as it shown that both and are critical for p53 to bind to and completely abolished interaction D. J. Biol. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). although Daxx did not bind to p53 and in were with Daxx and our data that MDM2 the interaction of p53 with Daxx in human MDM2 p53-Daxx in further the of MDM2 for Daxx-p53 interaction, we DKO MEF de Oca Luna R. Wagner D.S. Lozano G. Nature. 1995; 378: 203-206Crossref PubMed Scopus (1217) Google Scholar). was with of p53, its and in DKO MEF and The cell were with and the were with and MDM2 and p53 was in the of MDM2 but of p53 was in the of MDM2 expression p53 was p53 and were also with although to a than p53 and with in Interestingly, the p53 was In the of p53, with were the is the p53, and the be The other be p53. Interestingly, the with both in addition to not p53 were also with p53 and and the p53 was and with in that Daxx a role in of p53 MDM2 to with Daxx in the of p53 the of MDM2 was with and in Collectively, these results that the and Daxx not bind to p53 in the of all are a of MDM2, and p53 in DKO also of these In DKO MEF cells, all proteins were in the Daxx in as as in the and in as (8Zhao L.Y. Colosimo A.L. Liu Y. Wan Y. Liao D. J. Virol. 2003; 77: 11809-11821Crossref PubMed Scopus (47) Google Scholar), whereas both p53 and MDM2 were these and Interestingly, in of the cells, all proteins were simultaneously in both the and in The of p53 or MDM2 were both or were with Daxx the of p53 the biological significance of the Daxx-p53 interaction, we Daxx p53-mediated DKO MEF cells were with the that the of the of p53 led to a of activity of Daxx or MDM2 in the of p53 expression on the of p53 with Daxx or MDM2 in of the activity was to or of all proteins led to a further of the activity As p53 did not the in the of p53-binding in the Similarly, Daxx and MDM2 on in the of p53-binding Thus, of binding of p53 to the also Daxx by p53 or In the but not binds to Daxx whereas both bind to p53 in cells and As shown in both a to the with a positive role of acetylation these for p53-mediated J. M. Y. M. S. A. PubMed Scopus Google Scholar). Interestingly, Daxx or MDM2 the with of these p53 Coexpression of Daxx and MDM2 with p53 led to of the but was were with the p53 Daxx also of the the that the p53-binding and of both Daxx and MDM2 in further of p53-dependent Daxx p53-mediated of p53, and MDM2 in DKO we that a cells were p53 was but many cells were p53 was with Daxx or MDM2 or both to that Daxx inhibit apoptosis. this the as a effects. The was or with other expression as in In were The of cells and cells in these were As shown in of cells were was In cells, of cells were of cell of MDM2, or the in Interestingly, all MDM2, and with p53, in cells than p53 was Thus, MDM2 and Daxx can cells p53-mediated apoptosis. results were was as a and the cells were with not cells, a of p53 was These cells were but not in the data all were it that p53 expression in of and this was MDM2, or were these data that Daxx p53-dependent apoptosis. The data shown that expression of Daxx can suppress cell death in MEF DKO further this we p53-dependent apoptosis induced by not by p53 can also be by Daxx. HCT116 cells with expression for or with that for Daxx or MDM2 or The cell were with is known to induce p53-dependent cell death in HCT116 cells C. T. Zhang Y. J. C. B. J. 1999; PubMed Scopus Google Scholar). The cells cells were with the cells that in addition to also with and with in are for of cells normal of that is of in the and also with cells in were As shown in of cells were Coexpression of Daxx or MDM2 or both apoptosis to As the p53 protein was in to in with but not cells Thus, Daxx can inhibit p53-dependent apoptosis induced by further to of cell death by Daxx in HCT116 Daxx overexpression were by of the HCT116 Daxx with a with were or with and the cells were and for As shown in the protein of Daxx was higher in a than that in the with and induced p53 protein in both and cells with results C. T. Zhang Y. J. C. B. J. 1999; PubMed Scopus Google Scholar), HCT116 cells were to all cells the were In striking a of cells The of cells with in was than that in the the and The cell of and were in cells Daxx overexpression and resistance to apoptosis not Thus, the must not be of effects. Daxx resistance to and p53-dependent cell death in HCT116 cells, in with results shown in Daxx biological apoptosis to transcriptional Daxx was as a protein that binds to the of Fas and growth by activating the (11Yang X. Khosravi-Far R. Chang H.Y. Baltimore D. Cell. 1997; 89: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (840) Google Scholar, 14Perlman R. Schiemann W.P. Brooks M.W. Lodish H.F. Weinberg R.A. Nat. Cell Biol. 2001; 3: 708-714Crossref PubMed Scopus (307) Google Scholar). In cells, Daxx in the in it can induce apoptosis (12Zhong S. Salomoni P. Ronchetti S. Guo A. Ruggero D. Pandolfi P.P. J. Exp. Med. 2000; 191: 631-640Crossref PubMed Scopus (195) Google Scholar, 13Torii S. Egan D.A. Evans R.A. Reed J.C. EMBO J. 1999; 18: 6037-6049Crossref PubMed Scopus (236) Google Scholar). also that Daxx induce apoptosis in tumor cell Thus, Daxx in In deletion of the Daxx gene is lethal to mouse embryonic and cells apoptosis J.S. D. C. P. 1999; PubMed Scopus Google Scholar, J.S. P. J. Cell 2003; PubMed Scopus Google Scholar). with these of Daxx by cells to Fas and apoptosis L.Y. Mol. Cell. Biol. 2003; 23: PubMed Scopus Google Scholar). Daxx cell death and in in this that Daxx binds to p53 in and MDM2 Daxx-p53 interaction in cells also that Daxx can p53 target genes and cells p53-mediated apoptosis our are with a role for Daxx in cell Daxx can inhibit and apoptosis and thus a negative regulator of p53. is that MDM2 to the p53-Daxx interaction in the cell and These proteins also exhibit in p53-mediated MDM2 is a known negative regulator of p53 and it p53 binds to p53 and p53-mediated by that the transcriptional bind to p53 MDM2 can also inhibit acetylation of p53 A. Y. Y. EMBO J. 2002; PubMed Scopus Google Scholar, X. Y. D. S. A. 2000; PubMed Scopus Google Scholar, A. X. S. EMBO J. 2001; PubMed Scopus Google Scholar), negatively on p53 acetylation of p53 its binding to the of its target promoters J. M. Y. M. S. A. PubMed Scopus Google Scholar), and also inhibit of p53, thereby it Cell Biol. 2003; PubMed Scopus Google Scholar). the of regulation of p53 by MDM2 is its of p53 D. M. 2002; PubMed Scopus Google Scholar). MDM2 as a p53 thereby promoting of p53. it that MDM2 of p53, other that p53 to be results that Daxx also a role in of p53. in that the p53 with Daxx were it is also that p53 binds to Daxx studies are required to these a role in p53 Daxx also p53 in other Daxx is a corepressor and binds to C. J. X. J. Park E.J. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, E.J. R. G. J. Cell 2002; PubMed Google Scholar). Daxx also binds to J.S. D. C. P. 1999; PubMed Scopus Google and Thus, Daxx to p53 target promoters and the expression of p53 target in the of MDM2, Daxx binds to p53 as assessed in but their interaction remains in DKO MEF of the Thus, MDM2 but is not required for Daxx to bind to p53. with Daxx p53-mediated in the of MDM2 Daxx can inhibit cell death in the of MDM2 in DKO MEF Similarly, overexpression of Daxx can HCT116 cells cell death and although to Daxx-p53 interaction in the of MDM2 overexpression are that our of apoptosis not p53-Daxx interaction. Daxx p53 genes such as and and this is interaction of Daxx with proteins that in p53. Daxx also inhibit the of p53 to directly apoptosis a p53-Daxx interaction. As shown in Daxx and p53 in both the and Daxx be to suppress the of p53 to the of apoptosis. Daxx-p53 interaction in the of MDM2 interaction be in and to posttranslational modifications of the COOH-terminal domain of p53 that it is not in Daxx and p53 be a of the and both p53 and Daxx be for and Daxx that is for Daxx-p53 interaction. In with this we striking of Daxx and p53 in cells (8Zhao L.Y. Colosimo A.L. Liu Y. Wan Y. Liao D. J. Virol. 2003; 77: 11809-11821Crossref PubMed Scopus (47) Google Scholar). our results show that posttranslational modifications acetylation and phosphorylation of p53 in the COOH-terminal domain can inhibit the of Daxx with p53 and a the data in this the of for the of p53 posttranslational modifications on its binding to other human Daxx p53 as as many of these Thus, although that human proteins be in our data that Daxx-p53 interaction be in mutations of p53 Daxx-p53 interaction in In Daxx not bind to p53 cells in not also Importantly, expression of MDM2 Daxx-p53 interaction, and this deacetylation of p53 MDM2 expression is known that of stress p53 phosphorylation of p53 by a of and acetylation of p53 by and Cell Biol. 2003; PubMed Scopus Google Scholar). the of p53 in MDM2 p53 Cell Biol. 2003; PubMed Scopus Google Scholar). show that both phosphorylation and acetylation the COOH-terminal domain the of p53 with negative regulator of p53. data thus further the of posttranslational modifications of p53 in regulating p53-mediated stress results other known for a that the of p53 its of the or binding of to it can the of p53 J. C. Nat. Biol. 2001; PubMed Scopus Google Scholar, C.A. Lane Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). of the be by its or both J. C. Nat. Biol. 2001; PubMed Scopus Google Scholar). In expression of the p53 a COOH-terminal results in p53 S. J. S. N. X. G. Cooper B. C. Park S. T. G. Bradley A. Donehower L.A. Nature. 2002; PubMed Scopus Google Scholar). Recently, it was that a the of the p53 D. J. J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). Daxx binds to the COOH-terminal domain of p53 and both acetylation and phosphorylation can this interaction, Daxx be that the by to the p53 COOH-terminal Thus, our these in of the embryonic phenotype of mice J.S. D. C. P. 1999; PubMed Scopus Google Scholar), it is to that MDM2 and J. A. Lozano G. Nat. 2001; PubMed Scopus Google Scholar), Daxx also embryonic by p53-mediated effects. mice whereas Daxx and mice a de Oca Luna R. Wagner D.S. Lozano G. Nature. 1995; 378: 203-206Crossref PubMed Scopus (1217) Google Scholar, J.S. D. C. P. 1999; PubMed Scopus Google Scholar, J. A. Lozano G. Nat. 2001; PubMed Scopus Google Scholar). Thus, these proteins p53 activity in G. Lozano for B. for p53 and MDM2 expression and HCT116 cells, for and X. J. for

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