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Mechanisms of Met Induced Hepatocytes Survival

Met诱导肝细胞存活的机制

基本信息

批准号：
7874699
负责人：
Reza Zarnegar
金额：
$ 33.9万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-02-15 至 2014-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7874699
关键词：
Active Sites Address Albumins Animals Antibodies Apoptosis Apoptosis Promoter Apoptotic Arts Binding Biochemical Biological Biological Assay C-terminal Cancer Etiology Carcinoma Caspase Cell Death Cell Line Cell Survival Cell surface Cells Complex Cytoplasmic Tail Data Degenerative Disorder Development Drug Design Enhancers Enzymes Gene Targeting Genes Genetic Growth Hepatitis Hepatocarcinogenesis Hepatocyte Human Induction of Apoptosis Knock-in Mouse Liver diseases Liver neoplasms Longevity Malignant Epithelial Cell Malignant Neoplasms Measures Molecular Molecular Conformation Mus Names National Institute of Diabetes and Digestive and Kidney Diseases Pancreatic Adenocarcinoma Peptides Pharmaceutical Preparations Phosphotransferases Physiological Play Primary carcinoma of the liver cells Process Protein Tyrosine Kinase Proteins Proto-Oncogene Protein c-met Protocols documentation Receptor Protein-Tyrosine Kinases Recombinants Research Resistance Role Series Site Stress Structure Tail Testing Tissues Titrations Transgenic Mice Tyrosine adduct base cancer cell caspase-3 cell killing chemotherapeutic agent effective therapy gain of function in vivo insight loss of function meetings mutant novel overexpression promoter public health relevance receptor research study thioester tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Escape from apoptosis is a cardinal feature of cancer cells derived from liver tumors and other malignancies. The Hepatocyte Growth Factor Receptor (HGFR) known as Met is a transmembrane receptor tyrosine kinase (RTK) that plays an important role in promoting hepatocyte survival and proliferation, and it is overexpressed in various human carcinoma tissues and cell lines including hepatocellular carcinoma (HCC). Understanding the molecular mechanisms of HCC development is a key NIDDK initiative (i.e., the Action Plan for Liver Disease Research). Using structure-function studies, we discovered that the C-terminal end of human Met's intracellular domain harbors a novel tandem Caspase-3 cleavage site which we named the Met Caspase Decoy Site (MCDS). It has the following sequence: DNAD(DEVD(TRPASFWETS ((denotes the caspase cleavage site). Our central hypothesis to be tested in this A2 Renewal Application is that, by virtue of harboring a unique caspase substrate decoy motif (MCDS), the cytoplasmic tail of human Met functions as a 'bait' and traps the active site of Caspase-3 by forming a stable transition state intermediate during the cleavage process. This results in inhibition of Caspase-3 activity, apoptosis resistance and promotion of HCC. State-of-the-art molecular biochemical and biological approaches are planned to test this intriguing hypothesis. In Aim 1, we will investigate the functional role of the Met Caspase Decoy Site (MCDS) in Caspase-3 inhibition and promotion of hepatocyte survival and hepatocarcinogenesis using loss-of-function and gain-of-function approaches. In Aim 2, we will assess the molecular mechanisms involved in MCDS-Caspase-3 interaction and Caspase-3 inhibition. In Aim 3, we will determine whether MCDS function depends on the activation status of Met. From these studies, we should gather substantial insight into a novel pro-survival mechanism never before described. PUBLIC HEALTH RELEVANCE: Hepatocellular carcinoma (HCC) is the one of most lethal forms of cancer (only second to pancreatic adenocarcinoma). No effective treatment for HCC exists as these tumors are notorious for being resistant to chemotherapeutic agents which kill cells mainly via induction of apoptosis (or programmed cell death). We have discovered that Met, a cancer-causing protein, highjacks the cellular apoptotic machinery (specialized enzymes called caspases) that causes cell death hence contributing to survival and longevity of cancer cells. We will look at the molecular mechanisms of caspase inhibition by Met. Collectively our proposed studies will establish novel insights into the molecular mechanisms of HCC growth and cell survival. They may open avenues for rational drug design (i.e. drugs that mimic Met caspase decoy site) to treat liver diseases ranging from hepatitis to HCC.

描述（申请人提供）：逃避细胞凋亡是来源于肝脏肿瘤和其他恶性肿瘤的癌细胞的一个基本特征。肝细胞生长因子受体（HGFR）被称为Met，是一种跨膜受体酪氨酸激酶（RTK），在促进肝细胞存活和增殖中起重要作用，在包括肝细胞癌（HCC）在内的各种人类癌组织和细胞系中过表达。了解HCC发展的分子机制是NIDDK的一个关键倡议（即肝病研究行动计划）。通过结构-功能研究，我们发现人类Met细胞内结构域的c末端包含一个新的串联Caspase-3切割位点，我们将其命名为Met Caspase诱饵位点（MCDS）。其序列如下：DNAD(DEVD) (TRPASFWETS)(（表示caspase切割位点）。我们在A2更新申请中要测试的中心假设是，由于拥有独特的caspase底物诱饵基序（MCDS），人类Met的细胞质尾部作为“诱饵”，通过在切割过程中形成稳定的过渡态中间体来捕获caspase -3的活性位点。这导致抑制Caspase-3活性，细胞凋亡抵抗和促进HCC。最先进的分子生化和生物学方法被计划用来测试这个有趣的假设。在Aim 1中，我们将使用功能丧失和功能获得的方法研究Met Caspase诱饵位点（MCDS）在Caspase-3抑制和促进肝细胞存活和肝癌发生中的功能作用。在目标2中，我们将评估涉及MCDS-Caspase-3相互作用和Caspase-3抑制的分子机制。在Aim 3中，我们将确定MCDS功能是否取决于Met的激活状态。从这些研究中，我们应该对一种以前从未描述过的新的促生存机制有了实质性的了解。