Stimulation of c-Myc transcriptional activity by vIRF-3 of Kaposi sarcoma-associated herpesvirus.
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-1alpha. The vIRF-3 and MM-1alpha interaction was also demonstrated by glutathione S-transferase pulldown assay and coimmunoprecipitation of endogenous vIRF-3 and MM-1alpha 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-1alpha 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.
Lubyova
Barbora
B
Institute of Immunology and Microbiology, First Medical Faculty of Charles University, Studnickova 7, Prague 128 00, Czech Republic. bluby@lf1.cuni.cz
Kellum
Merrill J
MJ
Frisancho
Jose A
JA
Pitha
Paula M
PM
D045744:Cell Line, Tumor; D015723:Gene Library; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D054685:Lymphoma, Primary Effusion / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014764:Viral Proteins / Q000378:metabolism*
D050838:Interferon Regulatory Factor-3; D050835:Interferon Regulatory Factors; D016271:Proto-Oncogene Proteins c-myc; D014764:Viral Proteins; C413486:viral interferon regulatory factors