MECHANISM OF CELLULAR TRANSFORMATION BY HTLV-1 TAX

HTLV-1 TAX 的细胞转化机制

• 批准号: 2849538
• 负责人: SUSAN J MARRIOTT
• 金额: $ 19.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2849538
• 关键词: DNA damage; athymic mouse; cell cycle; cell transformation; expression cloning; gene expression; gene mutation; genetic library; genetic promoter element; human T cell lymphotropic virus type 1; natural gene amplification; neoplastic transformation; proliferating cell nuclear antigen; protein binding; protein localization; tissue /cell culture; transcription factor; viral carcinogenesis; virus protein

Human T-cell leukemia virus type I (HTLV-I) is the etiologic agent of adult T cell leukemia (ATL), an aggressive clonal malignancy of CD4+ T cells. HTLV-I encodes a regulatory protein, Tax, which is responsible for the transforming potential of HTLV-I. Tax transformation depends upon its ability to activate cellular growth regulatory genes, although the precise mechanism of transformation remains unknown. We have recently demonstrated that Tax can activate expression of the proliferating cell nuclear antigen (PCNA) promoter. PCNA is a required co-factor of DNA polymerase delta, and its expression is intimately linked to cell growth and transformation. PCNA coordinately regulates both DNA replication and repair via a complex series of stoichiometric interactions with cell cycle regulatory proteins. Aberrant PCNA expression is thought to uncouple replication and repair activities such that DNA can be replicated before repair is complete. Thus, activation of PCNA expression by Tax may contribute to cellular proliferation and abnormal repair of damaged DNA, ultimately resulting in oncogenic transformation. The proposed studies will determine the mechanism of Tax transactivation of the human PCNA promoter. In addition, the effects of Tax activated PCNA gene expression on the accumulation of cellular DNA damage and transformation will be investigated.

人类T细胞白血病病毒I型(HTLV-I)是成人T细胞白血病(ATL)的病原体，ATL是一种侵袭性的CD4+T细胞克隆性恶性肿瘤。HTLV-I编码一种调节蛋白Tax，它负责HTLV-I的转化潜力。税收转化取决于其激活细胞生长调控基因的能力，尽管转化的确切机制尚不清楚。我们最近证实，TAX可以激活增殖细胞核抗原(PCNA)启动子的表达。增殖细胞核抗原是DNA聚合酶Delta的必需辅助因子，其表达与细胞的生长和转化密切相关。增殖细胞核抗原通过与细胞周期调节蛋白的一系列复杂的化学计量相互作用来协调调节DNA复制和修复。异常的增殖细胞核抗原表达被认为使复制和修复活动解偶联，使得DNA可以在修复完成之前复制。因此，TAX激活增殖细胞核抗原的表达可能有助于细胞的增殖和受损DNA的异常修复，最终导致致癌转化。拟议的研究将确定人增殖细胞核抗原启动子反式激活的机制。此外，还将研究Tax激活的增殖细胞核抗原基因表达对细胞DNA损伤和转化积累的影响。