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

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, 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:
  • 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:
  • 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:
  • 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:
  • 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:
  • 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
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Kerry L Burnstein其他文献

Kerry L Burnstein的其他文献

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{{ truncateString('Kerry L Burnstein', 18)}}的其他基金

Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis
Covid-19:利用类固醇激素受体/TMPRSS2 轴进行快速治疗
  • 批准号:
    10814125
  • 财政年份:
    2021
  • 资助金额:
    $ 28.95万
  • 项目类别:
Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis
Covid-19:利用类固醇激素受体/TMPRSS2 轴进行快速治疗
  • 批准号:
    10153099
  • 财政年份:
    2021
  • 资助金额:
    $ 28.95万
  • 项目类别:
Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis
Covid-19:利用类固醇激素受体/TMPRSS2 轴进行快速治疗
  • 批准号:
    10341159
  • 财政年份:
    2021
  • 资助金额:
    $ 28.95万
  • 项目类别:
Cancer Research Career Enhancement and Related Activities
癌症研究职业提升及相关活动
  • 批准号:
    10190856
  • 财政年份:
    2019
  • 资助金额:
    $ 28.95万
  • 项目类别:
Cancer Research Career Enhancement and Related Activities
癌症研究职业提升及相关活动
  • 批准号:
    10443633
  • 财政年份:
    2019
  • 资助金额:
    $ 28.95万
  • 项目类别:
Cancer Research Career Enhancement and Related Activities
癌症研究职业提升及相关活动
  • 批准号:
    10670835
  • 财政年份:
    2019
  • 资助金额:
    $ 28.95万
  • 项目类别:
Cancer Research Career Enhancement and Related Activities
癌症研究职业提升及相关活动
  • 批准号:
    9789581
  • 财政年份:
    2019
  • 资助金额:
    $ 28.95万
  • 项目类别:
A Novel Drug Target for Aggressive Prostate Cancer
侵袭性前列腺癌的新药物靶点
  • 批准号:
    10083680
  • 财政年份:
    2018
  • 资助金额:
    $ 28.95万
  • 项目类别:
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。
  • 批准号:
    8056479
  • 财政年份:
    2009
  • 资助金额:
    $ 28.95万
  • 项目类别:
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。
  • 批准号:
    8257572
  • 财政年份:
    2009
  • 资助金额:
    $ 28.95万
  • 项目类别:

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Androgen receptor: A master regulator of lipid metabolism
雄激素受体:脂质代谢的主要调节因子
  • 批准号:
    DP230103210
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
  • 项目类别:
    Discovery Projects
Regulation of androgen receptor signaling in prostate cancer by protein arginine methylation
通过蛋白质精氨酸甲基化调节前列腺癌中的雄激素受体信号传导
  • 批准号:
    10584689
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
  • 项目类别:
Structural and functional analysis of a novel class of androgen receptor antagonists
一类新型雄激素受体拮抗剂的结构和功能分析
  • 批准号:
    10650956
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
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Role of the Androgen Receptor in Insulin Secretion in the Male
雄激素受体在男性胰岛素分泌中的作用
  • 批准号:
    10488954
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
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Targeting tumor cell macrophage lipid interactions to overcome resistance to androgen receptor targeted therapy
靶向肿瘤细胞巨噬细胞脂质相互作用以克服对雄激素受体靶向治疗的耐药性
  • 批准号:
    10651105
  • 财政年份:
    2023
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    $ 28.95万
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Preclinical development of ONCT-505, an Androgen Receptor Antagonist and Degrader, as new potential therapeutic for Kennedy's Disease
ONCT-505(一种雄激素受体拮抗剂和降解剂)的临床前开发,作为肯尼迪病的新潜在治疗方法
  • 批准号:
    10603636
  • 财政年份:
    2023
  • 资助金额:
    $ 28.95万
  • 项目类别:
Androgen receptor function in melanoma
雄激素受体在黑色素瘤中的功能
  • 批准号:
    10416658
  • 财政年份:
    2022
  • 资助金额:
    $ 28.95万
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Proliferating cell nuclear antigen in regulation of androgen receptor signalings in castration-resistant prostate cancer cells
增殖细胞核抗原对去势抵抗性前列腺癌细胞雄激素受体信号传导的调节
  • 批准号:
    10544062
  • 财政年份:
    2022
  • 资助金额:
    $ 28.95万
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Effects of androgen receptor (AR) signaling on CD4+ T cell metabolism during airway inflammation
气道炎症期间雄激素受体 (AR) 信号对 CD4 T 细胞代谢的影响
  • 批准号:
    10534943
  • 财政年份:
    2022
  • 资助金额:
    $ 28.95万
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TITLE: BLADDER CANCER CHEMOPREVENTION USING THE ANDROGEN RECEPTOR INHIBITOR APALUTAMIDE
标题:使用雄激素受体抑制剂阿帕鲁胺进行膀胱癌化学预防
  • 批准号:
    10677989
  • 财政年份:
    2022
  • 资助金额:
    $ 28.95万
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