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EXPRESSION & ROLE OF TA1 ONCOFETAL GENE--LIVER CANCER

表达

基本信息

批准号：
6628275
负责人：
NANCY L. THOMPSON
金额：
$ 24.17万
依托单位：
RHODE ISLAND HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2005-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6628275
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

项目摘要

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：(改编自研究人员的摘要)TA1被克隆作为一种在大鼠肝癌细胞系中高效表达的基因胎儿肝脏，而正常成人肝脏中不存在。它的编码区高度保守，编码241个氨基酸的疏水肽，与 6或7个与人类94%相同的跨膜结构域淋巴细胞即刻早期基因E16。尽管同系人最近已在非洲爪哇、血吸虫和线虫中克隆，其特异性功能仍不清楚。TA1/E16与酵母菌有显著同源性氨基酸通透性和哺乳动物的阳离子氨基酸转运体，强烈地暗示有这样的功能。我们已经报告了评估的E16 多种原发人类肿瘤标本中相关基因的表达正常组织，提示E16/TA1的表达上调是一种肿瘤发生中的常见事件。我们进一步证明了瞬变的大鼠急性肝损伤时的表达及正常肝组织的诱导表达精氨酸耗竭后体外培养的肝细胞，结果一致随着肿瘤细胞对氨基酸正常功能的开发运输。这项提案的重点是审查监管和 TA1/E16在肝细胞中的功能及其在肿瘤发生中的作用这个我们建议检验的假设是，当TA1/E16的表达是在正常肝细胞中受到严格调控，持续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。在这个提案中，我们将使用老鼠和人类模型检测TA1在体内肝癌发生过程中的表达并比较其在转化和未转化肝脏中的调节作用。体外培养的细胞。我们还将确定构成的后果 TA1在肝细胞中的过表达和阻断表达 TA1与细胞表面CD98hc/4F2的功能结合参与整合素激活和氨基酸转运的分子。这些研究将提供对TA1功能和其在肝癌发生中的作用。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transcriptional regulation of the LAT-1/CD98 light chain.

LAT-1/CD98 轻链的转录调控。

DOI：
10.1016/j.bbrc.2004.04.062
发表时间：
2004
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Padbury,JamesF;Diah,SriK;McGonnigal,Bethany;Miller,Carla;Fugere,Celine;Kuzniar,Magdalena;Thompson,NancyL
通讯作者：
Thompson,NancyL

Short-term arginine deprivation results in large-scale modulation of hepatic gene expression in both normal and tumor cells: microarray bioinformatic analysis.