JSRV Envelope Cytoplasmic Tail in Transformation

描述(申请人提供)：Jaagsiekte绵羊逆转录病毒(JSRV)是绵羊肺腺癌(OPA)的病原体。OPA肿瘤由转化的肺分泌上皮细胞组成，形态上与人类肺癌--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%，BAC的发病率似乎正在上升。BAC的病因目前尚不清楚，这说明JSRV作为研究肺癌发生的分子机制的唯一工具的重要性。初步实验表明，JSRV Env的表达是啮齿动物成纤维细胞转化所必需的，胞质尾部在转化过程中起着中心作用。在这个方案中，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胞质尾部负责转化的氨基酸残基；2)鉴定细胞蛋白，包括AKT和p38，在JSRV诱导转化中的作用。这些实验将对JSRV致癌的分子机制有新的认识。

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.