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delta-Catenin and Cell-Cell Adhesion in Prostate Cancer

前列腺癌中的 δ-连环蛋白和细胞间粘附

基本信息

批准号：
7345429
负责人：
QUN LU
金额：
$ 18.4万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2010-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7345429
关键词：
Adherens Junction Androgens Animals Area Armadillo Repeat Binding Brain Cancer Etiology Cell Line Cell physiology Cell-Cell Adhesion Cell-Matrix Junction Cells Co-Immunoprecipitations Complex Confocal Microscopy Cultured Cells Cytoplasm DNA-Binding Proteins Disease Disruption Down-Regulation E-Cadherin Event Family Family Dasypodidae GTP Binding Gene Expression Glutathione S-Transferase Goals Growth Factor Hepatocyte Growth Factor Intercellular Junctions Lasers Lead Malignant Neoplasms Malignant neoplasm of prostate Mediating Methods Modeling Modification Molecular Monoclonal Antibodies Monomeric GTP-Binding Proteins Morbidity - disease rate Neurons Nuclear Nuclear Protein Nuclear Proteins Pathway interactions Peptides Peripheral Phosphorylation Phosphotransferases Post-Translational Protein Processing Prevention Prostate Prostate Adenocarcinoma Prostatic Neoplasms Protein Analysis Protein Array Protein Overexpression Proteins RNA Interference Research Personnel Role Screening procedure Sequence Homology Signal Transduction Signaling Molecule Site-Directed Mutagenesis Study Section Technology Testing Tissue Microarray Tissues Transgenic Mice Transgenic Organisms Yeasts armadillo proteins catenin p120ctn protein cell growth cell motility delta-catenin in vivo insight men mortality mutant relating to nervous system response rho tumor tumor xenograft tumorigenesis yeast two hybrid system

项目摘要

Prostate cancer (CaP) is the most common malignancy in men in US and the second leading cause of cancer mortality. To reduce the significant morbidity and mortality, new strategies for CaP prevention and treatment depend on the determination of specific molecular mechanisms involved in this disease. 8-Catenin is a unique armadillo (ARM)domain-containing protein in that it is neural specific and primarily expresses in the brain. However, 8-catenin expression increases in prostatic adenocarcinomas, redistributes E-cadherin/120ctn from the cell-cell junction, and promotes CaP cell growth and invasion. To investigate this largely unexplored area of neuronal catenin gene expression in peripheral tissues of cancers, the overall goal of this project is to test the hypothesis that 8-catenin promotes CaP formation and progression by interacting with multiple cellular machineries, including cell-cell and cell-matrix adhesion, cell growth/survival, and invasion. There are three specific aims in this proposal. Specific Aim 1 will determine how 8-catenin promotes cell growth/survival and motility in response to the hepatocyte growth factor and/or androgen using CWR22 tumor xenografts and their derived cell lines. We will broadly screen and profile the S-catenin induced alteration of signaling molecules by array technology. These studies will identify cancer specific pathways that 8-catenin is involved in and will investigate their interactions with S-catenin using protein co-immunoprecipitation and yeast two-hybrid analyses. Specific Aim 2 will determine how 8-catenin interacts with Rho family small GTPases to disrupt adherens junction and promote CaP cell growth/survival and invasion. We will first identify the 8-catenin sequence responsible for this action. Then, the analyses of 8-catenin RNAi or its mutants that are defective in Rac-1 or E-cadherin binding will determine the interactions between GTP-Rac-1/IQGAP-1 and E-cadherin/p120ctn pathways to reveal possible differential modulations on cell-cell adhesion and cell growth/survival and invasion. We will also determine the cytoplasmic accumulation and nuclear signaling of (3-catenin that is released from E- cadherin complexes by IQGAP-1. Specific Aim 3 will apply Y311, a unique (dePhospho-specific) monoclonal antibody, and site-directed mutagenesis to determine how 8-catenin modifications occur and what are their roles in CaP. We will also investigate S-catenin proteolytic fragments and their potentials as DNA binding proteins and nuclear signaling for gene expression. Finally, we will generate transgenic mice displaying prostate tissue specific S-catenin expression to approach these questions at the animal level. These studies will place 8-catenin into the broad context of growth factor and kinase signaling machineries relevant to CaP. Understanding the posttranslational modifications that control 8-catenin functions will unravel mechanisms by which S-catenin modulates gene expression and promotes CaP in vivo.

前列腺癌（CaP）是美国男性最常见的恶性肿瘤，也是导致前列腺癌的第二大原因