Cooperative roles of Tat & k-cyclin Kaposi's sarcoma

Tat的合作角色

• 批准号: 7060791
• 负责人: Mengtao Li
• 金额: $ 17.58万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7060791
• 关键词: Kaposi' s sarcoma; cell proliferation; clinical research; cyclins; enzyme activity; human herpesvirus 8; human immunodeficiency virus; human tissue; neoplastic transformation; protein kinase; protein protein interaction; tissue /cell culture; transcription factor; vascular endothelium; virus genetics; virus virus interaction

DESCRIPTION (provided by applicant): Kaposi's sarcoma is a malignant tumor of endothelial origin and the most frequent cancer in AIDS patients. Sixty percent of AIDS-associated KS initiate in the oral cavity, representing a serious problem in oral health. Despite identification of human Herpesvirus 8 (HHV-8) as the etiological agent for all forms of KS, the extraordinarily higher prevalence of KS in HIV-infected patients suggests a cooperative interaction between HIV and HHV-8 in the development of KS. HIV Tat is one of the key regulating factors for viral gene expression and plays many roles in HIV-associated pathogenesis. Tat causes dysfunction and transformation of cultured endothelial cells and induces KS-like lesions in transgenic animals. HHV-8 k-cyclin, a homologue of cellular cyclin D, disrupts cell growth control by aberrantly activating Cdk6 and accelerating the G1/S transition of the cell cycle. The expression of k-cyclin promotes proliferation of endothelial cells. We have found that Tat interacts with k-cyclin in vivo, providing evidence of pathological links between HIV and HHV-8. Here, we propose to study the cooperative roles of Tat and k-cyclin in the development of KS by using immortalized primary endothelial cells. Using this in vitro model, we will dissect steps that are responsible for the HHV-8-infected endothelial cells to progress toward the development of KS malignancy. The specific aims are: (1) define the molecular interaction between Tat and k-cyclin and examine kinase activities associated with these two proteins, (2) determine cooperative effects of Tat and k-cyclin in promoting the proliferation of endothelial cells, (3) demonstrate roles of Tat in enhancing HHV-8 infection and HHV-8-induced cell transformation. These studies will increase our understanding of the pathogenesis of AIDS-associated KS, the cooperative role of Tat and k-cyclin, and suggest a strategy in combating this tumor.

描述（由申请人提供）：卡波西肉瘤是一种内皮源性恶性肿瘤，是艾滋病患者最常见的癌症。60%的艾滋病相关KS在口腔中开始，代表口腔健康的严重问题。尽管人类疱疹病毒8型（HHV-8）作为所有形式的KS的病原体的鉴定，非常高的患病率KS在HIV感染的患者表明合作的相互作用之间的HIV和HHV-8在KS的发展。HIV达特是病毒基因表达的关键调控因子之一，在HIV相关的发病机制中起着重要作用。达特导致培养的内皮细胞功能障碍和转化，并在转基因动物中诱导KS样病变。HHV-8 k-cyclin是细胞周期蛋白D的同源物，通过异常激活Cdk 6和加速细胞周期的G1/S转换来破坏细胞生长控制。k-cyclin的表达促进内皮细胞的增殖。我们已经发现，达特与k-细胞周期蛋白在体内相互作用，提供了HIV和HHV-8之间的病理联系的证据。在这里，我们建议研究达特和k-cyclin在KS的发展中的合作作用，通过使用永生化的原代内皮细胞。使用这种体外模型，我们将剖析负责HHV-8感染的内皮细胞向KS恶性肿瘤发展的步骤。具体目标是：（1）明确达特与k-cyclin的分子相互作用，并检测与这两种蛋白相关的激酶活性;（2）确定达特和k-cyclin在促进内皮细胞增殖中的协同作用;（3）证实达特在增强HHV-8感染和诱导的细胞转化中的作用。这些研究将增加我们对艾滋病相关KS的发病机制，达特和k-cyclin的协同作用的理解，并提出了一个战略，在打击这种肿瘤。