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：
7741765
负责人：
Kerry L Burnstein
金额：
$ 32.15万
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 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7741765
关键词：
Affinity Androgen Receptor Androgens Binding Biological Assay Cells Chemosensitization Chromatin Clinical Management Data Development Disease Disease Progression Drug Delivery Systems 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 Organ 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 cancer cell 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 platelet protein P47 public health relevance research study rho GTP-Binding Proteins therapeutic target tumor tumor progression tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: RELEVANCE: Levels of the Vav3 protein rise in human prostate cancer. Vav3 enhances the activity of the androgen receptor, increases growth of prostate cancer cells and causes prostate cancer in mice. This study seeks to understand these oncogenic effects of Vav3 in order to exploit currently available drugs that target Vav3 pathways for prostate cancer therapy.

描述（由申请人提供）：雄激素受体（AR）是一种配体激活的转录因子，也是核受体家族的成员，在前列腺癌的发生和进展中发挥着关键作用。虽然雄激素剥夺疗法仍然是晚期和非器官局限性前列腺癌临床治疗的基石，但大多数接受这种治疗的患者最终都会复发。这种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转录活性的 AR，即使在雄激素耗尽的条件下，它们的生长和存活也依赖于 AR。我们和其他人已经证明，在几种模型以及接受雄激素剥夺治疗的男性中，Vav3（一种 Rho GTPase 鸟嘌呤核苷酸交换因子 (GEF)）在前列腺癌的体外和体内进展到雄激素非依赖性的过程中上调。此外，Vav3蛋白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，在存在或不存在雄激素的情况下，Vav3 是前列腺癌细胞中 AR 转录活性的有效增强剂。在雄激素存在下（共激活），Vav3 对 AR 转录活性的增强不需要 Vav3 GEF 活性。此外，我们的初步数据表明，Vav3 而不是 Vav3 W493L（一种 pleckstrin 同源 (PH) 结构域突变体）被招募到染色质中的 AR 靶基因雄激素响应区。这种募集以雄激素依赖性方式发生，并揭示了 Vav3 的新核作用。相比之下，致癌（组成性活性）Vav3（或由生长因子激活的Vav3）通过需要Vav3 GEF功能和Rho GTPase Rac1的串扰来促进配体独立的AR激活。因此，Vav3 是 AR 活性的多功能调节剂。 Vav3 对 AR 的激素依赖性和非依赖性激活都可能有助于前列腺癌的进展，并且这两种途径均可用于治疗。由于抑制 Rac1 的药物的可用性，该项目的潜在影响很大。本研究将探讨 Vav3 增强 AR 转录活性和前列腺癌进展为雄激素独立的机制。我们将确定在肿瘤异种移植研究和前列腺癌基因工程小鼠模型中，Vav3/Rac1 信号传导对于引起雄激素非依赖性肿瘤形成是否是必要和充分的。我们将定义Vav3增强AR活动在此过程中的作用。鉴定 Vav3 增强 AR 活性的分子机制并检查 Vav3 对小鼠模型中前列腺癌进展的贡献对于开发 Vav3 通路作为治疗靶点至关重要。公共卫生相关性：相关性：人类前列腺癌中 Vav3 蛋白的水平升高。 Vav3 增强雄激素受体的活性，增加前列腺癌细胞的生长并导致小鼠患前列腺癌。本研究旨在了解 Vav3 的这些致癌作用，以便利用目前可用的针对 Vav3 通路的药物来治疗前列腺癌。