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Journal of Virology, January 2002, p. 232-242, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.232-242.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Nuclear Antigen 3C Putative Repression Domain Mediates Coactivation of the LMP1 Promoter with EBNA-2

Jeffrey Lin, Eric Johannsen, Erle Robertson,{dagger}, and Elliott Kieff*

Virology Program and Departments of Medicine and Microbiology and Molecular Genetics, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115

Received 2 July 2001/ Accepted 4 October 2001

The Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA-3C) regulates virus and cell genes and is essential for EBV-mediated transformation of primary B lymphocytes. EBNA-3C associates with the cellular DNA sequence-specific transcription factors RBP-J{kappa} and PU.1 and coactivates the EBV LMP1 promoter with EBNA-2 in BL2 and Raji cells under conditions of restrictive growth. We now find that EBNA-3C is similar to EBNA-LP in coactivating the LMP1 promoter with EBNA-2 in non-EBV-infected Burkitt lymphoma cells under conditions of maximal cell growth, whereas the EBV Cp promoter is repressed under the same conditions. EBNA-3A and EBNA-3B coactivation are at most 40% that of EBNA-3C. The RBP-J{kappa} binding sites of EBNA-2 and the LMP1 promoter are not required for EBNA-3C coactivation, whereas the PU.1 site in the LMP1 promoter is required for EBNA-2-mediated activation and EBNA-3C coactivation. EBNA-3C amino acids (aa) 365 to 545, including most of the previously identified repression domain (M. Bain, R. J. Watson, P. J. Farrell, and M. J. Allday, J. Virol. 70:2481–2489, 1996), are necessary and sufficient for coactivation with wild-type EBNA-2. EBNA-3C can also coactivate with the EBNA-2 acidic activating domain; this activation does not require aa 343 to 545. These data indicate that there are at least two mechanisms by which EBNA-3C coactivates the LMP1 promoter with EBNA-2. Of the proteins that interact with EBNA-3C in a yeast two-hybrid screen, only the ubiquitin-like proteins SUMO-1 and SUMO-3/hSMT3B map to aa 365 to 545, implicating these molecules in EBNA-3C coactivation. In addition, SUMO-1 associates at a high level with EBNA-3C in lymphoblasts. Promoter coactivation by EBNA-3C is likely to be important in ensuring adequate levels of LMP1, while inhibition of the EBNA-Cp promoter under the same conditions prevents uncontrolled up-regulation of EBNA expression from a positive-feedback loop.

* Corresponding author. Mailing address: Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-4252. Fax: (617) 525-4257. Email: ekieff{at}rics.bwh.harvard.edu.

{dagger} Present address: Department of Microbiology and Immunology and the Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109.

Journal of Virology, January 2002, p. 232-242, Vol. 76, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.1.232-242.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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