JSRV Envelope Cytoplasmic Tail in Transformation

描述（由申请人提供）：羊Jaagsiekte逆转录病毒（JSRV）是羊肺腺癌（OPA）的病原体。OPA肿瘤由转化的肺分泌性上皮细胞组成，其形态与人肺癌细支气管肺泡癌（BAC）相似。肺癌是美国癌症死亡的主要原因。BAC约占所有人类肺癌的25%，并且BAC的发病率似乎在上升。BAC的病因目前尚不清楚，这说明了JSRV作为研究肺癌发生分子机制的独特工具的重要性。初步实验表明，JSRV Env的表达对于啮齿动物成纤维细胞的转化是必要的，并且胞质尾部在转化中起核心作用。在这篇文章中，我们将描述JSRV env诱导细胞转化的分子机制。具体目标包括：1)鉴定JSRV Env细胞质尾部负责转化的氨基酸残基；2)细胞蛋白（包括AKT和p38）在jsrv诱导转化中的作用。这些实验将对JSRV致瘤的分子机制产生新的认识。

DESCRIPTION (provided by applicant): Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA). OPA tumors consist of transformed secretory epithelial cells of the lung and have morphological resemblance to that of a human lung cancer, bronchioloalveolar carcinoma (BAC). Lung cancer is the leading cause of cancer mortality in the United States. BAC accounts for approximately 25 percent of all human lung cancers and the incidence of BAC appears to be rising. The etiology of BAC is currently unknown, which illuminates the importance of JSRV as a unique tool to investigate the molecular mechanism of lung carcinogenesis. Preliminary experiments have demonstrated that expression of JSRV Env is necessary for transformation of rodent fibroblasts and that the cytoplasmic tail plays a central role in transformation. In this proposal, we will characterize the molecular mechanism of JSRV Env-induced cell transformation. Specific aims include: 1) Identification of amino acid residues in the JSRV Env cytoplasmic tail responsible for transformation; 2) Characterization of the role of cellular proteins, including AKT and p38, in JSRV-induced transformation. These experiments will generate new insight into the molecular mechanism of oncogenesis by JSRV.