An androgen receptor coactivator regulated in prostate

前列腺中调节的雄激素受体共激活剂

• 批准号: 7683054
• 负责人: Susan K. Logan
• 金额: $ 35.17万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683054
• 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 Proliferation; Cells; Complex; DNA-Directed RNA Polymerase; Development; Diagnostic Neoplasm Staging; Dose; Enhancers; Epithelial Cells; Gene Expression Regulation; Gene Mutation; Gene Targeting; Genes; Genetic Programming; Genetic Transcription; Genomics; Goals; Grant; Growth; 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; public health relevance; receptor; therapy resistant; tumor progression; yeast two hybrid system

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. PUBLIC HEALTH RELEVANCE: While prostate cancers are initially treatable by anti-hormone therapy, they inevitably become resistant to therapy resulting in few treatment options. The focus of this grant is to understand the biology leading to anti- hormone resistant prostate cancer.

描述（由申请人提供）：本提案的重点是雄激素受体捕获克隆 27 (ART-27) 和非常规前折叠蛋白 RBP5 相互作用蛋白 (URI)，这两种蛋白质彼此相互作用，并对通过雄激素受体 (AR) 进行的转录调节产生重大影响。在人类前列腺发育过程中，ART-27 在分化的管腔上皮细胞中表达，但在未分化的上皮细胞前体中未检测到，这表明 ART-27 在 AR 介导的生长抑制和分化中发挥作用。与生长抑制功能一致，ART-27在人前列腺癌中的表达水平降低，并且在雄激素敏感的LNCaP前列腺癌细胞系中调节ART-27的表达抑制雄激素介导的细胞增殖。此外，源自前列腺癌的 AR (AR P340L) 体细胞改变显示出增强 ART-27 介导的 AR 转录激活的能力减弱。此外，最近的一份报告和我们的两种杂交结果表明，ART-27 与非常规前折叠蛋白 RBP5 相互作用子 (URI) 结合，与 RPB5（RNA 聚合酶的一个亚基）形成复合物，以控制转录程序。 URI 与基因组完整性的维持有关，最近对分期癌症样本的分析表明，URI 是前列腺上皮内瘤变 (PIN) 中上调的一组基因之一，PIN 是一种增殖性病变，被认为是前列腺癌的先兆。基于这些发现，我们假设 ART-27 是一种细胞类型特异性的发育调节蛋白，它将 AR 与 URI 转录调节复合物连接起来，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) 识别 ART-27 依赖性 AR 靶基因以及 ART-27 和 URI 对细胞周期进展的影响 2) 确定 ART-27 和 URI 是否独立发挥作用，指导 AR 介导的基因转录；3) 阐明 ART-27 在体内前列腺上皮细胞生长和分化中的作用。该提议的首要假设是 AR 辅助因子调节特定的基因转录程序，从而帮助和促进肿瘤进展。 ART-27 和 URI 是转录复合物的新成员，显然在 AR 信号传导中发挥着重要作用，但人们对这些蛋白质在前列腺中的功能知之甚少。长期目标是了解 AR 如何在某些细胞环境中指导细胞代谢和分化以及在其他细胞环境中指导细胞增殖。公共卫生相关性：虽然前列腺癌最初可以通过抗激素疗法治疗，但它们不可避免地会对治疗产生耐药性，导致治疗选择很少。这笔资助的重点是了解导致抗激素抵抗性前列腺癌的生物学原理。