Stimulation of c-Myc transcriptional activity by vIRF-3 of Kaposi sarcoma-associated herpesvirus

Barbora Lubyova, Merrill J. Kellum, Jose A. Frisancho, Paula M. Pitha

Research output: Contribution to journalArticle

Abstract

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-1α. The vIRF-3 and MM-1α interaction was also demonstrated by glutathione S-transferase pulldown assay and coimmunoprecipitation of endogenous vIRF-3 and MM-1α 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-1α 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.

Original languageEnglish (US)
Pages (from-to)31944-31953
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number44
DOIs
StatePublished - Nov 2 2007

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Human Herpesvirus 8
Primary Effusion Lymphoma
Transcription
viral interferon regulatory factors
Genes
Interferon Regulatory Factor-3
Interferon Regulatory Factors
Association reactions
Giant Lymph Node Hyperplasia
Acetylation
Deregulation
Lymphoproliferative Disorders
Viral Genes
Cell growth
Glutathione Transferase
Histones
Yeast
Cell Differentiation
Assays
B-Lymphocytes

ASJC Scopus subject areas

  • Biochemistry

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Stimulation of c-Myc transcriptional activity by vIRF-3 of Kaposi sarcoma-associated herpesvirus. / Lubyova, Barbora; Kellum, Merrill J.; Frisancho, Jose A.; Pitha, Paula M.

In: Journal of Biological Chemistry, Vol. 282, No. 44, 02.11.2007, p. 31944-31953.

Research output: Contribution to journalArticle

Lubyova, Barbora ; Kellum, Merrill J. ; Frisancho, Jose A. ; Pitha, Paula M. / Stimulation of c-Myc transcriptional activity by vIRF-3 of Kaposi sarcoma-associated herpesvirus. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 44. pp. 31944-31953.
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AB - 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-1α. The vIRF-3 and MM-1α interaction was also demonstrated by glutathione S-transferase pulldown assay and coimmunoprecipitation of endogenous vIRF-3 and MM-1α 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-1α 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.

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