Mechanisms of HTLV-1 p30 in Transcription and DMA Repair

HTLV-1 p30 转录和 DMA 修复机制

• 批准号: 7383661
• 负责人: MICHAEL D. LAIRMORE
• 金额: $ 14.32万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-21 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7383661
• 关键词: Acetylation; Adult; Amino Acid Motifs; Animals; Ataxia-Telangiectasia-Mutated protein kinase; Binding; Biological Assay; Biology; Cell Cycle; Cell Survival; Cell physiology; Cellular biology; Code; Complex; Consensus; DNA Repair; Data; Disease; EP300 gene; Environment; Equilibrium; Family member; Gagging; Genes; Genetic Transcription; Goals; Human; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; Infection; Localized; Lymphocyte; Lymphocyte Activation; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Modification; Molecular Cloning; Mutation; Nuclear; Nucleolar Proteins; Open Reading Frames; Oryctolagus cuniculus; Phase; Post-Transcriptional Regulation; Process; Proteins; Publishing; Retroviridae; Role; Signal Transduction; Site; T-Cell Leukemia; T-Cell Lymphoma; T-Lymphocyte; Taxes; Testing; Therapeutic Intervention; Transactivation; Transcriptional Regulation; Translations; Viral; Viral Proteins; Virus; adult leukemia; base; cell transformation; comparative; computer studies; env Gene Products; in vivo; insight; leukemia; novel; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; pol genes; ranpirnase; repaired; tool; transcription factor; transmission process

Insights gained through the study of retroviruses have established basic paradigms of cell biology, including mechanisms of lymphocyte activation and proliferation. In Project 1 of P01 CA100730 we seek to continue to investigate fundamental questions of Human T-lymphotropic Virus Type 1 (HTLV-1), a complex retrovirus that causes adult T-cell lymphoma/leukemia (ATL). HTLV-1 encodes typical gag, pol, and env gene products, and unique genes encoded in its pX region. In this highly collaborative PPG, we have pioneered the examination of the role of HTLV-1 proteins in viral replication in vivo and in lymphocyte activation, an important antecedent to virus transmission and cell transformation. The focus of this project emerged from these studies and concentrates our proposed studies on p30 encoded in pX ORF II of HTLV-1. This nuclear/nucleolar protein has homology to transcription factors and contains G/SK consensus acetylation sites. Our collaborative studies with Drs. Green, Ratner, and Boris-Lawrie (Projects 2, 3, 5, Cores A, B, & C) of this PPG provided the first evidence that p30 is required by the virus to establish infection in animals, acts as a transcription factor, is positively influenced by acetylation and binds the KIX domain of the co-activator, p300. We now provide exciting new data that implicate p30 in DMA damage/repair signaling that results in cell cycle perturbation and likely promote viral integration. Our data indicate that HTLV-1 uses p30 in a novel manner to modulate the cellular environment to favor cell survival and balances the influence of viral transactivation (i.e., Tax) to allow viral persistence. In our next phase of this PPG, we provide interdependent approaches to identify the roles of HTLV-1 p30 and HTLV-2 p28 (Project 2) by comparative testing of essential transcriptional and post-transcriptional control parameters. We have focused specific aims for this competitive renewal of Project 1 on: 1) Localize important structural motifs of HTLV-1 p30 that mediated transcriptional regulation and DNA damage/repair signaling in T lymphocytes, 2) Determine the role of posttranslation modifications in HTLV-1 p30 -mediated transcriptional regulation and DNA damage/repair signaling in T lymphocytes, and 3) Test structural motifs important in p30 -mediated transcriptional regulation and DNA damage/repair signaling in the spatial and temporal distribution of early virus expression in rabbits with HTLV-1 molecular clones with selective mutations in pX ORF II. Our long-term goal is to understand how retroviruses, like HTLV-1 alter T cell physiology and thereby gain insight into mechanisms of the early phases of cell transformation and new targets of therapeutic intervention.

通过逆转录病毒研究获得的见解建立了细胞生物学的基本范式，包括 淋巴细胞活化和增殖的机制。在 P01 CA100730 的项目 1 中，我们寻求继续 研究 1 型人类 T 淋巴细胞病毒 (HTLV-1)（一种复杂的逆转录病毒）的基本问题 导致成人 T 细胞淋巴瘤/白血病 (ATL)。 HTLV-1 编码典型的 gag、pol 和 env 基因 产品，以及在其 pX 区域编码的独特基因。在这个高度协作的 PPG 中，我们开创了 检查 HTLV-1 蛋白在体内病毒复制和淋巴细胞激活中的作用， 病毒传播和细胞转化的重要前提。该项目的重点来自于 这些研究集中于我们提出的对 HTLV-1 的 pX ORF II 编码的 p30 的研究。这 核/核仁蛋白与转录因子具有同源性，并含有 G/SK 共有乙酰化 网站。我们与博士的合作研究。 Green、Ratner 和 Boris-Lawrie（项目 2、3、5，核心 A、B 和 C） 该 PPG 提供了第一个证据，证明病毒需要 p30 才能在动物中建立感染， 作为转录因子，受到乙酰化的积极影响并结合辅激活因子的 KIX 结构域， p300。我们现在提供了令人兴奋的新数据，表明 p30 参与 DMA 损伤/修复信号，从而导致 细胞周期扰动并可能促进病毒整合。我们的数据表明 HTLV-1 在小说中使用了 p30 调节细胞环境以有利于细胞存活并平衡病毒反式激活的影响的方式 （即税收）以允许病毒持续存在。在 PPG 的下一阶段，我们提供相互依赖的方法 通过对必需物质的比较测试来确定 HTLV-1 p30 和 HTLV-2 p28 的作用（项目 2） 转录和转录后控制参数。我们为此制定了具体目标 项目 1 的竞争性更新：1) 定位 HTLV-1 p30 介导的重要结构基序 T淋巴细胞中的转录调控和DNA损伤/修复信号传导，2)确定翻译后的作用 HTLV-1 p30 介导的转录调节和 DNA 损伤/修复的修饰 T 淋巴细胞中的信号转导，以及 3) 测试 p30 介导的转录中重要的结构基序 早期病毒表达时空分布的调控和 DNA 损伤/修复信号传导 HTLV-1 分子克隆在 pX ORF II 中选择性突变的兔子。我们的长期目标是 了解 HTLV-1 等逆转录病毒如何改变 T 细胞生理学，从而深入了解 细胞转化的早期阶段和治疗干预的新目标。