EXPRESSION & ROLE OF TA1 ONCOFETAL GENE--LIVER CANCER

表达

• 批准号: 6497693
• 负责人: NANCY L. THOMPSON
• 金额: $ 23.46万
• 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/6497693
• 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：（改编自研究者的摘要）TA1 被克隆 作为在大鼠肝癌细胞系中高水平表达的 cDNA， 胎儿肝脏但不存在于正常成人肝脏中。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 淋巴细胞立即早期基因E16。虽然同系物最近 已在爪蟾、血吸虫和秀丽隐杆线虫中被克隆，其特异性 功能仍未知。 TA1/E16 与酵母具有显着的同源性 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。我们已报告评估E16 在多种原发性人类癌症标本中的表达相对于 正常组织，表明 E16/TA1 表达上调是 肿瘤发生过程中的常见事件。我们进一步证明了瞬态 大鼠急性肝损伤中的表达及正常大鼠中的诱导表达 精氨酸耗尽后的体外肝细胞，结果一致 肿瘤细胞利用氨基酸的正常功能 运输。该提案的重点是审查监管和 TA1/E16在肝细胞中的功能及其在癌变中的作用。这 我们建议测试的假设是，虽然 TA1/E16 的表达是 在正常肝细胞中受到严格调控，组成高水平 表达有助于恶性表型，很可能是通过 赋予与氨基酸相关的生长和/或生存优势 运输活动。在本提案中，我们将使用大鼠和人体模型 体内检测肝癌发生过程中 TA1 的表达 并比较其在转化肝和非转化肝中的调节 体外细胞。我们还将确定构成性后果 肝细胞中 TA1 过表达和表达阻断对表型的影响 以及 TA1 与 CD98hc/4F2（细胞表面）的功能关联 参与整合素激活和氨基酸转运的分子。 这些研究将为 TA1 功能及其作用提供机制见解 在肝癌发生中的作用。