Androgen Signaling and Coactivator Regulation in PCA

PCA 中的雄激素信号转导和共激活因子调节

基本信息

批准号：
8610257
负责人：
Hsing-Jien Kung
金额：
$ 29.97万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610257
关键词：
Androgen Receptor Androgens Antibodies Arginine Attention Basic Science Binding Sites Biochemical Biological Biological Markers Cancer Biology Castration Cell Cycle Cell Cycle Progression Cell Line Complex Coupled Cyclin A Data Development Disease Enzymes Epidermal Growth Factor Receptor Epigenetic Process Excision Exhibits Family Gene Targeting Genes Genome Growth Growth Factor Health Histone Code Histone Deacetylase Inhibitor Histones Hormones In Vitro Intervention Knowledge Ligand Binding Lysine Malignant neoplasm of prostate Methylation Molecular Monitor Mutation Peptides Pharmaceutical Preparations Play Post-Translational Protein Processing Property Protein Tyrosine Kinase PubMed Publications Published Comment Refractory Regulation Resistance Role Signal Transduction Site Specificity Specimen Substrate Specificity Tail Tissues Transcription Coactivator Transducers Transfection Translational Research Vorinostat Work Xenograft procedure base castration resistant prostate cancer chromatin immunoprecipitation chromatin remodeling clinically significant effective therapy enzyme substrate fascinate histone acetyltransferase in vivo inhibitor/antagonist overexpression progression marker promoter prostate cancer cell prostate carcinogenesis receptor receptor binding receptor expression response small molecule src-Family Kinases therapeutic target tumor

项目摘要

Androgen receptor plays a significant role in prostate carcinogenesis and its overexpression and aberrant activation are considered to be the underlying cause for the development of castration- resistant tumors, which at present defy any effective treatment. As a transcriptional factor, androgen receptor is involved in the assembly of transcriptional complex including coactivators on the target genome site. One special class of coactivators are histone modifying enzymes and the best understood are histone acetylases. A newly emerging class is histone demethylase, which serves to remodel the chromatin surrounding the androgen receptor binding site. They are thus both transcriptional coactivator and epigenetic regulator. The present proposal is based on our identification of a new histone demethylase with all the hallmarks of a strong coactivator of androgen receptor and is overexpressed in prostate cancer. It enhances androgen response, accelerates cell cycle progression, and exhibits a substrate specificity different from the known histone demethylases. Intriguingly, it is regulated by growth factor and is phosphorylated by tyrosine kinases. The enzyme is cell cycle regulated but also regulates cell cycle. Based on these preliminary observations, we wish to elucidate its biochemical properties as a demetylation enzyme, its regulation as a signal transducer, and its biological effects as an androgen receptor coactivator. Its potential as a biomarker and/or a target for therapy will also be evaluated.

雄激素受体在前列腺癌发生及其过表达和异常激活被认为是cast割发展的根本原因 - 抗性肿瘤目前无视任何有效治疗的肿瘤。作为转录因子，雄激素受体参与转录复合物的组装，包括目标的共激活因子基因组部位。一类特殊的共激活因子是组蛋白修饰酶，是最好的理解是组蛋白乙酰基酶。新兴类是组蛋白脱甲基酶重塑周围雄激素受体结合位点的染色质。他们俩都是转录共激活因子和表观遗传调节剂。本提案基于我们的身份证明新的组蛋白脱甲基酶，其所有标志是雄激素受体和在前列腺癌中过表达。它增强了雄激素反应，加速了细胞周期进展，表现出与已知组蛋白脱甲基酶不同的底物特异性。有趣的是，它受生长因子的调节，并由酪氨酸激酶磷酸化。酶是细胞周期调节，但也调节细胞周期。基于这些初步观察，我们希望阐明其生化特性作为降替酶，其调节为信号传感器，及其作为雄激素受体共激活剂的生物学作用。它作为生物标志物和/或A的潜力还将评估治疗靶标。