Molecular Analysis of Viral Cyclin

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DESCRIPTION (provided by applicant): The proposed research investigates how Kaposi's sarcoma herpesvirus (KSHV)-encoded cyclin (K-cyclin) regulates transcription. K-cyclin associates predominantly in the transcriptionally active fraction of chromatin along with other proteins that have a role in gene activation suggesting that K-cyclin may also activate transcription. K-cyclin binds a DNA consensus found in promoters regulated by retinoblastoma protein/Sp/Kruppel-like factor (Rb/Sp/KLF) complexes. K-cyclin/cdkG complexes phosphorylate the chromatin-associated transcriptional coactivator, p300 and exogenous expression of p300 along with K-cyclin synergistically activates NF-kappa B-dependent transcription, a process known to require p300 for activation. These findings suggest that K-cyclin/cdkG complexes may be responsible for the constitutive activation of NF-kappa B in primary effusion lymphoma, a tumor caused by KSHV. Collectively, these preliminary studies suggest that K-cyclin may not only deregulate the cell cycle, but may also modulate transcription of cellular and possibly viral genes. The investigator proposes to investigate the role of K-cyclin as a transcriptional regulator by addressing two specific hypotheses. In specific aim 1, the hypothesis that K-cyclin through sequence-specific interactions with KRE-containing promoters activates actives genes normally repressed by the Rb/Sp/KLF protein complexes will be examined. In specific aim 2, the hypothesis that independent of DNA-binding, K-cyclin regulates transcription through protein-protein interactions, which may be cyclin-dependent kinase (cdk) dependent and independent will be examined. Understanding how K-cyclin modulates transcription will expand current knowledge regarding the role of this highly conserved gamma 2-herpesvirus protein in the pathogenesis of diseases linked to KSHV infection. This knowledge may lead to novel therapeutic approaches for the treatment of KSHV-related malignancies.