Molecular Analysis of Viral Cyclin

病毒周期的分子分析

• 批准号: 6754360
• 负责人: STEPHEN J. BRANDT
• 金额: $ 30.24万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6754360
• 关键词: cell cycle; cyclin dependent kinase; cyclins; gene induction /repression; genetic promoter element; genetic transcription; human herpesvirus 8; phosphorylation; protein binding; protein protein interaction; retinoblastoma protein; site directed mutagenesis; virus protein; virus related neoplasm /cancer

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.

描述（由申请人提供）：拟议的研究调查了Kaposi的肉瘤疱疹病毒（KSHV）编码的细胞周期蛋白（K-Cyclin）如何调节转录。 K-Cyclin主要在染色质的转录活性分数中与其他在基因激活中作用的蛋白质相关联，这表明K-Cyclin也可能激活转录。 K-Cyclin结合了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共有的。 K-Cyclin/CDKG复合物磷酸化染色质相关的转录共激活因子P300和p300的外源表达以及K-Cyclin协同激活NF-KAPPA B依赖性转录，这一过程已知需要P300进行P300进行激活。这些发现表明，K-Cyclin/CDKG复合物可能是导致NF-KAPPA B在原发性淋巴瘤中的组成型激活，这是KSHV引起的肿瘤。总的来说，这些初步研究表明，K-cyclin可能不仅可以放松细胞周期，还可以调节细胞和可能的病毒基因的转录。研究者建议通过解决两个特定假设来研究K-Cyclin作为转录调节剂的作用。在特定的目标1中，将研究通常检查通常由RB/SP/KLF蛋白复合物抑制的活性基因通过序列特异性相互作用激活活性基因的假设。在特定的目标2中，将独立于DNA结合的假设通过蛋白质 - 蛋白质相互作用来调节转录，这可能是细胞周期蛋白依赖性激酶（CDK）依赖性和独立的。了解K-Cyclin如何调节转录将扩大有关这种高度保守的γ2-hepesvirus蛋白在与KSHV感染相关的疾病的发病机理中的作用的当前知识。这些知识可能会导致用于治疗KSHV相关恶性肿瘤的新型治疗方法。