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Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein

Nature volume 399, pages 276–279 (1999)Cite this article

Abstract

Adenovirus E1A proteins prepare the host cell for viral replication, stimulating cell cycling and viral transcription through interactions with critical cellular regulatory proteins such as RB1,2 and CBP3. Here we show that the E1A zinc-finger domain that is required to activate transcription of viral early genes binds to a host-cell multiprotein complex containing homologues of yeast Srb/Mediator proteins4,5. This occurs through a stable interaction with the human homologue of Caenorhabditis elegans SUR-2, a protein required for many developmental processes in the nematode6. This human Srb/Mediator complex stimulates transcription in vitro in response to both the E1A zinc-finger and the herpes simplex virus VP16 activation domains. Interaction with human Sur-2 is also required for transcription to be activated by the activation domain of a transcription factor of the ETS-family in response to activated mitogen-activated protein (MAP) kinase.

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Figure 1: Identification of hSur-2.
Figure 2: Purification and characterization of hMediator.
Figure 3: hMediator transcriptional activity.
Figure 4: Overexpression of hSur-2 inhibits activation by specific activation domains.

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References

  1. Whyte, P., Williamson, N. M. & Harlow, E. Cellular targets for transformation by the adenovirus E1A. Cell 56, 67–75 (1989).

    Article  CAS  Google Scholar 

  2. Zhu, L. et al. Growth suppression by members of the retinoblastoma protein family. Cold Spring Harbor Symp. Quant. Biol. 59, 75–84 (1994).

    Article  CAS  Google Scholar 

  3. 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 77, 799– 800 (1994).

    Article  CAS  Google Scholar 

  4. Meyer, V. E. & Young, R. A. RNA polymerase II holoenzymes and subcomplexes. J. Biol. Chem. 273, 27757– 27760 (1998).

    Article  Google Scholar 

  5. Myers, L. C. et al. The Med proteins of yeast and their function through the RNA polymerase II carboxy-terminal domain. Genes Dev. 12 , 45–54 (1998).

    Article  CAS  Google Scholar 

  6. Singh, N. & Han, M. sur-2, a novel gene, functions late in the let-60 ras-mediated signaling pathway during Caenorhabiditis elegans vulval induction. Genes Dev. 9, 2251–2265 (1995).

    Article  CAS  Google Scholar 

  7. Boyer, T. G. & Berk, A. J. Functional interaction of adenovirus E1A with holo-TFIID. Genes Dev. 7, 1810– 1823 (1993).

    Article  CAS  Google Scholar 

  8. Webster, L. C. & Ricciardi, R. P. trans -Dominant mutants of E1A provide genetic evidence that the zinc finger of the transactivating domain binds a transcription factor. Mol. Cell. Biol. 11, 4287–4296 (1991).

    Article  CAS  Google Scholar 

  9. Brauer, A. W., Oman, C. L. & Margolies, M. N. Use of o -phthalaldehyde to reduce background during automated Edman degradation. Analyt. Biochem. 137, 134–142 (1984).

    Article  CAS  Google Scholar 

  10. Graham, F. L., Smiley, J., Russell, W. & Nairn, R. Characteristics of a human cell line transformed by DNA from human adenovirus type 5. J. Gen. Virol. 36, 59–74 (1977).

    Article  CAS  Google Scholar 

  11. Flint, J. & Shenk, T. Adenovirus E1A protein: paradigm viral transactivator. Annu. Rev. Genet. 23, 141 –161 (1989).

    Article  CAS  Google Scholar 

  12. Tassan, J.-P., Jaquenoud, M., Leopold, P., Schultz, S. J. & Nigg, E. Identification of human cyclin-dependent kinase 8, a putative protein kinase partner for cyclin C. Proc. Natl Acad. Sci. USA 92, 8871–8875 (1995).

    Article  ADS  CAS  Google Scholar 

  13. Liao, S. M. et al. Akinase-cyclin pair in the RNA polymerase II holoenzyme. Nature 374, 193–196 ( 1995).

    Article  ADS  CAS  Google Scholar 

  14. Rickert, P., Seghezzi, W., Shanahan, F., Cho, H. & Lees, E. Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. Oncogene 12, 2631–2640 (1996).

    CAS  PubMed  Google Scholar 

  15. Gold, M. O., Tassan, J.-P., Nigg, E. A., Rice, A. P. & Herrmann, C. H. Viral transactivators E1A and VP16 interact with a large complex that is associated with CTD kinase activity and contains CDK8. Nucleic Acids Res. 24, 3771–3777 (1996).

    Article  CAS  Google Scholar 

  16. Jiang, Y. W. et al. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Natl Acad. Sci. USA 95, 8538–8543 (1998).

    Article  ADS  CAS  Google Scholar 

  17. Greenblatt, J. RNA polymerase II holoenzyme and transcriptional regulation. Curr. Opin. Cell Biol. 9, 310–319 (1997).

    Article  CAS  Google Scholar 

  18. Kaiser, K. & Meisterernst, M. The human general co-factors. Trends Biochem. Sci. 9, 342– 345 (1996).

    Article  Google Scholar 

  19. Janknecht, R. & Nordheim, A. Gene regulation by Ets proteins. Biochem. Biophys. Acta 1155, 346– 356 (1993).

    CAS  PubMed  Google Scholar 

  20. Faris, M., Kokot, N., Lee, L. & Nel, A. E. Regulation of interleukin-2 transcription by inducible stable expression of dominant negative and dominant active mitogen-activated protein kinase kinase kinase in jurkat T cells. Evidence for the importance of Ras in a pathway that is controlled by dual receptor stimulation. J. Biol. Chem. 271, 27366– 27373 (1996).

    Article  CAS  Google Scholar 

  21. Denhardt, D. T. Signal-transducing protein phosphorylation cascades mediated by Ras/Rho protein in the mammalian cell: the potential for multiplex signalling. Biochem. J. 318, 729–747 (1996).

    Article  CAS  Google Scholar 

  22. Sun, X. et al. NAT, a human complex containing Srb polypeptides that functions as a negative regulator of activated transcription. Mol. Cell 2, 213–222 (1998).

    Article  CAS  Google Scholar 

  23. Cho, H. et al. Ahuman RNA polymerase II complex containing factors that modify chromatin structure. Mol. Cell. Biol. 18, 5355–5363 (1998).

    Article  CAS  Google Scholar 

  24. Gu, W. et al. Anovel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell 3, 97–108 (1999).

    Article  CAS  Google Scholar 

  25. Ryu, S., Zhou, S., Ladurner, A. G. & Tijan, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999).

    Article  ADS  CAS  Google Scholar 

  26. Holstege, F. C. P. et al. Dissecting the regulatory circuitry of a eukaryotic genome. Cell 95, 717–728 (1998).

    Article  CAS  Google Scholar 

  27. Mes-Masson, A. M., McLaughlin, J., Daley, G. Q., Paskind, M. & Witte, O. N. Overlapping cDNA clones define the complete coding region for the P210c-abl gene product associated with chronic myelogenous leukemia cells containing the Philadelphia chromosome. Proc. Natl Acad. Sci. USA 83, 9768– 9772 (1986).

    Article  ADS  CAS  Google Scholar 

  28. Bryant, G. O., Martel, L. S., Burley, S. K. & Berk, A. J. Radical mutagenesis reveals TATA-box binding protein surfaces required for activated transcription in vivo. Genes Dev. 10, 2491–2504 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Kornberg for anti-mMed7 antibody and P. Rickert for anti-Cdk8 and anti-cyclin C antibodies; M. Carey, W. Huang, S. Rundlett, S. Smale, J. Stevens and P. R. Yew for advice and comments; and C. Eng for technical assistance. This work was supported by the NIH. T.G.B. was initially supported by a postdoctoral fellowship from the California Division of the American Cancer Society.

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Author notes

  1. Thomas G. Boyer

    Present address: Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Sciences Center, San Antonio, Texas, 78245, USA

Authors and Affiliations

  1. Molecular Biology Institute, UCLA , Los Angeles, 90095-1570, California, USA

    Thomas G. Boyer, Michelle E. D. Martin & Arnold J. Berk

  2. DNAX, Palo Alto, 94304-1104, California, USA

    Emma Lees

  3. Department of Microbiology, and Department of Biochemistry/Biophysics, School of Dental Medicine, School of Medicine University of Pennsylvania, Philadelphia, 19104, Pennsylvania , USA

    Robert P. Ricciardi

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Boyer, T., Martin, M., Lees, E. et al. Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein . Nature 399, 276–279 (1999). https://doi.org/10.1038/20466

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