An androgen receptor coactivator regulated in prostate

描述（由申请人提供）：本申请的重点是雄激素受体捕获克隆-27 （ART-27）和非常规预折叠蛋白RBP5相互作用因子（URI），这两种蛋白相互作用，并通过雄激素受体（AR）对转录调控产生重大影响。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在人类前列腺癌中的表达水平降低，在雄激素敏感的LNCaP前列腺癌细胞系中，ART-27的表达调节可抑制雄激素介导的细胞增殖。此外，来自前列腺癌的AR （AR P340L）的体细胞改变显示增强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双杂交结果表明，ART-27与RPB5 （RNA聚合酶的一个亚基）形成复合物的非传统折叠蛋白RBP5相互作用子（URI）结合，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是一种增生性病变，被认为是前列腺癌的前兆。基于这些发现，我们假设ART-27是一种细胞类型特异性和发育调控蛋白，将AR与URI转录调控复合体连接起来，并影响在前列腺生长调控中重要的AR靶基因。为了验证这一假设，我们提出：1)鉴定ART-27依赖的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是否独立地指导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。这一提议的首要假设是AR辅助因子调节了帮助和促进肿瘤进展的特定基因转录程序。ART-27和URI是转录复合体的新成员，它们在AR信号传导中明显发挥重要作用，但对这些蛋白在前列腺中的功能知之甚少。长期目标是了解AR在某些细胞环境下如何指导细胞代谢和分化，以及在其他细胞环境下如何指导细胞增殖。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，但它们不可避免地对治疗产生耐药性，导致治疗选择很少。这项拨款的重点是了解导致抗激素抵抗前列腺癌的生物学原理。

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.