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：（根据调查员的摘要改编）TA1被克隆了 作为在大鼠肝癌细胞系中具有高水平表达的cDNA， 胎儿肝，但不在正常的成年肝脏中。它的编码区域高 保守的，编码预测的241个氨基酸疏水肽 6或7个跨膜结构域与人类相同94％ 淋巴细胞立即早期基因E16。尽管同源物最近有 被克隆在爪蟾，血吸虫和秀丽隐杆线虫中，其特异性 功能仍然未知。 TA1/E16与酵母具有重要同源性 氨基酸渗透和哺乳动物阳离子氨基酸转运蛋白， 强烈建议这样的功能。我们报道了评估E16 相对于多种原发性人类癌标本的表达相对于 正常组织，表明E16/TA1表达的上调为A 肿瘤发生中的常见事件。我们进一步证明了瞬态 急性大鼠肝损伤的表达和诱导的正常表达 精氨酸耗竭后体外肝细胞，发现一致 通过肿瘤细胞在氨基酸中的正常功能的剥削 运输。该提案的重点是检查法规和 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 在正常肝细胞中严格调节，高水平 表达有助于恶性表型，最有可能 赋予与氨基酸有关的生长和/或生存优势 运输活动。在此提案中，我们将使用老鼠和人类模型 其中在体内检查肝癌发生期间的TA1表达 并比较其在变换和未转化的肝脏中的调节 细胞体外。我们还将确定本构的后果 TA1过表达并阻塞表型的纵向细胞中的表达 TA1与CD98HC/4F2（细胞表面）的功能关联 分子与整联蛋白活化和氨基酸转运有关。 这些研究将提供有关TA1功能及其ITS的机械洞察力 在肝癌发生中的作用。