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. 1998 Aug 3;17(15):4469–4477. doi: 10.1093/emboj/17.15.4469

E1A directly binds and regulates the P/CAF acetyltransferase.

J L Reid 1, A J Bannister 1, P Zegerman 1, M A Martínez-Balbás 1, T Kouzarides 1
PMCID: PMC1170778  PMID: 9687513

Abstract

The P/CAF protein has intrinsic histone acetyltransferase (HAT) activity and is capable of binding the transcriptional co-activator CBP. Here we show that P/CAF can regulate transcription and that this function is independent of its binding to CBP. The HAT domain of P/CAF has transcriptional activation potential in yeast. In mammalian cells P/CAF can stimulate transcription of the RSV promoter, using the activity of its HAT domain. We show that the adenovirus protein E1A targets P/CAF and sequesters its transcriptional activity. Binding of E1A to P/CAF is direct, independent of CBP and requires residues within E1A conserved region 1. We find that the P/CAF binding residues in E1A are within a motif shown to be essential for efficient disruption of myogenesis by E1A. The fact that E1A can directly bind and regulate the activity of P/CAF, independently of its regulation of CBP, highlights an important role for P/CAF in the process of cell differentiation.

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Selected References

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  1. Arany Z., Newsome D., Oldread E., Livingston D. M., Eckner R. A family of transcriptional adaptor proteins targeted by the E1A oncoprotein. Nature. 1995 Mar 2;374(6517):81–84. doi: 10.1038/374081a0. [DOI] [PubMed] [Google Scholar]
  2. Bannister A. J., Cook A., Kouzarides T. In vitro DNA binding activity of Fos/Jun and BZLF1 but not C/EBP is affected by redox changes. Oncogene. 1991 Jul;6(7):1243–1250. [PubMed] [Google Scholar]
  3. Bannister A. J., Kouzarides T. CBP-induced stimulation of c-Fos activity is abrogated by E1A. EMBO J. 1995 Oct 2;14(19):4758–4762. doi: 10.1002/j.1460-2075.1995.tb00157.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bannister A. J., Kouzarides T. The CBP co-activator is a histone acetyltransferase. Nature. 1996 Dec 19;384(6610):641–643. doi: 10.1038/384641a0. [DOI] [PubMed] [Google Scholar]
  5. Bannister A. J., Oehler T., Wilhelm D., Angel P., Kouzarides T. Stimulation of c-Jun activity by CBP: c-Jun residues Ser63/73 are required for CBP induced stimulation in vivo and CBP binding in vitro. Oncogene. 1995 Dec 21;11(12):2509–2514. [PubMed] [Google Scholar]
  6. Bhattacharya S., Eckner R., Grossman S., Oldread E., Arany Z., D'Andrea A., Livingston D. M. Cooperation of Stat2 and p300/CBP in signalling induced by interferon-alpha. Nature. 1996 Sep 26;383(6598):344–347. doi: 10.1038/383344a0. [DOI] [PubMed] [Google Scholar]
  7. Brownell J. E., Zhou J., Ranalli T., Kobayashi R., Edmondson D. G., Roth S. Y., Allis C. D. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell. 1996 Mar 22;84(6):843–851. doi: 10.1016/s0092-8674(00)81063-6. [DOI] [PubMed] [Google Scholar]
  8. Candau R., Berger S. L. Structural and functional analysis of yeast putative adaptors. Evidence for an adaptor complex in vivo. J Biol Chem. 1996 Mar 1;271(9):5237–5245. doi: 10.1074/jbc.271.9.5237. [DOI] [PubMed] [Google Scholar]
  9. Candau R., Moore P. A., Wang L., Barlev N., Ying C. Y., Rosen C. A., Berger S. L. Identification of human proteins functionally conserved with the yeast putative adaptors ADA2 and GCN5. Mol Cell Biol. 1996 Feb;16(2):593–602. doi: 10.1128/mcb.16.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Candau R., Zhou J. X., Allis C. D., Berger S. L. Histone acetyltransferase activity and interaction with ADA2 are critical for GCN5 function in vivo. EMBO J. 1997 Feb 3;16(3):555–565. doi: 10.1093/emboj/16.3.555. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen H., Lin R. J., Schiltz R. L., Chakravarti D., Nash A., Nagy L., Privalsky M. L., Nakatani Y., Evans R. M. Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell. 1997 Aug 8;90(3):569–580. doi: 10.1016/s0092-8674(00)80516-4. [DOI] [PubMed] [Google Scholar]
  12. Chrivia J. C., Kwok R. P., Lamb N., Hagiwara M., Montminy M. R., Goodman R. H. Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature. 1993 Oct 28;365(6449):855–859. doi: 10.1038/365855a0. [DOI] [PubMed] [Google Scholar]
  13. Dai P., Akimaru H., Tanaka Y., Hou D. X., Yasukawa T., Kanei-Ishii C., Takahashi T., Ishii S. CBP as a transcriptional coactivator of c-Myb. Genes Dev. 1996 Mar 1;10(5):528–540. doi: 10.1101/gad.10.5.528. [DOI] [PubMed] [Google Scholar]
  14. Eckner R., Ewen M. E., Newsome D., Gerdes M., DeCaprio J. A., Lawrence J. B., Livingston D. M. Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev. 1994 Apr 15;8(8):869–884. doi: 10.1101/gad.8.8.869. [DOI] [PubMed] [Google Scholar]
  15. Eckner R., Yao T. P., Oldread E., Livingston D. M. Interaction and functional collaboration of p300/CBP and bHLH proteins in muscle and B-cell differentiation. Genes Dev. 1996 Oct 1;10(19):2478–2490. doi: 10.1101/gad.10.19.2478. [DOI] [PubMed] [Google Scholar]
  16. Eckner R. p300 and CBP as transcriptional regulators and targets of oncogenic events. Biol Chem. 1996 Nov;377(11):685–688. [PubMed] [Google Scholar]
  17. Grant P. A., Duggan L., Côté J., Roberts S. M., Brownell J. E., Candau R., Ohba R., Owen-Hughes T., Allis C. D., Winston F. Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev. 1997 Jul 1;11(13):1640–1650. doi: 10.1101/gad.11.13.1640. [DOI] [PubMed] [Google Scholar]
  18. Grunstein M. Histone acetylation in chromatin structure and transcription. Nature. 1997 Sep 25;389(6649):349–352. doi: 10.1038/38664. [DOI] [PubMed] [Google Scholar]
  19. Gu W., Roeder R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell. 1997 Aug 22;90(4):595–606. doi: 10.1016/s0092-8674(00)80521-8. [DOI] [PubMed] [Google Scholar]
  20. Guarente L. Transcriptional coactivators in yeast and beyond. Trends Biochem Sci. 1995 Dec;20(12):517–521. doi: 10.1016/s0968-0004(00)89120-3. [DOI] [PubMed] [Google Scholar]
  21. Hagemeier C., Bannister A. J., Cook A., Kouzarides T. The activation domain of transcription factor PU.1 binds the retinoblastoma (RB) protein and the transcription factor TFIID in vitro: RB shows sequence similarity to TFIID and TFIIB. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1580–1584. doi: 10.1073/pnas.90.4.1580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hebbes T. R., Thorne A. W., Crane-Robinson C. A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J. 1988 May;7(5):1395–1402. doi: 10.1002/j.1460-2075.1988.tb02956.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Imhof A., Yang X. J., Ogryzko V. V., Nakatani Y., Wolffe A. P., Ge H. Acetylation of general transcription factors by histone acetyltransferases. Curr Biol. 1997 Sep 1;7(9):689–692. doi: 10.1016/s0960-9822(06)00296-x. [DOI] [PubMed] [Google Scholar]
  24. Jones N. Transcriptional modulation by the adenovirus E1A gene. Curr Top Microbiol Immunol. 1995;199(Pt 3):59–80. doi: 10.1007/978-3-642-79586-2_4. [DOI] [PubMed] [Google Scholar]
  25. Kaelin W. G., Jr, Krek W., Sellers W. R., DeCaprio J. A., Ajchenbaum F., Fuchs C. S., Chittenden T., Li Y., Farnham P. J., Blanar M. A. Expression cloning of a cDNA encoding a retinoblastoma-binding protein with E2F-like properties. Cell. 1992 Jul 24;70(2):351–364. doi: 10.1016/0092-8674(92)90108-o. [DOI] [PubMed] [Google Scholar]
  26. Kamei Y., Xu L., Heinzel T., Torchia J., Kurokawa R., Gloss B., Lin S. C., Heyman R. A., Rose D. W., Glass C. K. A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell. 1996 May 3;85(3):403–414. doi: 10.1016/s0092-8674(00)81118-6. [DOI] [PubMed] [Google Scholar]
  27. Kuo M. H., Zhou J., Jambeck P., Churchill M. E., Allis C. D. Histone acetyltransferase activity of yeast Gcn5p is required for the activation of target genes in vivo. Genes Dev. 1998 Mar 1;12(5):627–639. doi: 10.1101/gad.12.5.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kwok R. P., Lundblad J. R., Chrivia J. C., Richards J. P., Bächinger H. P., Brennan R. G., Roberts S. G., Green M. R., Goodman R. H. Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature. 1994 Jul 21;370(6486):223–226. doi: 10.1038/370223a0. [DOI] [PubMed] [Google Scholar]
  29. Lavender P., Vandel L., Bannister A. J., Kouzarides T. The HMG-box transcription factor HBP1 is targeted by the pocket proteins and E1A. Oncogene. 1997 Jun 5;14(22):2721–2728. doi: 10.1038/sj.onc.1201243. [DOI] [PubMed] [Google Scholar]
  30. Loidl P. Histone acetylation: facts and questions. Chromosoma. 1994 Dec;103(7):441–449. doi: 10.1007/BF00337382. [DOI] [PubMed] [Google Scholar]
  31. Lundblad J. R., Kwok R. P., Laurance M. E., Harter M. L., Goodman R. H. Adenoviral E1A-associated protein p300 as a functional homologue of the transcriptional co-activator CBP. Nature. 1995 Mar 2;374(6517):85–88. doi: 10.1038/374085a0. [DOI] [PubMed] [Google Scholar]
  32. Mizzen C. A., Yang X. J., Kokubo T., Brownell J. E., Bannister A. J., Owen-Hughes T., Workman J., Wang L., Berger S. L., Kouzarides T. The TAF(II)250 subunit of TFIID has histone acetyltransferase activity. Cell. 1996 Dec 27;87(7):1261–1270. doi: 10.1016/s0092-8674(00)81821-8. [DOI] [PubMed] [Google Scholar]
  33. Moran E. DNA tumor virus transforming proteins and the cell cycle. Curr Opin Genet Dev. 1993 Feb;3(1):63–70. doi: 10.1016/s0959-437x(05)80342-9. [DOI] [PubMed] [Google Scholar]
  34. Ogryzko V. V., Schiltz R. L., Russanova V., Howard B. H., Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell. 1996 Nov 29;87(5):953–959. doi: 10.1016/s0092-8674(00)82001-2. [DOI] [PubMed] [Google Scholar]
  35. Orphanides G., Lagrange T., Reinberg D. The general transcription factors of RNA polymerase II. Genes Dev. 1996 Nov 1;10(21):2657–2683. doi: 10.1101/gad.10.21.2657. [DOI] [PubMed] [Google Scholar]
  36. Pazin M. J., Kadonaga J. T. What's up and down with histone deacetylation and transcription? Cell. 1997 May 2;89(3):325–328. doi: 10.1016/s0092-8674(00)80211-1. [DOI] [PubMed] [Google Scholar]
  37. Perkins N. D., Felzien L. K., Betts J. C., Leung K., Beach D. H., Nabel G. J. Regulation of NF-kappaB by cyclin-dependent kinases associated with the p300 coactivator. Science. 1997 Jan 24;275(5299):523–527. doi: 10.1126/science.275.5299.523. [DOI] [PubMed] [Google Scholar]
  38. Pugh B. F., Tjian R. Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell. 1990 Jun 29;61(7):1187–1197. doi: 10.1016/0092-8674(90)90683-6. [DOI] [PubMed] [Google Scholar]
  39. Puri P. L., Sartorelli V., Yang X. J., Hamamori Y., Ogryzko V. V., Howard B. H., Kedes L., Wang J. Y., Graessmann A., Nakatani Y. Differential roles of p300 and PCAF acetyltransferases in muscle differentiation. Mol Cell. 1997 Dec;1(1):35–45. doi: 10.1016/s1097-2765(00)80005-2. [DOI] [PubMed] [Google Scholar]
  40. Roeder R. G. The role of general initiation factors in transcription by RNA polymerase II. Trends Biochem Sci. 1996 Sep;21(9):327–335. [PubMed] [Google Scholar]
  41. Sandmöller A., Meents H., Arnold H. H. A novel E1A domain mediates skeletal-muscle-specific enhancer repression independently of pRB and p300 binding. Mol Cell Biol. 1996 Oct;16(10):5846–5856. doi: 10.1128/mcb.16.10.5846. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Smith C. L., Oñate S. A., Tsai M. J., O'Malley B. W. CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8884–8888. doi: 10.1073/pnas.93.17.8884. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Spencer T. E., Jenster G., Burcin M. M., Allis C. D., Zhou J., Mizzen C. A., McKenna N. J., Onate S. A., Tsai S. Y., Tsai M. J. Steroid receptor coactivator-1 is a histone acetyltransferase. Nature. 1997 Sep 11;389(6647):194–198. doi: 10.1038/38304. [DOI] [PubMed] [Google Scholar]
  44. Tjian R., Maniatis T. Transcriptional activation: a complex puzzle with few easy pieces. Cell. 1994 Apr 8;77(1):5–8. doi: 10.1016/0092-8674(94)90227-5. [DOI] [PubMed] [Google Scholar]
  45. Trouche D., Cook A., Kouzarides T. The CBP co-activator stimulates E2F1/DP1 activity. Nucleic Acids Res. 1996 Nov 1;24(21):4139–4145. doi: 10.1093/nar/24.21.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Trouche D., Kouzarides T. E2F1 and E1A(12S) have a homologous activation domain regulated by RB and CBP. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1439–1442. doi: 10.1073/pnas.93.4.1439. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Turner B. M., O'Neill L. P. Histone acetylation in chromatin and chromosomes. Semin Cell Biol. 1995 Aug;6(4):229–236. doi: 10.1006/scel.1995.0031. [DOI] [PubMed] [Google Scholar]
  48. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]
  49. Wang L., Liu L., Berger S. L. Critical residues for histone acetylation by Gcn5, functioning in Ada and SAGA complexes, are also required for transcriptional function in vivo. Genes Dev. 1998 Mar 1;12(5):640–653. doi: 10.1101/gad.12.5.640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wang L., Mizzen C., Ying C., Candau R., Barlev N., Brownell J., Allis C. D., Berger S. L. Histone acetyltransferase activity is conserved between yeast and human GCN5 and is required for complementation of growth and transcriptional activation. Mol Cell Biol. 1997 Jan;17(1):519–527. doi: 10.1128/mcb.17.1.519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Wong H. K., Ziff E. B. Complementary functions of E1a conserved region 1 cooperate with conserved region 3 to activate adenovirus serotype 5 early promoters. J Virol. 1994 Aug;68(8):4910–4920. doi: 10.1128/jvi.68.8.4910-4920.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Yang X. J., Ogryzko V. V., Nishikawa J., Howard B. H., Nakatani Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature. 1996 Jul 25;382(6589):319–324. doi: 10.1038/382319a0. [DOI] [PubMed] [Google Scholar]
  53. Yao T. P., Ku G., Zhou N., Scully R., Livingston D. M. The nuclear hormone receptor coactivator SRC-1 is a specific target of p300. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10626–10631. doi: 10.1073/pnas.93.20.10626. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yuan W., Condorelli G., Caruso M., Felsani A., Giordano A. Human p300 protein is a coactivator for the transcription factor MyoD. J Biol Chem. 1996 Apr 12;271(15):9009–9013. doi: 10.1074/jbc.271.15.9009. [DOI] [PubMed] [Google Scholar]

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