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: 6594793
• 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 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6594793
• 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(申请人提供)：HIV-1很早就被认为是 获得性免疫缺陷综合征(艾滋病)的病原体。虽然 与其他形式相比，HIV-1感染患者更容易发生肿瘤 在免疫抑制方面，HIV-1作为致癌病毒的作用尚未被 澄清了。HIV-1编码Tat转录蛋白，这是必不可少的 用于高效的病毒复制。Tat是一位有可能做出贡献的候选人 HIV-1感染患者促生长作用的肿瘤发病机制 活性、血管生成功能和细胞凋亡途径的调节。这个 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%的艾滋病患者发展为原发中枢 神经系统(CNS)淋巴瘤，其中98%是B细胞淋巴瘤。 最近，一种涉及Rb2/PL30的淋巴肿瘤发生的病毒连锁机制 艾滋病相关性Burkitt‘s淋巴瘤(BL)的信号转导途径已被提出。一个 RB相关蛋白对细胞生长控制的解除调控可能是第一次 参与HIV-1感染患者的淋巴肿大。然而，人们对此知之甚少 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。在后者中，CDK9(PITALRE)， 在我们实验室鉴定和克隆的，是最有可能是 参与艾滋病相关肿瘤的发展。CDK9，一个与CDC2相关的基因 激酶，通过激活转录因子，促进转录的普遍延长 RNA聚合酶II的C末端结构域(CTD)。CDK9是细胞周期蛋白T1的合作伙伴， 它与HIV的Tat蛋白结合，支持CDK9的积极参与 在艾滋病毒复制中的作用，并表明其在发展中的可能作用 与艾滋病相关的肿瘤。这项提案的目标是调查 HIV基因产物与细胞周期调控蛋白的相互作用 它们在最常见的艾滋病相关中枢神经系统的发展/增长中的作用和 其他亚型淋巴瘤。特别是，我们将把注意力集中在细胞上 周期调节蛋白，pRb2/PL30，CDK9和CycT1，似乎参与了 在艾滋病相关肿瘤发生中的作用。