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Vav3 Oncogene Potentiation of Androgen Receptor Signaling in Prostate Cancer.

Vav3 致癌基因对前列腺癌中雄激素受体信号传导的增强作用。

基本信息

批准号：
8459533
负责人：
Kerry L Burnstein
金额：
$ 28.95万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8459533
关键词：
Affinity Androgen Receptor Androgens Binding Biological Assay Cancer Etiology Cells Chemosensitization Chromatin Clinical Management Data Development Disease Disease Progression Drug Targeting Enhancers Environment Exhibits Family Gene Expression Gene Expression Regulation Gene Targeting Genetically Engineered Mouse Growth Growth Factor Guanine Nucleotide Exchange Factors Histones Hormones Human In Vitro Lead Ligands Lipid Binding Malignant neoplasm of prostate Mediating Mediator of activation protein Membrane Lipids Modeling Molecular Molecular Profiling Mus Mutant Strains Mice Nuclear Nuclear Receptors Oncogenes Oncogenic PC3 cell line PH Domain Pathway interactions Patients Pharmaceutical Preparations Phospholipids Play Post-Translational Protein Processing Process Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Receptor Activation Receptor Signaling Recruitment Activity Recurrent Malignant Neoplasm Recurrent disease Refractory Relapse Relative (related person)Role Signal Transduction Signal Transduction Pathway Signaling Protein Specificity Specimen Staging Testing Tumor Burden Two-Hybrid System Techniques Up-Regulation Work Xenograft Model Yeasts activating transcription factor androgen independent prostate cancer base cell growth chromatin immunoprecipitation deprivation design in vivo in vivo Model knock-down member men mouse model mutant mutant mouse model novel novel diagnostics overexpression prostate cancer cell research study rho GTP-Binding Proteins therapeutic target tumor tumor progression tumor xenograft

项目摘要

The androgen receptor (AR), a ligand-activated transcription factor and member of the nuclear receptor family, plays a key role in the development and progression of prostate cancer. While androgen deprivation therapy remains the cornerstone of clinical management for advanced and non-organ confined prostate cancer, the majority of patients undergoing this treatment eventually relapse. The recurrent disease is termed androgen independent or hormone refractory. Androgen independent tumors not only maintain transcriptionally active AR, they are dependent on AR for growth and survival even under androgen-depleted conditions. We and others have demonstrated that Vav3, a Rho GTPase guanine nucleotide exchange factor (GEF), is upregulated during in vitro and in vivo progression of prostate cancer to androgen-independence in several models as well as in men undergoing androgen deprivation therapy. Further, Vav3 protein is overexpressed in approximately one-third of human prostate cancer. We have demonstrated that Vav3, is a potent enhancer of AR transcriptional activity in prostate cancer cells in the presence or absence of androgen. Vav3 potentiation of AR transcriptional activity in the presence of androgen (coactivation) does not require Vav3 GEF activity. Further, our preliminary data show that Vav3 but not Vav3 W493L (a pleckstrin homology (PH) domain mutant) is recruited to an AR target gene androgen responsive region in chromatin. This recruitment occurs in an androgen-dependent manner and reveals a novel nuclear role for Vav3. In contrast, oncogenic (constitutively active) Vav3 (or Vav3 activated by growth factors) promotes ligand-independent AR activation via cross-talk that requires Vav3 GEF function and the Rho GTPase, Rac1. Thus, Vav3 is a versatile modulator of AR activity. Both the hormone-dependent and -independent activation of AR by Vav3 may contribute to prostate cancer progression and both pathways are exploitable therapeutically. The potential impact of this project is high due to the availability of drugs that inhibit Rac1. This study will investigate the mechanisms by which Vav3 enhances AR transcriptional activity and prostate cancer progression to androgen independence. We will determine whether Vav3/Rac1 signaling is necessary and sufficient to cause androgen independent tumor formation in tumor xenograft studies and in genetically engineered mouse models of prostate cancer. We will define the role of Vav3 enhancement of AR activity in this process. Identification of the molecular mechanisms of Vav3 potentiation of AR activity and examination of the contribution of Vav3 to prostate cancer progression in mouse models is essential for the development of Vav3 pathways as therapeutic targets.

雄激素受体（AR）是一种配体激活的转录因子，也是核受体的成员在前列腺癌的发生和发展中起着关键作用。而雄激素剥夺治疗仍然是晚期和非器官局限性前列腺癌的临床管理的基石，大多数接受这种治疗的患者最终都会复发。复发性疾病被称为雄激素非依赖性或激素难治性。雄激素非依赖性肿瘤不仅维持由于AR是转录活性的，它们依赖于AR生长和存活，即使在雄激素耗尽的情况下也是如此。条件我们和其他人已经证明，Vav 3，一个Rho GT3鸟嘌呤核苷酸交换因子， (GEF)在前列腺癌向雄激素非依赖性的体外和体内进展过程中，几种模型以及接受雄激素剥夺治疗的男性。此外，Vav 3蛋白是在大约三分之一的人类前列腺癌中过度表达。我们已经证明Vav 3是一个在存在或不存在雄激素的情况下，前列腺癌细胞中AR转录活性的有效增强剂。在雄激素存在下，Vav 3增强AR转录活性（共激活）并不需要全环基金的活动。此外，我们的初步数据显示Vav 3而不是Vav 3 W 493 L（pleckstrin同源物 (PH)结构域突变体）被募集到染色质中的AR靶基因雄激素应答区。这募集以雄激素依赖的方式发生，并揭示了Vav 3的新的核作用。与此相反的是，致癌（组成型活性）Vav 3（或由生长因子激活的Vav 3）促进配体非依赖性AR 通过串扰激活，需要Vav 3 GEF功能和Rho GTvalve，Rac 1。因此，Vav 3是一个通用的 AR活性的调节剂。Vav 3对AR的依赖性和非依赖性激活都可能是由于Vav 3对AR的依赖性和非依赖性激活。有助于前列腺癌的进展，这两种途径都是治疗上可利用的。的潜在由于抑制Rac 1的药物的可用性，该项目的影响很大。本研究将探讨 Vav 3增强AR转录活性和前列腺癌进展为雄激素的机制独立我们将确定Vav 3/Rac 1信号传导是否是引起雄激素分泌的必要和充分条件。在肿瘤异种移植研究中和在基因工程小鼠模型中，前列腺癌我们将定义Vav 3增强AR活性在此过程中的作用。鉴定 Vav 3增强AR活性的分子机制和Vav 3对AR活性的贡献的检测。小鼠模型中的前列腺癌进展对于开发Vav 3途径作为治疗性前列腺癌的方法至关重要。目标的

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The microRNA-23b/-27b cluster suppresses prostate cancer metastasis via Huntingtin-interacting protein 1-related.

DOI：
10.1038/onc.2016.6
发表时间：
2016-09-08
期刊：
Oncogene
影响因子：
8
作者：
Rice MA;Ishteiwy RA;Magani F;Udayakumar T;Reiner T;Yates TJ;Miller P;Perez-Stable C;Rai P;Verdun R;Dykxhoorn DM;Burnstein KL
通讯作者：
Burnstein KL

Targeting AR Variant-Coactivator Interactions to Exploit Prostate Cancer Vulnerabilities.

DOI：
10.1158/1541-7786.mcr-17-0280
发表时间：
2017-11
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
Magani F;Peacock SO;Rice MA;Martinez MJ;Greene AM;Magani PS;Lyles R;Weitz JR;Burnstein KL
通讯作者：
Burnstein KL

A novel calcium-dependent mechanism of acquired resistance to IGF-1 receptor inhibition in prostate cancer cells.

DOI：
10.18632/oncotarget.2346
发表时间：
2014-10-15
期刊：
Oncotarget
影响因子：
0
作者：
Fahrenholtz CD;Greene AM;Beltran PJ;Burnstein KL
通讯作者：
Burnstein KL

The microRNA -23b/-27b cluster suppresses the metastatic phenotype of castration-resistant prostate cancer cells.

DOI：
10.1371/journal.pone.0052106
发表时间：
2012
期刊：
PloS one
影响因子：
3.7
作者：
Ishteiwy RA;Ward TM;Dykxhoorn DM;Burnstein KL
通讯作者：
Burnstein KL

Identification of an oncogenic network with prognostic and therapeutic value in prostate cancer.

DOI：
10.15252/msb.20188202
发表时间：
2018-08-14
期刊：
Molecular systems biology
影响因子：
9.9
作者：
Magani F;Bray ER;Martinez MJ;Zhao N;Copello VA;Heidman L;Peacock SO;Wiley DJ;D'Urso G;Burnstein KL
通讯作者：
Burnstein KL