Molecular Analysis of Viral Cyclin

描述（由申请人提供）：拟研究卡波西肉瘤疱疹病毒（KSHV）编码的细胞周期蛋白（K-cyclin）如何调节转录。K-cyclin主要与染色质的转录活性部分以及其他在基因激活中起作用的蛋白质相关，这表明K-cyclin也可能激活转录。K-cyclin结合在视网膜母细胞瘤蛋白/Sp/ kruppel样因子（Rb/Sp/KLF）复合物调控的启动子中发现的DNA共识。K-cyclin/cdkG复合物磷酸化染色质相关的转录辅激活因子p300， p300的外源表达与K-cyclin协同激活nf - κ b依赖性转录，这一过程已知需要p300来激活。这些发现表明，K-cyclin/cdkG复合物可能在KSHV引起的原发性积液性淋巴瘤中负责nf - κ B的组成性激活。总的来说，这些初步研究表明，K-cyclin不仅可以解除对细胞周期的调节，还可以调节细胞和病毒基因的转录。研究者建议通过解决两个特定的假设来研究K-cyclin作为转录调节因子的作用。在具体目标1中，将检验K-cyclin通过序列特异性相互作用与含有kre的启动子激活通常被Rb/Sp/KLF蛋白复合物抑制的活性基因的假设。在特定目标2中，K-cyclin独立于dna结合，通过蛋白-蛋白相互作用调节转录的假设将被检验，这可能是周期蛋白依赖性激酶（cdk）依赖和独立的。了解K-cyclin如何调节转录将扩大目前对这种高度保守的γ - 2疱疹病毒蛋白在与KSHV感染相关的疾病发病机制中的作用的认识。这一知识可能会导致新的治疗方法治疗kshv相关的恶性肿瘤。

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.