Molecular Analysis of Viral Cyclin

描述（由申请人提供）：拟议的研究调查卡波西肉瘤疱疹病毒（KSHV）编码的细胞周期蛋白（K-细胞周期蛋白）如何调节转录。K-细胞周期蛋白主要与染色质的转录活性部分沿着与在基因活化中起作用的其他蛋白质结合，这表明K-细胞周期蛋白也可以活化转录。K-细胞周期蛋白结合在由视网膜母细胞瘤蛋白/Sp/Kruppel样因子（Rb/Sp/KLF）复合物调节的启动子中发现的DNA共有序列。K-细胞周期蛋白/cdkG复合物磷酸化染色质相关的转录辅激活因子p300，并且p300的外源表达与K-细胞周期蛋白一起沿着协同激活NF-κ B依赖性转录，这是已知需要p300来激活的过程。这些发现表明，K-细胞周期蛋白/cdkG复合物可能是原发性渗出性淋巴瘤（一种由KSHV引起的肿瘤）中NF-κ B组成性激活的原因。总的来说，这些初步研究表明，K-细胞周期蛋白不仅可以解除细胞周期的调节，而且还可以调节细胞基因和可能的病毒基因的转录。研究者提出了两个具体的假设，以探讨K-细胞周期蛋白作为转录调节因子的作用。在具体目标1中，将检查K-细胞周期蛋白通过与含KRE的启动子的序列特异性相互作用激活通常被Rb/Sp/KLF蛋白复合物抑制的活性基因的假设。在具体目标2中，将检验K-细胞周期蛋白独立于DNA结合通过蛋白质-蛋白质相互作用调节转录的假设，所述蛋白质-蛋白质相互作用可能是细胞周期蛋白依赖性激酶（cdk）依赖性的和独立的。了解K-细胞周期蛋白如何调节转录将扩大目前的知识，这种高度保守的γ 2-疱疹病毒蛋白在与KSHV感染相关的疾病的发病机制中的作用。这些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.