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：
8207952
负责人：
YOUNG E WHANG
金额：
$ 26.45万
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 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8207952
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 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 Methodology 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）：前列腺癌是美国男性癌症死亡的第三主要原因，因为雄激素剥夺疗法最终失败。尚未完全阐明到激素难治阶段进展的机制，但目前的证据表明，在低雄激素环境中，雄激素受体（AR）的激活在此过程中可能起关键作用。我们的目标是了解酪氨酸激酶对AR信号的调节。我们的研究集中在两个激酶HER-2和ACK1（激活CDC42相关激酶）上。配体调节蛋白对HER-2的激活增加了AR的反式激活和细胞增殖，并导致AR募集到雄激素响应增强子。通过减少AR募集到雄激素响应增强子，抑制HER-2会损害AR的转录功能。新的证据表明，活化的ACK1通过激活AR转录功能和AR蛋白的磷酸化的能力来促进前列腺癌的雄激素非依赖性进展。现在，我们证明ACK1在Tyr -267和-363残基上磷酸化。 AR通过这里依赖于糖蛋白的HER-2激活来磷酸化，而ACK1可能是AR磷酸化中HER-2的下游介质。从我们发现，在原代雄激素独立的前列腺肿瘤组织样品中发现了该途径的临床相关性。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，从而导致AR转录复合物组装和AR依赖性转录的调节的变化。为了检验我们的假设，我们将集中精力遵循特定目标。在AIM 1中，我们将表征HER-2信号传导对AR转录复合物组装的影响。在AIM 2中，我们将表征ACK1增强AR转录活性的机制。在AIM 3中，我们将表征AR酪氨酸磷酸化位点的功能意义。支持该建议的初步研究导致临床方案的启动，该方案测试了HER-2激酶抑制作用可能是前列腺癌的一种有用的治疗方法。该提案有可能产生有关细胞质信号通路AR调控的前列腺癌生物学和AR调节机制的基本信息，并有助于开发新的针对前列腺癌的靶向治疗。