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（由申请人提供）：逃避凋亡是源自肝肿瘤和其他恶性肿瘤的癌细胞的基本特征。称为MET的肝细胞生长因子受体（HGFR）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着重要作用，并且在包括肝细胞癌（Hepatocellular Carcinoma）（HCC）在内的各种人类癌组织和细胞系中过表达。了解HCC开发的分子机制是一项关键的NIDDK倡议（即肝病研究计划）。使用结构功能研究，我们发现人MET的细胞内结构域的C末端端具有一个新型的串联caspase-3裂解位点，我们将其命名为MET Caspase诱饵位点（MCDS）。它具有以下序列：DNAD（DEVD（TRPASFWETS（（表示caspase裂解位点））。我们将在此A2更新应用中测试的中心假设是，通过携带独特的caspase sisbase粘液型基序（MCDS），通过人类的尾部功能和casp octive a'''''''''''''''''过渡状态在裂解过程中导致抑制caspase-3活性，凋亡耐药性和促进HCC的最先进的分子生物化学方法和生物学方法。使用功能丧失和功能增益方法，我们将在AIM 2中评估MCDS-Caspase-3相互作用和Caspase-3抑制作用的分子机制。从这些研究中，我们应该对从未有描述的新型亲寿世机制进行大量了解。公共卫生相关性：肝细胞癌（HCC）是最致命的癌症形式之一（仅次于胰腺腺癌）。由于这些肿瘤对化学治疗剂具有抗性，这些肿瘤主要通过诱导细胞凋亡（或程序性细胞死亡）杀死细胞，因此没有有效的HCC治疗。我们发现Met是一种引起癌症的蛋白质，高插座是细胞凋亡机制（称为caspases的专业酶），从而导致细胞死亡，从而导致癌细胞的生存和寿命。我们将研究MET抑制caspase抑制的分子机制。我们提出的研究集体将对HCC生长和细胞存活的分子机制建立新的见解。他们可能会为理性药物设计（即模仿caspase诱饵部位的药物）开放途径，以治疗从肝炎到HCC的肝脏疾病。