An androgen receptor coactivator regulated in prostate

前列腺中调节的雄激素受体共激活剂

基本信息

批准号：
8761290
负责人：
Susan K. Logan
金额：
$ 25.59万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-19 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8761290
关键词：
AR gene Ablation Accounting Affect Androgen Receptor Androgens Antiandrogen Therapy Apoptosis Binding Biology Cancer Biology Cell Cycle Checkpoint Cell Cycle Progression Cell Differentiation process Cell Proliferation Cells Complex DNA-Directed RNA Polymerase Development Diagnostic Neoplasm Staging Dose Enhancers Epithelial Cells Gene Amplification Gene Expression Regulation Gene Mutation Gene Targeting Genes Genetic Programming Genetic Transcription Genomics Goals Grant Growth Health Hormones Human Intervention Investigation LNCaP Lesion Maintenance Malignant - descriptor Malignant neoplasm of prostate Mediating Messenger RNA Metabolism Minority Multiprotein Complexes Mus Mutagenesis Mutation Nuclear Extract Outcome PC3 cell line Physiological Play Prostate Prostate Cancer therapy Prostatic Intraepithelial Neoplasias Proteins Receptor Gene Receptor Signaling Refractory Disease Regulation Regulator Genes Reporting Resistance Role Sampling Sedimentation process Testing Transcriptional Activation Transcriptional Regulation Undifferentiated base cell growth cell type cofactor hormone therapy in vivo link protein member novel prefoldin programs promoter protein function receptor therapy resistant tumor progression yeast two hybrid system

项目摘要

DESCRIPTION (provided by applicant): The focus of this proposal is on Androgen Receptor Trapped clone-27 (ART-27) and Unconventional prefoldin RBP5 Interactor (URI), two proteins that interact with one another and have a major impact on transcriptional regulation through the Androgen Receptor (AR). During prostate development in humans, ART-27 is expressed in differentiated luminal epithelial cells but is not detected in undifferentiated epithelial cell precursors, suggesting a role for ART-27 in AR-mediated growth suppression and differentiation. Consistent with a growth suppressive function, ART-27 expression levels are decreased in human prostate cancer and regulated expression of ART-27 in the androgen sensitive LNCaP prostate cancer cell line inhibits androgen- mediated cellular proliferation. Moreover, a somatic alteration in AR (AR P340L) derived from a prostate cancer shows diminished capacity to enhance ART-27 mediated AR-transcriptional activation. Further, a recent report and our two-hybrid results indicate that ART-27 associates with Unconventional prefoldin RBP5 Interactor (URI) forming complexes with RPB5, a subunit of RNA polymerase, to control transcription programs. URI is implicated in maintenance of genomic integrity and a recent profiling of staged cancer samples indicates that URI is one a group of genes up-regulated in Prostatic Intraepithelial Neoplasia (PIN), a proliferative lesion thought to be a precursor to prostate cancer. Based on these findings, we hypothesize that ART-27 is a cell type specific and developmentally regulated protein that links AR to the URI transcriptional regulatory complex and affects AR target genes important in prostate growth regulation. To test this hypothesis we propose to: 1) Identify ART-27-dependent AR- target genes and the impact of ART-27 and URI on cell cycle progression 2) Determine if ART-27 and URI function independently to direct AR-mediated gene transcription and 3) Elucidate the role of ART-27 in prostate epithelial cell growth and differentiation in vivo. The over-riding hypothesis of this proposal is that AR cofactors modulate specific programs of gene transcription that aid and abet tumor progression. ART-27 and URI are novel members of a transcription complex that clearly play an important role in AR signaling, yet very little is known about the function of these proteins in the prostate. The long-term goal is to understand how AR directs cell metabolism and differentiation in some cellular contexts and proliferation in others.

描述（由申请人提供）：该提案的重点是雄激素受体捕获的克隆-27（ART-27）和非常规的预折叠蛋白RBP5相互作用器（URI），两种蛋白质相互作用，并通过雄激素受体（AR）对转录调节产生重大影响。在人类前列腺发育期间，ART-27在分化的腔上皮细胞中表达，但未在未分化的上皮细胞前体中检测到，这表明ART-27在AR介导的生长抑制和分化中起作用。与生长抑制功能一致，人类前列腺癌中ART-27表达水平降低，并且在雄激素敏感的LNCAP前列腺癌细胞系中ART-27的调节表达抑制了雄激素介导的细胞增殖。此外，从前列腺癌衍生的AR（AR p340L）的体细胞改变显示出增强ART-27介导的AR-AR转录激活的能力下降。此外，最近的一份报告和我们的两性杂交结果表明，ART-27与非常规的prefoldin RBP5 Itesconter（URI）相关联，与RNA聚合酶的亚基RPB5形成复合物，以控制转录程序。 URI与维持基因组完整性有关，并且最近对分期癌症样品进行了分析表明，URI是在前列腺上皮内肿瘤（PIN）中上调的一组基因，这是一种增殖性病变，被认为是前列腺癌的前体。基于这些发现，我们假设ART-27是一种特异性细胞类型和发育调节的蛋白质，将AR与URI转录调节复合物联系起来，并影响在前列腺生长调节中重要的AR靶基因。为了检验这一假设，我们建议：1）确定ART-27依赖性AR靶基因以及ART-27和URI对细胞周期进程的影响2）确定ART-27和URI是否独立起作用以指导AR介导的基因转录，3）阐明ART-27在Vivo中的前列腺上皮细胞生长和分化中的作用。该提议的过度载假说是AR辅助因子调节了辅助和abet肿瘤进展的基因转录的特定程序。 ART-27和URI是转录复合物的新成员，在AR信号传导中显然起着重要作用，但对这些蛋白质在前列腺中的功能知之甚少。长期的目标是了解AR如何在某些细胞环境中指导细胞代谢和分化，而在其他细胞环境中如何引导。