Skip to main content
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1996 Jul;16(7):3454–3464. doi: 10.1128/mcb.16.7.3454

Association of p300 and CBP with simian virus 40 large T antigen.

R Eckner 1, J W Ludlow 1, N L Lill 1, E Oldread 1, Z Arany 1, N Modjtahedi 1, J A DeCaprio 1, D M Livingston 1, J A Morgan 1
PMCID: PMC231340  PMID: 8668161

Abstract

p300 and the CREB-binding protein CBP are two large nuclear phosphoproteins that are structurally highly related. Both function, in part, as transcriptional adapters and are targeted by the adenovirus E1A oncoprotein. We show here that p300 and CBP interact with another transforming protein, the simian virus 40 large T antigen (T). This interaction depends on the integrity of a region of T which is critical for its transforming and mitogenic properties and includes its LXCXE Rb-binding motif. T interferes with normal p300 and CBP function on at least two different levels. The presence of T alters the phosphorylation states of both proteins and inhibits their transcriptional activities on certain promoters. Although E1A and T show little sequence similarity, they interact with the same domain of p300 and CBP, suggesting that this region exhibits considerable flexibility in accommodating diverse protein ligands.

Full Text

The Full Text of this article is available as a PDF (1,005.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  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. Arany Z., Sellers W. R., Livingston D. M., Eckner R. E1A-associated p300 and CREB-associated CBP belong to a conserved family of coactivators. Cell. 1994 Jun 17;77(6):799–800. doi: 10.1016/0092-8674(94)90127-9. [DOI] [PubMed] [Google Scholar]
  3. Avantaggiati M. L., Carbone M., Graessmann A., Nakatani Y., Howard B., Levine A. S. The SV40 large T antigen and adenovirus E1a oncoproteins interact with distinct isoforms of the transcriptional co-activator, p300. EMBO J. 1996 May 1;15(9):2236–2248. [PMC free article] [PubMed] [Google Scholar]
  4. Banerjee A. C., Recupero A. J., Mal A., Piotrkowski A. M., Wang D. M., Harter M. L. The adenovirus E1A 289R and 243R proteins inhibit the phosphorylation of p300. Oncogene. 1994 Jun;9(6):1733–1737. [PubMed] [Google Scholar]
  5. 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]
  6. Chen S., Paucha E. Identification of a region of simian virus 40 large T antigen required for cell transformation. J Virol. 1990 Jul;64(7):3350–3357. doi: 10.1128/jvi.64.7.3350-3357.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cherington V., Brown M., Paucha E., St Louis J., Spiegelman B. M., Roberts T. M. Separation of simian virus 40 large-T-antigen-transforming and origin-binding functions from the ability to block differentiation. Mol Cell Biol. 1988 Mar;8(3):1380–1384. doi: 10.1128/mcb.8.3.1380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. 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]
  9. Cleveland D. W., Fischer S. G., Kirschner M. W., Laemmli U. K. Peptide mapping by limited proteolysis in sodium dodecyl sulfate and analysis by gel electrophoresis. J Biol Chem. 1977 Feb 10;252(3):1102–1106. [PubMed] [Google Scholar]
  10. DeCaprio J. A., Ludlow J. W., Figge J., Shew J. Y., Huang C. M., Lee W. H., Marsilio E., Paucha E., Livingston D. M. SV40 large tumor antigen forms a specific complex with the product of the retinoblastoma susceptibility gene. Cell. 1988 Jul 15;54(2):275–283. doi: 10.1016/0092-8674(88)90559-4. [DOI] [PubMed] [Google Scholar]
  11. Dickmanns A., Zeitvogel A., Simmersbach F., Weber R., Arthur A. K., Dehde S., Wildeman A. G., Fanning E. The kinetics of simian virus 40-induced progression of quiescent cells into S phase depend on four independent functions of large T antigen. J Virol. 1994 Sep;68(9):5496–5508. doi: 10.1128/jvi.68.9.5496-5508.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dyson N., Buchkovich K., Whyte P., Harlow E. The cellular 107K protein that binds to adenovirus E1A also associates with the large T antigens of SV40 and JC virus. Cell. 1989 Jul 28;58(2):249–255. doi: 10.1016/0092-8674(89)90839-8. [DOI] [PubMed] [Google Scholar]
  13. Eckner R., Arany Z., Ewen M., Sellers W., Livingston D. M. The adenovirus E1A-associated 300-kD protein exhibits properties of a transcriptional coactivator and belongs to an evolutionarily conserved family. Cold Spring Harb Symp Quant Biol. 1994;59:85–95. doi: 10.1101/sqb.1994.059.01.012. [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. Egan C., Jelsma T. N., Howe J. A., Bayley S. T., Ferguson B., Branton P. E. Mapping of cellular protein-binding sites on the products of early-region 1A of human adenovirus type 5. Mol Cell Biol. 1988 Sep;8(9):3955–3959. doi: 10.1128/mcb.8.9.3955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Endo T. SV40 large T inhibits myogenic differentiation partially through inducing c-jun. J Biochem. 1992 Sep;112(3):321–329. doi: 10.1093/oxfordjournals.jbchem.a123899. [DOI] [PubMed] [Google Scholar]
  17. Ewen M. E., Ludlow J. W., Marsilio E., DeCaprio J. A., Millikan R. C., Cheng S. H., Paucha E., Livingston D. M. An N-terminal transformation-governing sequence of SV40 large T antigen contributes to the binding of both p110Rb and a second cellular protein, p120. Cell. 1989 Jul 28;58(2):257–267. doi: 10.1016/0092-8674(89)90840-4. [DOI] [PubMed] [Google Scholar]
  18. Fei Z. L., D'Ambrosio C., Li S., Surmacz E., Baserga R. Association of insulin receptor substrate 1 with simian virus 40 large T antigen. Mol Cell Biol. 1995 Aug;15(8):4232–4239. doi: 10.1128/mcb.15.8.4232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gruda M. C., Zabolotny J. M., Xiao J. H., Davidson I., Alwine J. C. Transcriptional activation by simian virus 40 large T antigen: interactions with multiple components of the transcription complex. Mol Cell Biol. 1993 Feb;13(2):961–969. doi: 10.1128/mcb.13.2.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gu W., Schneider J. W., Condorelli G., Kaushal S., Mahdavi V., Nadal-Ginard B. Interaction of myogenic factors and the retinoblastoma protein mediates muscle cell commitment and differentiation. Cell. 1993 Feb 12;72(3):309–324. doi: 10.1016/0092-8674(93)90110-c. [DOI] [PubMed] [Google Scholar]
  21. Halevy O., Novitch B. G., Spicer D. B., Skapek S. X., Rhee J., Hannon G. J., Beach D., Lassar A. B. Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD. Science. 1995 Feb 17;267(5200):1018–1021. doi: 10.1126/science.7863327. [DOI] [PubMed] [Google Scholar]
  22. Hannon G. J., Demetrick D., Beach D. Isolation of the Rb-related p130 through its interaction with CDK2 and cyclins. Genes Dev. 1993 Dec;7(12A):2378–2391. doi: 10.1101/gad.7.12a.2378. [DOI] [PubMed] [Google Scholar]
  23. Harlow E., Crawford L. V., Pim D. C., Williamson N. M. Monoclonal antibodies specific for simian virus 40 tumor antigens. J Virol. 1981 Sep;39(3):861–869. doi: 10.1128/jvi.39.3.861-869.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Harlow E., Franza B. R., Jr, Schley C. Monoclonal antibodies specific for adenovirus early region 1A proteins: extensive heterogeneity in early region 1A products. J Virol. 1985 Sep;55(3):533–546. doi: 10.1128/jvi.55.3.533-546.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Harlow E., Whyte P., Franza B. R., Jr, Schley C. Association of adenovirus early-region 1A proteins with cellular polypeptides. Mol Cell Biol. 1986 May;6(5):1579–1589. doi: 10.1128/mcb.6.5.1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Herrmann C. H., Su L. K., Harlow E. Adenovirus E1A is associated with a serine/threonine protein kinase. J Virol. 1991 Nov;65(11):5848–5859. doi: 10.1128/jvi.65.11.5848-5859.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kaelin W. G., Jr, Pallas D. C., DeCaprio J. A., Kaye F. J., Livingston D. M. Identification of cellular proteins that can interact specifically with the T/E1A-binding region of the retinoblastoma gene product. Cell. 1991 Feb 8;64(3):521–532. doi: 10.1016/0092-8674(91)90236-r. [DOI] [PubMed] [Google Scholar]
  28. Kalderon D., Smith A. E. In vitro mutagenesis of a putative DNA binding domain of SV40 large-T. Virology. 1984 Nov;139(1):109–137. doi: 10.1016/0042-6822(84)90334-9. [DOI] [PubMed] [Google Scholar]
  29. Kitabayashi I., Eckner R., Arany Z., Chiu R., Gachelin G., Livingston D. M., Yokoyama K. K. Phosphorylation of the adenovirus E1A-associated 300 kDa protein in response to retinoic acid and E1A during the differentiation of F9 cells. EMBO J. 1995 Jul 17;14(14):3496–3509. doi: 10.1002/j.1460-2075.1995.tb07356.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Kleinberger T., Shenk T. A protein kinase is present in a complex with adenovirus E1A proteins. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11143–11147. doi: 10.1073/pnas.88.24.11143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kohrman D. C., Imperiale M. J. Simian virus 40 large T antigen stably complexes with a 185-kilodalton host protein. J Virol. 1992 Mar;66(3):1752–1760. doi: 10.1128/jvi.66.3.1752-1760.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Ludlow J. W., DeCaprio J. A., Huang C. M., Lee W. H., Paucha E., Livingston D. M. SV40 large T antigen binds preferentially to an underphosphorylated member of the retinoblastoma susceptibility gene product family. Cell. 1989 Jan 13;56(1):57–65. doi: 10.1016/0092-8674(89)90983-5. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Manfredi J. J., Prives C. The transforming activity of simian virus 40 large tumor antigen. Biochim Biophys Acta. 1994 May 27;1198(1):65–83. doi: 10.1016/0304-419x(94)90006-x. [DOI] [PubMed] [Google Scholar]
  36. Marsilio E., Cheng S. H., Schaffhausen B., Paucha E., Livingston D. M. The T/t common region of simian virus 40 large T antigen contains a distinct transformation-governing sequence. J Virol. 1991 Oct;65(10):5647–5652. doi: 10.1128/jvi.65.10.5647-5652.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Michael-Michalovitz D., Yehiely F., Gottlieb E., Oren M. Simian virus 40 can overcome the antiproliferative effect of wild-type p53 in the absence of stable large T antigen-p53 binding. J Virol. 1991 Aug;65(8):4160–4168. doi: 10.1128/jvi.65.8.4160-4168.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Missero C., Calautti E., Eckner R., Chin J., Tsai L. H., Livingston D. M., Dotto G. P. Involvement of the cell-cycle inhibitor Cip1/WAF1 and the E1A-associated p300 protein in terminal differentiation. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5451–5455. doi: 10.1073/pnas.92.12.5451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Montano X., Millikan R., Milhaven J. M., Newsom D. A., Ludlow J. W., Arthur A. K., Fanning E., Bikel I., Livingston D. M. Simian virus 40 small tumor antigen and an amino-terminal domain of large tumor antigen share a common transforming function. Proc Natl Acad Sci U S A. 1990 Oct;87(19):7448–7452. doi: 10.1073/pnas.87.19.7448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nevins J. R. E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science. 1992 Oct 16;258(5081):424–429. doi: 10.1126/science.1411535. [DOI] [PubMed] [Google Scholar]
  41. Peeper D. S., Zantema A. Adenovirus-E1A proteins transform cells by sequestering regulatory proteins. Mol Biol Rep. 1993 Apr;17(3):197–207. doi: 10.1007/BF00986728. [DOI] [PubMed] [Google Scholar]
  42. Pipas J. M. Common and unique features of T antigens encoded by the polyomavirus group. J Virol. 1992 Jul;66(7):3979–3985. doi: 10.1128/jvi.66.7.3979-3985.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Quartin R. S., Cole C. N., Pipas J. M., Levine A. J. The amino-terminal functions of the simian virus 40 large T antigen are required to overcome wild-type p53-mediated growth arrest of cells. J Virol. 1994 Mar;68(3):1334–1341. doi: 10.1128/jvi.68.3.1334-1341.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Santos M., Butel J. S. Detection of a complex of SV40 large tumor antigen and 53K cellular protein on the surface of SV40-transformed mouse cells. J Cell Biochem. 1982;19(2):127–144. doi: 10.1002/jcb.240190204. [DOI] [PubMed] [Google Scholar]
  45. Srinivasan A., Peden K. W., Pipas J. M. The large tumor antigen of simian virus 40 encodes at least two distinct transforming functions. J Virol. 1989 Dec;63(12):5459–5463. doi: 10.1128/jvi.63.12.5459-5463.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Symonds H. S., McCarthy S. A., Chen J., Pipas J. M., Van Dyke T. Use of transgenic mice reveals cell-specific transformation by a simian virus 40 T-antigen amino-terminal mutant. Mol Cell Biol. 1993 Jun;13(6):3255–3265. doi: 10.1128/mcb.13.6.3255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Thompson D. L., Kalderon D., Smith A. E., Tevethia M. J. Dissociation of Rb-binding and anchorage-independent growth from immortalization and tumorigenicity using SV40 mutants producing N-terminally truncated large T antigens. Virology. 1990 Sep;178(1):15–34. doi: 10.1016/0042-6822(90)90375-2. [DOI] [PubMed] [Google Scholar]
  48. Umek R. M., Friedman A. D., McKnight S. L. CCAAT-enhancer binding protein: a component of a differentiation switch. Science. 1991 Jan 18;251(4991):288–292. doi: 10.1126/science.1987644. [DOI] [PubMed] [Google Scholar]
  49. Wang H. G., Draetta G., Moran E. E1A induces phosphorylation of the retinoblastoma protein independently of direct physical association between the E1A and retinoblastoma products. Mol Cell Biol. 1991 Aug;11(8):4253–4265. doi: 10.1128/mcb.11.8.4253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Wang H. G., Rikitake Y., Carter M. C., Yaciuk P., Abraham S. E., Zerler B., Moran E. Identification of specific adenovirus E1A N-terminal residues critical to the binding of cellular proteins and to the control of cell growth. J Virol. 1993 Jan;67(1):476–488. doi: 10.1128/jvi.67.1.476-488.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Whyte P., Williamson N. M., Harlow E. Cellular targets for transformation by the adenovirus E1A proteins. Cell. 1989 Jan 13;56(1):67–75. doi: 10.1016/0092-8674(89)90984-7. [DOI] [PubMed] [Google Scholar]
  52. Wright W. E., Binder M., Funk W. Cyclic amplification and selection of targets (CASTing) for the myogenin consensus binding site. Mol Cell Biol. 1991 Aug;11(8):4104–4110. doi: 10.1128/mcb.11.8.4104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Yaciuk P., Carter M. C., Pipas J. M., Moran E. Simian virus 40 large-T antigen expresses a biological activity complementary to the p300-associated transforming function of the adenovirus E1A gene products. Mol Cell Biol. 1991 Apr;11(4):2116–2124. doi: 10.1128/mcb.11.4.2116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Yaciuk P., Moran E. Analysis with specific polyclonal antiserum indicates that the E1A-associated 300-kDa product is a stable nuclear phosphoprotein that undergoes cell cycle phase-specific modification. Mol Cell Biol. 1991 Nov;11(11):5389–5397. doi: 10.1128/mcb.11.11.5389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Yee S. P., Branton P. E. Detection of cellular proteins associated with human adenovirus type 5 early region 1A polypeptides. Virology. 1985 Nov;147(1):142–153. doi: 10.1016/0042-6822(85)90234-x. [DOI] [PubMed] [Google Scholar]
  56. Zhu J. Y., Rice P. W., Chamberlain M., Cole C. N. Mapping the transcriptional transactivation function of simian virus 40 large T antigen. J Virol. 1991 Jun;65(6):2778–2790. doi: 10.1128/jvi.65.6.2778-2790.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Zhu J., Rice P. W., Gorsch L., Abate M., Cole C. N. Transformation of a continuous rat embryo fibroblast cell line requires three separate domains of simian virus 40 large T antigen. J Virol. 1992 May;66(5):2780–2791. doi: 10.1128/jvi.66.5.2780-2791.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES