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）：Kaposi的肉瘤是内皮起源的恶性肿瘤，是艾滋病患者中最常见的癌症。 60％的与艾滋病相关的KS在口腔中启动，代表了口腔健康方面的严重问题。尽管将人类疱疹病毒8（HHV-8）鉴定为所有形式的KS的病因，但在HIV感染的患者中，KS的高度较高，表明KS发育中HIV和HHV-8之间的合作相互作用存在合作的相互作用。 HIV TAT是病毒基因表达的关键调节因素之一，在与HIV相关的发病机理中起许多作用。 TAT引起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。细胞细胞蛋白D的同源物HHV-8 K-Cyclin，通过异常激活CDK6并加速细胞周期的G1/S转变来破坏细胞生长的控制。 K-Cyclin的表达促进了内皮细胞的增殖。我们发现TAT与体内的K-Cyclin相互作用，提供了HIV和HHV-8之间病理联系的证据。在这里，我们建议通过使用永生的原代内皮细胞来研究TAT和K-Cyclin在KS发展中的合作作用。使用这种体外模型，我们将剖析负责HHV-8感染的内皮细胞的步骤，以发展KS恶性肿瘤的发展。具体目的是：（1）定义TAT和K-Cyclin之间的分子相互作用，并检查与这两种蛋白质相关的激酶活性，（2）确定TAT和K-Cyclin在促进内皮细胞增殖中的合作作用，（3）表明TAT在增强HHV-8感染和HHV-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8-8- indentigation indentactions indentactions indentactions indentions引起。这些研究将增加我们对与艾滋病相关的KS的发病机理，TAT和K-Cyclin的合作作用，并提出了打击该肿瘤的策略。