Interaction between HIV-1 and cell cycle proteins

HIV-1 和细胞周期蛋白之间的相互作用

• 批准号: 6608078
• 负责人: Antonio Giordano
• 金额: $ 15.05万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-05 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6608078
• 关键词: AIDS related neoplasm /cancer; B cell lymphoma; cell cycle proteins; cell line; central nervous system neoplasms; cyclin dependent kinase; disease /disorder etiology; gene interaction; gene mutation; host organism interaction; human immunodeficiency virus 1; immunoprecipitation; laser capture microdissection; oncogenes; pathologic process; phosphorylation; polymerase chain reaction; protein binding; protein protein interaction; retinoblastoma protein; single cell analysis; single strand conformation polymorphism; southern blotting; transcription factor; viral carcinogenesis; western blottings

DESCRIPTION (provided by applicant): HIV-1 has long been recognized as the etiological agent in acquired immunodeficiency syndrome (AIDS). Although neoplasms arise in HIV-1-infected patients more frequently than in other forms of immunosuppression, the role of HIV-1 as an oncogenic virus has not yet been clarified. HIV-1 encodes for the Tat transcription protein, which is essential for efficient viral replication. Tat is a likely candidate to contribute to tumor pathogenesis in HIV-1-infected patients because of its growth promoting activity, angiogenic function and regulation of the apoptotic pathway. The oncogenic role of Tat is further supported by an increased incidence of tumors in Tat-transgenic mice. 2-12 percent of AIDS patients develop primary central nervous system (CNS) lymphomas, of which 98 percent are B-cell lymphomas. Recently, a virus-linked mechanism of lymphomagenesis involving the Rb2/pl30 pathway has been proposed in AIDS-related Burkitt's lymphoma (BL). A deregulation of cell growth control by RB-related proteins may be the first step in lymphomagenesis in HIV-1-infected patients. However, little is known about the mechanisms by which HIV-1 gene products interact with the RB family and other cell cycle regulatory proteins. Among the latter, Cdk9 (PITALRE), identified and cloned in our laboratory, is the most likely candidate to be involved in the development of AIDS-related neoplasms. Cdk9, a cdc2-related kinase, promotes general elongation of transcription by activating the C-Terminal Domain (CTD) of RNA Polymerase II. Cdk9 is a partner of cyclin T1, which binds to the HIV Tat protein, supporting the positive involvement of Cdk9 in HIV replication and suggesting its possible role in the development of AIDS-related neoplasms. The goal of this proposal is to investigate the interaction between HIV gene products and cell cycle regulatory proteins and their role in the development/growth of the most common AIDS-related CNS and other subtype lymphomas. In particular, we will focus our attention on the cell cycle regulatory proteins, pRb2/pl30, Cdk9 and cycT1, which seem to be involved in AIDS-related tumorigenesis.

描述（由申请人提供）：HIV-1 长期以来被认为是 获得性免疫缺陷综合症（艾滋病）的病原体。虽然 HIV-1 感染患者中肿瘤发生的频率高于其他形式 免疫抑制方面，HIV-1 作为致癌病毒的作用尚未明确 澄清。 HIV-1 编码重要的 Tat 转录蛋白 以实现有效的病毒复制。 Tat 是有可能做出贡献的候选人 HIV-1 感染患者的肿瘤发病机制，因为其促进生长 活性、血管生成功能和细胞凋亡途径的调节。这 肿瘤发病率的增加进一步支持了 Tat 的致癌作用 在Tat转基因小鼠中。 2-12% 的艾滋病患者出现原发性中枢性 神经系统 (CNS) 淋巴瘤，其中 98% 是 B 细胞淋巴瘤。 最近，涉及 Rb2/pl30 的病毒相关淋巴瘤发生机制 已在与艾滋病相关的伯基特淋巴瘤（BL）中提出了该途径。一个 RB相关蛋白对细胞生长控制的失调可能是第一个 HIV-1 感染患者淋巴瘤发生的一步。然而，鲜为人知 关于 HIV-1 基因产物与 RB 家族相互作用的机制 和其他细胞周期调节蛋白。后者中，Cdk9（PITALRE）， 在我们的实验室中鉴定和克隆的，是最有可能的候选者 参与艾滋病相关肿瘤的发展。 cdk9，cdc2相关的 激酶，通过激活 RNA 聚合酶 II 的 C 端结构域 (CTD)。 Cdk9是细胞周期蛋白T1的伙伴， 与 HIV Tat 蛋白结合，支持 Cdk9 的积极参与 HIV复制并表明其在发展中的可能作用 艾滋病相关肿瘤。该提案的目的是调查 HIV基因产物与细胞周期调节蛋白之间的相互作用 它们在最常见的艾滋病相关中枢神经系统的发育/生长中的作用 其他亚型淋巴瘤。我们将特别关注细胞 循环调节蛋白 pRb2/pl30、Cdk9 和 cycT1 似乎参与其中 与艾滋病相关的肿瘤发生。