Interferon Regulatory Factor-2 Regulates Cell Growth through Its Acetylation

Abstract

We have previously shown that interferon regulatory factor-2 (IRF-2) is acetylated by p300 and PCAF in vivo and in vitro. In this study we identified, by mass spectrometry, two lysine residues in the DNA binding domain (DBD), Lys-75 and Lys-78, to be the major acetylation sites in IRF-2. Although acetylation of IRF-2 did not alter DNA binding activity in vitro, mutation of Lys-75 diminished the IRF-2-dependent activation of histone H4 promoter activity. Acetylation of IRF-2 and IRF-2-stimulated H4 promoter activity were inhibited by the adenovirus E1A, indicating the involvement of p300/CBP. Mutation of Lys-78, a residue conserved throughout the IRF family members, led to the abrogation of DNA binding activity independently of acetylation. H4 is transcribed only in rapidly growing cells and its promoter activity is dependent on cell growth. Consistent with a role for acetylated IRF-2 in cell growth control, IRF-2 was acetylated only in growing NIH 3T3 cells, but not in growth-arrested counterparts. Chromatin immunoprecipitation assays showed that IRF-2 interacted with p300 and bound to the endogenous H4 promoter only in growing cells, although the levels of total IRF-2 were comparable in both growing and growth-arrested cells. These results indicate that IRF-2 is acetylated in a cell growth-dependent manner, which enables it to contribute to transcription of cell growth-regulated promoters. We have previously shown that interferon regulatory factor-2 (IRF-2) is acetylated by p300 and PCAF in vivo and in vitro. In this study we identified, by mass spectrometry, two lysine residues in the DNA binding domain (DBD), Lys-75 and Lys-78, to be the major acetylation sites in IRF-2. Although acetylation of IRF-2 did not alter DNA binding activity in vitro, mutation of Lys-75 diminished the IRF-2-dependent activation of histone H4 promoter activity. Acetylation of IRF-2 and IRF-2-stimulated H4 promoter activity were inhibited by the adenovirus E1A, indicating the involvement of p300/CBP. Mutation of Lys-78, a residue conserved throughout the IRF family members, led to the abrogation of DNA binding activity independently of acetylation. H4 is transcribed only in rapidly growing cells and its promoter activity is dependent on cell growth. Consistent with a role for acetylated IRF-2 in cell growth control, IRF-2 was acetylated only in growing NIH 3T3 cells, but not in growth-arrested counterparts. Chromatin immunoprecipitation assays showed that IRF-2 interacted with p300 and bound to the endogenous H4 promoter only in growing cells, although the levels of total IRF-2 were comparable in both growing and growth-arrested cells. These results indicate that IRF-2 is acetylated in a cell growth-dependent manner, which enables it to contribute to transcription of cell growth-regulated promoters. The discovery that transcriptional coactivators have histone acetylase activity provided important insights into the process that links chromatin acetylation to transcriptional activation (1Nakatani Y. Genes Cells. 2001; 2: 79-86Crossref Scopus (49) Google Scholar, 2Yamauchi T. Yamauchi J. Kuwata T. Tamura T. Yamashita T. Bae N. Westphal H. Ozato K. Nakataui Y. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 11303-11306Crossref PubMed Scopus (187) Google Scholar, 3Ikura T. Ogryzko V.V. Grioriev M. Groisman R. Wang J. Horikoshi M. Scully R. Qin J. Nakatani Y. Cell. 2000; 102: 463-473Abstract Full Text Full Text PDF PubMed Scopus (871) Google Scholar, 4Vassilev A. Yamauchi J. Kotani T. Prives C. Avantaggiati M.L. Qin J. Nakatani Y. Mol. 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In addition to histones, PCAF 1The abbreviations used are: PCAF, p300/CBP-associated factor; IRF, interferon regulatory factor; DBD, DNA binding domain; GST, glutathione S-transferase; CBP, CREB-binding protein; CREB, cAMP-response element-binding protein; PBS, phosphate-buffered saline.1The abbreviations used are: PCAF, p300/CBP-associated factor; IRF, interferon regulatory factor; DBD, DNA binding domain; GST, glutathione S-transferase; CBP, CREB-binding protein; CREB, cAMP-response element-binding protein; PBS, phosphate-buffered saline. and p300/CBP are known to acetylate and regulate various transcription-related proteins other than histones. p300/CBP is a ubiquitously expressed, global transcriptional coactivator that has critical roles in a wide variety of cellular processes, including cell cycle control, differentiation, and apoptosis. The known factor acetyltransferase substrates of p300/CBP, including high mobility group I(Y), activators p53, E2F, GATA-1, erythroid Kruppel-like factor, Drosophila T-cell factor, and human immunodeficiency virus Tat, nuclear receptor coactivators SRC-1, ACTR, and TIF2, and general factors TFIIE and TFIIF (6Benkirane M. Chun R.F. Xiao H. Ogryzko V.V. Howard B.H. Nakatani Y. Jeang K.T. J. Biol. Chem. 1998; 273: 24898-24905Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 10Bergel M. Herrera J.E. Thatcher B.J. Prymakowska-Bosak M. Vassilev A. Nakatani Y. Martin B. Bustin M. J. Biol. Chem. 2000; 275: 11514-11520Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 11Liu L. Scolnick D.M. Trievel R.C. Zhang H.B. Marmorstein R. Halazonetis T.D. Berger S.L. Mol. Cell. Biol. 1999; 1999: 1202-1209Crossref Scopus (653) Google Scholar, 12Herrera J.E. Sakaguchi K. Bergel M. Trieshmann L. Nakatani Y. Bustin M. Mol. Cell. 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The IRF regulatory family of transcription factors has in the of and of this family have DNA binding binding to the and IRF proteins regulate transcription of interferon and IRF proteins with other transcription factors coactivators p300 and PCAF Ozato K. Mol. Cell. Biol. 1996; PubMed Scopus Google Scholar, A. Wang B. Nakatani Y. Ozato K. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar, M. W. Y. M. E. T. EMBO J. 1998; PubMed Scopus Google Scholar, M. B. Ogryzko V. Ozato K. Mol. Cell. Biol. 2000; PubMed Scopus Google Scholar, Mol. Cell. Biol. 1998; 18: PubMed Scopus Google Scholar). IRF-2 has a transcriptional and it is to by with the transcriptional IRF-2 a for including the H4 promoter F. Wu S. H. T. J.L. Nature. PubMed Scopus Google promoter R. J. Biol. 1998; PubMed Scopus Google and promoter W. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). IRF-2 is to factors and which both transcriptional and Y. E. T. Cell. Full Text PDF PubMed Scopus Google Scholar). IRF-2 important role in cell growth and has shown to be a of IRF-2 growth in NIH 3T3 cells and in H. M. N. H. K. M. T. PubMed Scopus Google Scholar). We previously that IRF-2 in cells is with PCAF, and is acetylated A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). Consistent with IRF-2 was acetylated by and to a by PCAF, in A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google the of acetylation in the IRF members, and were shown to be acetylated in vivo and in W. M. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In a A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google we that acetylation of IRF-2 not alter its DNA binding although acetylation DNA binding activity and transcription for transcription acetylation of IRF-2 led to of histone acetylation by a for transcriptional by IRF-2. In this we two lysine residues in the IRF-2 DNA binding domain that are We that Lys-75 is important for the with p300 and the of histone H4 promoter activity. H4 is transcribed cell IRF-2 F. H. T. J.L. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). of the of IRF-2 we that IRF-2 is acetylated only in rapidly growing NIH 3T3 cells but not in growth-arrested cells, although IRF-2 is a in both of cells. Chromatin immunoprecipitation that acetylated IRF-2 a and to the endogenous H4 IRF-2 is acetylated by p300 in NIH 3T3 cells in a cell growth-dependent manner, it to in for cell growth 3T3 cells were in with with and in and cells were in with were by the of with including the addition of a to was previously A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The the cell of total proteins were in the with on and for The was with in a and for with and for and in The was by in a and to of Acetylation of was with of for in of acetyltransferase A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). The was with of for to the and was by high was with of in a and for were to mass and and were by a into the a was by and into the and proteins were in and previously A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). IRF-2 IRF-2 was by to the by to and were provided Y. Nakatani H4 were into NIH 3T3 cells with H4 A. Wang B. Nakatani Y. Ozato K. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google by and activity was of cells, E1A, and were by and of human PCAF was in cells by a and previously A. Wang B. Nakatani Y. Ozato K. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). human p300 were and T. T. T. M. Genes 2000; Google Scholar). In were a previously A. Wang B. Nakatani Y. Ozato K. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). In Acetylation proteins were with of p300 PCAF in of acetylation and with were for and by The were by with to acetylation and the was to with to the of proteins used in were by by were with in a and and were in on by DNA and DNA binding was A. Wang B. Nakatani Y. Ozato K. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar, A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). nuclear of were with to the H4 F. Wu S. H. T. J.L. Nature. PubMed Scopus Google Scholar). were with and mobility assays were a H4 promoter F. Wu S. H. T. J.L. Nature. PubMed Scopus Google by In were with a of and of in the of a were the by on in a The was and by Chromatin chromatin immunoprecipitation was M.-H. Allis D. Methods. 1999; 19: 425-433Crossref PubMed Scopus (486) Google with total NIH 3T3 cells were with for were with and in of a on for and to of by cell of chromatin were in of and with of DNA and of in for was with of and of DNA were to immunoprecipitation and for were for in a and were with of to and DNA were with a a total of was used in the used in were the H4 promoter and the were The were for which was the of Lys-75 and of IRF-2 of previously that the of IRF-2 is acetylated by p300 and PCAF in A. Ozato K. J. Biol. 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In did not acetylation The did not acetylation acetylation of was acetylation was by not We to lysine residues the IRF-2 that are acetylated by p300 and this the were acetylated by p300 and PCAF in vitro, by and the were to mass to acetylated We that and in were by acetylation other and major acetylation sites were in which of the residues was to These were acetylated in by p300 and PCAF, and the levels of acetylation were by with was acetylated both by p300 and PCAF and were although than the levels of acetylation were for both by PCAF and In acetylation by PCAF was for although the was with p300 These results indicate that Lys-75 is the major of acetylation by p300 and PCAF, is acetylated by PCAF, to a The lysine residue is and but not in other IRF family is a residue conserved in IRF family and is critical for binding activity A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). although mass other residues and to be the acetylation of residues Lys-75 and the sites of IRF-2 acetylation in vitro, it was important to residues were acetylated in IRF-2 IRF-2 and were into cells. were by and by with shown in the for IRF-2 than the and and Acetylation of was with with the that the IRF-2 were comparable These results that Lys-75 and are acetylated in The Acetylation to H4 previously showed that acetylation of IRF-2 not alter DNA binding activity A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). we the of to in DNA binding activity. In and were in mobility assays the of the histone H4 promoter a The bound to the the IRF-2. In the to to the is conserved throughout the IRF family and is in DNA binding J. D. Nature. 1998; PubMed Scopus Google and the mutation of this residue a for DNA mutation of the residue in IRF family proteins DNA binding activity A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. Kuwata T. Ozato K. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). IRF-2 on the promoter IRF-2 for the H4 promoter in NIH 3T3 cells F. Wu S. H. T. J.L. Nature. PubMed Scopus Google Scholar). the mutation of Lys-75 the of IRF-2 to H4 promoter assays were for and and a with NIH 3T3 cells are shown in of IRF-2 the H4 promoter activity in a the only promoter of the by IRF-2. The that did not to the did not the H4 mutation of the residue Lys-75 of the role for acetylation of Lys-75 in the transcriptional activity of IRF-2. that activation of H4 promoter activity on acetylation of we to the of p300/CBP PCAF to H4 promoter activity. levels of PCAF are in NIH 3T3 cells, p300/CBP is the acetylase IRF-2 in cells. has shown that p300/CBP to the adenovirus E1A, and that this binding transcription activation J. 1998; PubMed Google Scholar). the to to and not transcription C. M. Fu M. G. B. Avantaggiati M. K. B. R.G. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, D. E. D. R. Nature. PubMed Scopus Google Scholar, Y. V. V. Wu Wang Nakatani Y. L. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M.L. Nature. PubMed Scopus Google Scholar, J.L. P. M.A. Kouzarides T. EMBO J. 1998; PubMed Scopus Google Scholar, Ogryzko V.V. J. Howard B.H. Nakatani Y. Nature. 1996; PubMed Scopus Google Scholar). In shown in H4 promoter activity was of IRF-2 and with the of inhibited the H4 promoter by IRF-2. the other did not the H4 promoter that endogenous p300 in IRF-2-dependent activation of H4 promoter activity. IRF-2 acetylation is inhibited by E1A, was for IRF-2 with in cells. shown in of E1A, but not of the acetylation of IRF-2 in These results that p300/CBP its transcriptional activity. the promoter activity of the IRF-2 was with into NIH 3T3 cells. inhibited the activation of H4 promoter activity by IRF-2 that of IRF-2 IRF-2 in but in NIH 3T3 has by cell growth in NIH 3T3 cells H. M. N. H. K. M. T. PubMed Scopus Google Scholar). acetylation of IRF-2 is to cell growth control, we the of IRF-2 acetylation in growth-arrested NIH 3T3 cells. IRF-2 was by and for acetylation by in IRF-2 was a comparable in growing and growth-arrested cells. acetylation of IRF-2 was only in growing cells, but not in growth-arrested cells. These results indicate that acetylation of IRF-2 on the of cell growth. These results were histone H4 is a cell the and is not in cells F. H. T. J.L. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). we to acetylated IRF-2 to the H4 promoter in a cell growth-dependent this we a DNA binding with H4 promoter that to growing and growth-arrested cells were with the H4 promoter and bound IRF-2 was by are shown in of IRF-2 to the H4 promoter was only with growing cells, but not growth-arrested cells, that levels of total IRF-2 in the that only acetylated IRF-2 to the H4 We that in addition to H4 promoter DNA bound to only growing cells, but not growth-arrested cells. the total levels of p300 were growing and cells. it was of to that IRF-2 to the promoter of the endogenous H4 in a cell growth-dependent we chromatin immunoprecipitation assays for growing and growth-arrested NIH 3T3 cells. were with and chromatin was to DNA were by and DNA was to to a H4 promoter shown in the IRF-2 the H4 promoter DNA growing cells. the to DNA growth-arrested cells. The did not a These results that IRF-2 to the H4 promoter in growing NIH 3T3 cells, but not in growth-arrested the role of IRF-2 acetylation in H4 transcription and cell growth. wide of DNA binding transcription factors has shown to be acetylated (6Benkirane M. Chun R.F. Xiao H. Ogryzko V.V. Howard B.H. Nakatani Y. Jeang K.T. J. Biol. Chem. 1998; 273: 24898-24905Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar, 10Bergel M. Herrera J.E. Thatcher B.J. Prymakowska-Bosak M. Vassilev A. Nakatani Y. Martin B. Bustin M. J. Biol. Chem. 2000; 275: 11514-11520Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 14Martinez-Balbas M.A. Baner U.M. Nielsen S.J. Brehm A. Kouzarides T. EMBO J. 2000; 19: 662-671Crossref PubMed Scopus (568) Google Scholar, 17Zhang W. Bieker J.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 9855-9860Crossref PubMed Scopus (328) Google Scholar, 18Boyes J. Byfield P. Nakatani Y. Ogryzko V. Nature. 1998; 396: 594-598Crossref PubMed Scopus (634) Google Scholar, 21Deng L. de la Fuente C. Fu P. Wang L. Donnelly R. J.D. P. H. F. 2000; PubMed Scopus Google Scholar, Y. V. V. Wu Wang Nakatani Y. L. Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Acetylation of transcription factors DNA binding and transcriptional to regulatory Mol. Sci. 2000; PubMed Scopus Google Scholar). In the we IRF-2 acetylation in in vivo and in vitro. We showed that IRF-2 is acetylated the DBD, and that two Lys-75 and Lys-78, the are major sites of acetylation. is a residue a important for binding activity and is conserved throughout the IRF family T. T. Kuwata T. Ozato K. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the residue in was shown to be acetylated in vivo and in A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Mutation of this residue in both IRF-2 and DNA binding activity DNA binding activity is not dependent on the acetylation of this in which this residue be acetylated DNA binding activity A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). this the residue is in IRF is not acetylated by p300/CBP PCAF, a mutation of this residue binding A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, T. T. Kuwata T. Ozato K. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). acetylation of Lys-75 is not to binding activity in acetylation of IRF-2 not alter DNA binding activity in mobility assays A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). results indicate that acetylation of Lys-75 is for transcriptional activity of a mutation of Lys-75 diminished H4 promoter with levels of IRF-2 acetylation in vivo to be acetylated the in that this residue is acetylated both in vivo and in vitro. The to the indicating that this residue is important for DNA binding acetylation. on the in binding assays and a by A. A. E. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google DNA binding activity not on the acetylation of this In the of DNA binding activity by the the of acetylation be only with the We that p300/CBP, than PCAF, is the acetylase for IRF-2 in NIH 3T3 cells, p300 is a high in NIH 3T3 cells, PCAF is Lys-75 is by both p300 and PCAF in vitro, PCAF acetylate IRF-2 this residue in other cell In with the role of p300/CBP, that with cellular factors for p300/CBP binding inhibited H4 promoter activity. H4 promoter activity was not inhibited by which not to p300/CBP. with the of promoter IRF-2 acetylation in vivo was inhibited by These indicate that p300/CBP with IRF-2 and Lys-75 in NIH 3T3 cells, and that this to by E1A, is critical for IRF-2 activation of the H4 M. C. E. N. Biol. PubMed Scopus Google the of to to and its activity in transcription We the involvement of which has histone acetyltransferase activity and to the of to in p300 IRF-2 than that of PCAF in vitro, and a of p300 with IRF-2 in NIH 3T3 cells. These that p300 acetylase is for IRF-2 transcriptional in cells, although acetylase other than p300/CBP has to be in in the In with has to with the acetylation of DNA binding and transcription in V. Y. Ogryzko V.V. Howard B.H. L. Wang A. Nakatani Y. M. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google showed that a with PCAF and p300/CBP to the acetylation of which is critical for of this process by acetylation and the of the In J. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google showed that acetylation of in vivo in manner, which is to transcriptional activity of Although acetylation is not for to to the mutation that acetylation the of to cellular J. Mol. Cell. Biol. 1999; 19: PubMed Scopus Google Scholar). IRF-2 has a activity and a for H. E. S. K. T. Mol. Cell. Biol. PubMed Scopus Google Scholar). In this we previously that acetylation of IRF-2 acetylation of histones, that acetylated IRF-2 transcription in A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). acetylated IRF-2 be dependent on promoters. We have study to the role of acetylated IRF-2 in cell and showed that IRF-2 is acetylated only in growing cells, but not growth-arrested cells. DNA a chromatin immunoprecipitation we that IRF-2 to the H4 promoter only in growing cells, and that IRF-2 was IRF-2 was in growth-arrested cells levels comparable with rapidly growing cells, but was not acetylated bound to the H4 promoter in growth-arrested cells, that only acetylated IRF-2 to the H4 promoter and H4 promoter activity. indicate that acetylated IRF-2 has for the H4 promoter in although acetylation did not alter the DNA binding activity of IRF-2 in mobility assays A. Ozato K. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). a endogenous IRF-2 is to to the H4 promoter by with IRF-2 a that of and to the promoter than IRF-2 in the of acetylation not have with mobility assays DNA binding is In this L. K. Halazonetis T.D. Berger S.L. Mol. Cell. 2001; Full Text Full Text PDF PubMed Scopus Google showed that acetylated to the transcriptional and than p53, although acetylated and to the promoter in the W. M. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that was acetylated into the that and that a p300 histone acetylase activity to DNA binding indicating that acetylation of is important for the DNA binding activity of the These results the that acetylation the DNA binding activity of IRF family members, results indicate that IRF-2 is acetylated by p300/CBP in a cell growth-regulated The of IRF-2 acetylation and transcriptional activity a for cell transcription of the H4 F. Wu S. H. T. J.L. Nature. PubMed Scopus Google Scholar). has shown that although p300/CBP is throughout the cell levels of and coactivator the cell cycle P. E. Mol. Cell. Biol. PubMed Scopus Google Scholar). is by the the histone acetylase activity this of the cell cycle S. A. S. R. A. P. A. D. F. A. 2000; 19: PubMed Scopus Google Scholar). p300/CBP is by a L. J.E. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). acetylation of IRF-2 be to cell activity of p300/CBP. In nuclear be to acetylated than in IRF-2 with other but not with p300 in NIH 3T3 cells and it to the H4 promoter In in growing NIH 3T3 cells IRF-2 with p300 and is IRF-2 to the H4 promoter by factors that cell growth. acetylation of IRF-2 and H4 activation by of IRF-2 and In growth-arrested cells, IRF-2 only for it in In we Lys-75 a major of IRF-2 acetylation. The acetylation of this residue is for activation of histone H4 acetylated in a cell growth-dependent by IRF-2 cell growth-dependent transcription of the H4 We Y. L. V. and Wang for and and We K. for and A. Y. and M. for general