EXPRESSION & ROLE OF TA1 ONCOFETAL GENE--LIVER CANCER

表达

• 批准号: 6350217
• 负责人: NANCY L. THOMPSON
• 金额: $ 22.78万
• 依托单位: RHODE ISLAND HOSPITAL
• 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/6350217
• 关键词: aminoacid transport; carcinogenesis; gene expression; genetic regulation; human subject; laboratory rat; liver cells; liver neoplasms; oncogenes; phenotype; protein structure function; tissue /cell culture

DESCRIPTION: (adapted from the investigator's abstract) TA1 was cloned as a cDNA with high level expression in rat hepatoma cell lines and fetal liver but not in normal adult liver. It's coding region is highly conserved, encoding a predicted 241 amino acid hydrophobic peptide with 6 or 7 transmembrane domains that is 94 percent identical to the human lymphocyte immediate early gene E16. Although homologs have recently been cloned in Xenopus, Schistosoma and C. elegans, its specific function remains unknown. TA1/E16 bears significant homology with yeast amino acid permeases and mammalian cationic amino acid transporters, strongly suggesting such a function. We have reported evaluated E16 expression in a variety of primary human cancer specimens relative to normal tissue, suggesting that upregulation of E16/TA1 expression is a common event in tumorigenesis. We have further demonstrated transient expression in acute rat liver injury and induced expression in normal hepatocytes in vitro following arginine depletion, findings consistent with the exploitation by tumor cells of a normal function in amino acid transport. The focus of this proposal is to examine the regulation and function of TA1/E16 in hepatic cells and its role in carcinogenesis. The hypothesis we propose to test is that while expression of TA1/E16 is tightly regulated in normal hepatic cells, consistutive high level expression contributes to the malignant phenotype, most likely by conferring a growth and/or survival advantage related to amino acid transport activity. In this proposal, we will use rat and human models in which to examine TA1 expression during hepatocarcinogenesis in vivo and compare its regulation in transformed and nontransformed hepatic cells in vitro. We will also determine the consequences of constitutive TA1 overexpression and blocked expression in heptatic cells on phenotype and the functional association of TA1 with CD98hc/4F2, a cell surface molecule implicated in integrin activation and amino acid transport. These studies will provide mechanistic insight into TA1 function and its role in liver carcinogenesis.

描述：（改编自研究者摘要）克隆了TA 1 作为在大鼠肝癌细胞系中具有高水平表达的cDNA， 胎儿肝脏中没有，而正常成人肝脏中没有。它的编码区高度 保守的，编码预测的241个氨基酸的疏水肽， 6或7个跨膜结构域，与人类94%相同 淋巴细胞即早基因E16。尽管最近同源物 在非洲爪蟾、血吸虫和C. elegans，其具体 功能仍然未知。TA 1/E16与酵母菌有很高的同源性 氨基酸渗透酶和哺乳动物阳离子氨基酸转运蛋白， 强烈建议这样的功能。我们已经报告评估了E16 相对于多种原发性人类癌症标本的表达 正常组织，表明E16/TA 1表达的上调是一个重要因素。 肿瘤发生中的常见事件。我们进一步证明了瞬态 在大鼠急性肝损伤中表达和在正常肝组织中诱导表达 精氨酸耗竭后的体外肝细胞，结果一致 肿瘤细胞利用氨基酸的正常功能， 运输这项建议的重点是审查条例， TA 1/E16在肝细胞中的功能及其在肝癌发生中的作用的 我们提出要检验假设是，当TA 1/E16的表达是 在正常肝细胞中严格调节，组成性高水平 表达有助于恶性表型，最有可能是通过 赋予与氨基酸相关的生长和/或存活优势 运输活动。在这个提议中，我们将使用大鼠和人类模型 在体内检测肝癌发生过程中TA 1表达 并比较其在转化和非转化肝细胞中的调节作用 体外细胞我们还将确定构成性的后果 TA 1在肝细胞中的过表达和表型上的表达阻断 以及TA 1与CD 98 hc/4F 2的功能性结合， 与整合素活化和氨基酸转运有关的分子。 这些研究将为TA 1功能及其作用机制提供深入的认识。 在肝癌发生中的作用。