MECHANISM OF CELLULAR TRANSFORMATION BY HTLV-1 TAX

人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，ATL是CD4+ T细胞的侵袭性克隆恶性肿瘤。HTLV-I编码一种调节蛋白Tax，负责HTLV-I的转化潜能。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。我们最近证明了Tax可以激活增殖细胞核抗原（PCNA）启动子的表达。PCNA是DNA聚合酶必需的辅助因子，其表达与细胞生长和转化密切相关。PCNA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的复制和修复。异常的PCNA表达被认为断开了复制和修复活动，使得DNA可以在修复完成之前复制。因此，Tax激活PCNA表达可能促进细胞增殖和受损DNA的异常修复，最终导致致癌转化。拟建的研究将确定人类PCNA启动子的税务转激活机制。此外，还将研究Tax激活PCNA基因表达对细胞DNA损伤和转化积累的影响。

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.