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J. Biol. Chem., Vol. 282, Issue 44, 31944-31953, November 2, 2007

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Stimulation of c-Myc Transcriptional Activity by vIRF-3 of Kaposi Sarcoma-associated Herpesvirus^*

Barbora Lubyova¹, Merrill J. Kellum, Jose A. Frisancho, and Paula M. Pitha^¶

From the Institute of Immunology and Microbiology, First Medical Faculty of Charles University, Studnickova 7, Prague 128 00, Czech Republic and the Sidney Kimmel Comprehensive Cancer Center and ^¶Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231

Kaposi sarcoma-associated herpesvirus is associated with two lymphoproliferative disorders, primary effusion lymphoma (PEL) and Castleman disease. In PEL, Kaposi sarcoma-associated herpesvirus is present in a latent form expressing only few viral genes. Among them is a viral homologue of cellular interferon regulatory factors, vIRF-3. To study the role of vIRF-3 in PEL lymphomagenesis, we analyzed the interaction of vIRF-3 with cellular proteins. Using yeast two-hybrid screen, we detected the association between vIRF-3 and c-Myc suppressor, MM-1. The vIRF-3 and MM-1 interaction was also demonstrated by glutathione S-transferase pulldown assay and coimmunoprecipitation of endogenous vIRF-3 and MM-1 in PEL-derived cell lines. Overexpression of vIRF-3 enhanced the c-Myc-dependent transcription of the gene cdk4. Addressing the molecular mechanism of the vIRF-3-mediated stimulation, we demonstrated that the association between MM-1 and c-Myc was inhibited by vIRF-3. Furthermore, the recruitment of vIRF-3 to the cdk4 promoter and the elevated levels of the histone H3 acetylation suggest the direct involvement of vIRF-3 in the activation of c-Myc-mediated transcription. These findings indicate that vIRF-3 can effectively stimulate c-Myc function in PEL cells and consequently contribute to de-regulation of B-cell growth and differentiation.

Received for publication, August 3, 2007 , and in revised form, August 29, 2007.

^* This work was supported by National Institutes of Health Grant RO1CA76946 (to P. M. P.), by a Johns Hopkins University Institutional Research Grant, by the Academy of Sciences of the Czech Republic (Grant IAA501050701 to B. L.), and by the Ministry of Education of the Czech Republic Project MSM0021620806. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 420-224-968-460; Fax: 420-224-968-496; E-mail: bluby{at}lf1.cuni.cz.

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