Regulation of androgen receptor by HER-2 and Ack1 tyrosine kinases

HER-2 和 Ack1 酪氨酸激酶对雄激素受体的调节

基本信息

批准号：
7758780
负责人：
YOUNG E WHANG
金额：
$ 27.27万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-02-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7758780
关键词：
Address Affect Affinity American Androgen Receptor Androgens Cancer Biology Cancer Etiology Cell Proliferation Cessation of life Clinical Protocols Complex Critiques DNA Binding Data Development ERBB2 gene Electrophoretic Mobility Shift Assay Enhancers Environment Failure Genetic Transcription Goals Heregulin Hormones Human Subject Research In Vitro Lead Left Ligands Malignant neoplasm of prostate Maps Mediator of activation protein Methods Minor N-terminal Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Play Process Prostate Prostate Cancer therapy Prostatic Neoplasms Protein Tyrosine Kinase RNA Interference Receptor Activation Receptor Signaling Refractory Regulation Research Design Research Personnel Role Serine/Threonine Phosphorylation Signal Pathway Signal Transduction Specimen Staging Testing Text Therapeutic Threonine Phosphorylation Site Transactivation Tumor Tissue Two-Hybrid System Techniques Tyrosine Tyrosine Phosphorylation Tyrosine Phosphorylation Site Work Xenograft procedure cancer cell chromatin immunoprecipitation clinically relevant coactivator-associated arginine methyltransferase 1 deprivation human subject protection in vivo men mutant novel nuclear receptor coactivator 1 programs receptor receptor function response tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the third leading cause of cancer death in American men because of the eventual failure of androgen deprivation therapy. Mechanisms underlying progression to the hormone refractory stage have not been completely elucidated, but current evidence suggests that activation of the androgen receptor (AR) in the low androgen environment may play a critical role in this process. Our goal is to understand the regulation of AR signaling by tyrosine kinases. Our studies focused on two kinases, HER-2 and Ack1 (activated cdc42-associated kinase). Activation of HER-2 by the ligand heregulin increases AR transactivation and cell proliferation and leads to recruitment of AR to the androgen responsive enhancer. Inhibition of HER-2 impairs AR transcriptional function by decreasing recruitment of AR to the androgen responsive enhancer. New evidence indicates that activated Ack1 promotes androgen-independent progression of prostate cancer through its ability to activate AR transcriptional function and phosphorylation of AR protein. We now demonstrate that Ack1 phosphorylates AR at Tyr-267 and -363 residues. AR is phosphorylated by heregulin-dependent HER-2 activation and Ack1 may be a downstream mediator of HER-2 in AR phosphorylation. The clinical relevance of this pathway is apparent from our finding that phosphorylated AR and activated Ack1 are found together in primary androgen-independent prostate tumor tissue specimens. The main objective of this proposal is to characterize the mechanisms by which HER-2 and Ack1 tyrosine kinases regulate AR function. Our central working hypothesis is that HER-2 and Ack1 signaling regulates the tyrosine phosphorylation status of the AR protein, leading to alterations in the assembly of the AR transcriptional complex and modulation of AR-dependent transcription. To test our hypothesis, we will concentrate on following specific aims. In Aim 1, we will characterize the effect of HER-2 signaling on assembly of the AR transcription complex. In Aim 2, we will characterize the mechanisms by which Ack1 enhances AR transcriptional activity. In Aim 3, we will characterize the functional significance of AR tyrosine phosphorylation sites. Preliminary studies supporting this proposal led to the initiation of a clinical protocol testing the concept that HER-2 kinase inhibition may be a useful therapeutic approach in prostate cancer. This proposal has the potential to yield fundamental information about prostate cancer biology and mechanisms of AR regulation by cytoplasmic signaling pathways and contribute to development of novel targeted therapy for prostate cancer.

描述（由申请人提供）：由于雄激素剥夺疗法最终失败，前列腺癌是美国男性癌症死亡的第三大原因。进展到激素不应期的机制尚未完全阐明，但目前的证据表明，低雄激素环境中雄激素受体（AR）的激活可能在此过程中发挥关键作用。我们的目标是了解酪氨酸激酶对 AR 信号传导的调节。我们的研究重点是两种激酶：HER-2 和 Ack1（激活的 cdc42 相关激酶）。配体调蛋白激活 HER-2 会增加 AR 反式激活和细胞增殖，并导致 AR 募集至雄激素反应增强子。抑制 HER-2 会减少 AR 向雄激素反应增强子的募集，从而损害 AR 转录功能。新证据表明，激活的 Ack1 通过激活 AR 转录功能和 AR 蛋白磷酸化的能力，促进前列腺癌的非雄激素依赖性进展。我们现在证明 Ack1 在 Tyr-267 和 -363 残基处磷酸化 AR。 AR 通过调蛋白依赖性 HER-2 激活而磷酸化，Ack1 可能是 AR 磷酸化中 HER-2 的下游介质。我们发现磷酸化的 AR 和激活的 Ack1 在原发性雄激素非依赖性前列腺肿瘤组织标本中同时存在，这一通路的临床相关性显而易见。该提案的主要目的是表征 HER-2 和 Ack1 酪氨酸激酶调节 AR 功能的机制。我们的中心工作假设是 HER-2 和 Ack1 信号传导调节 AR 蛋白的酪氨酸磷酸化状态，导致 AR 转录复合物组装的改变和 AR 依赖性转录的调节。为了检验我们的假设，我们将集中精力实现特定目标。在目标 1 中，我们将描述 HER-2 信号传导对 AR 转录复合物组装的影响。在目标 2 中，我们将描述 Ack1 增强 AR 转录活性的机制。在目标 3 中，我们将描述 AR 酪氨酸磷酸化位点的功能意义。支持这一提议的初步研究导致启动了一项临床方案，测试 HER-2 激酶抑制可能是前列腺癌的有效治疗方法这一概念。该提案有可能提供有关前列腺癌生物学和细胞质信号通路 AR 调节机制的基本信息，并有助于开发前列腺癌的新型靶向疗法。