Project 1

项目1

基本信息

  • 批准号:
    8744370
  • 负责人:
  • 金额:
    $ 45.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2005
  • 资助国家:
    美国
  • 起止时间:
    2005-08-23 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

We found that expression and activity of RalA & RalB are induced by hypoxia and androgen deprivation (AD) in vitro in parallel with CD24 expression. We determined that a hypoxia-Inducible factor 1a (HlF1a) response element in the 5' region ofthe CD24 gene underlies this effect. Since H!F1a expression is necessary for metastasis in prostate cancer (PCa) and its translation is regulated by mTOR, we evaluated HlF1a protein expression and discovered that expression of RalA and RalB Is required for maximal HlF1a response in hypoxia and AD. We also found that, like HlF1a, RalA undergoes proline dehydroxylation during hypoxia and this promotes engagement with its effector, phospholipase D (PLD), a regulator of mTOR. Further, we identified the elF3b translation initiation component that binds to mTOR. as a direct RalB binding partner. Hence propose the hypothesis that in PCa. Ral GTPases are oxygen and androgen biosensors and their activity allows metastatic PCa cells to overcome the natural and therapeutic adversity of hypoxia and AD by maintaining mTOR-mediated translation of HlF1a. Specific Aims will test this hypothesis: Aim 1 will investigate the role of post-translational Ral modifications on HlF1a expression. We will map proline hydroxylation sites in RalA and determine their role in RalA activity and HlF1a expression. We will also evaluate the role of RalB phosphorylation on HIF1a expression, since we have discovered that RalB is activated by phosphorylation at S198 by PKC, a hypoxia activated kinase. In Aim 2 we determine the nature of Ral expression on global and HlF1a translation and assembly and activity of cap-dependent translational complexes in hypoxia and AD. We also examine these characteristics in RalB mutants deficient in interaction with elF3b. Aim 3 will determine the requirement for Ral in PCa using human xenografts and novel transgenic models. Gene expression signatures associated with post-translational modifications of Ral will be evaluated in tumors from patients treated by prostatectomy to determine their ability to predict recurrence. Our project provides a new paradigm by showing Ral GTPases are oxygen and androgen sensors that regulate HlF1a while integrating in the P01 by shared aims with other projects and use of all cores.
我们发现RalA和RalB的表达和活性在体外由缺氧和雄激素剥夺(AD)诱导,与CD 24的表达平行。我们确定,在CD 24基因5'区的缺氧诱导因子1a(HlF 1a)反应元件是这种效应的基础。自从H!F1 a的表达是前列腺癌(PCa)转移所必需的,其翻译受mTOR调节,我们评估了H1 F1 a蛋白的表达,发现RalA和RalB的表达是缺氧和AD中最大H1 F1 a反应所必需的。我们还发现,与HIF 1a一样,RalA在缺氧期间经历脯氨酸脱羟基化,这促进与其效应物磷脂酶D(PLD)(mTOR的调节剂)的接合。此外,我们鉴定了与mTOR结合的eIF 3b翻译起始组分。作为RalB的直接结合伴侣。因此,提出假设,在PCa。Ral GTP酶是氧和雄激素生物传感器,并且它们的活性允许转移性PCa细胞通过维持mTOR介导的HIFla翻译来克服缺氧和AD的自然和治疗逆境。具体目的将检验这一假设:目的1将研究翻译后Ral修饰对HIF 1a表达的作用。我们将绘制RalA中的脯氨酸羟基化位点,并确定它们在RalA活性和HIF 1a表达中的作用。我们还将评估RalB磷酸化对HIF 1a表达的作用,因为我们已经发现RalB通过PKC(一种缺氧激活的激酶)在S198处磷酸化而被激活。在目的2中,我们确定Ral在缺氧和AD中对全局和HIF 1a翻译和组装的表达的性质以及帽依赖性翻译复合物的活性。我们还研究了RalB突变体与eIF 3b相互作用缺陷的这些特征。目的3将使用人异种移植物和新的转基因模型来确定PCa中对Ral的需求。将在接受前列腺切除术治疗的患者的肿瘤中评估与Ral翻译后修饰相关的基因表达特征,以确定其预测复发的能力。我们的项目通过显示Ral GTP酶是氧和雄激素传感器提供了一种新的范例,其调节HIFla,同时通过与其他项目的共同目标和使用所有核心整合在POl中。

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
专利数量(0)

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DAN THEODORESCU其他文献

DAN THEODORESCU的其他文献

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{{ truncateString('DAN THEODORESCU', 18)}}的其他基金

The Role of the Y Chromosome in Bladder Tumor Development, Growth And Progression
Y 染色体在膀胱肿瘤发生、生长和进展中的作用
  • 批准号:
    10629079
  • 财政年份:
    2023
  • 资助金额:
    $ 45.23万
  • 项目类别:
BLADDER TISSUE BANK
膀胱组织库
  • 批准号:
    8167199
  • 财政年份:
    2010
  • 资助金额:
    $ 45.23万
  • 项目类别:
Understanding the AGL metastasis suppressor for therapeutic gain
了解 AGL 转移抑制因子的治疗效果
  • 批准号:
    9223676
  • 财政年份:
    2010
  • 资助金额:
    $ 45.23万
  • 项目类别:
Understanding the AGL metastasis suppressor for therapeutic gain
了解 AGL 转移抑制因子的治疗效果
  • 批准号:
    9030867
  • 财政年份:
    2010
  • 资助金额:
    $ 45.23万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7728883
  • 财政年份:
    2008
  • 资助金额:
    $ 45.23万
  • 项目类别:
Signaling and Progression in Prostate Cancer
前列腺癌的信号传导和进展
  • 批准号:
    7115394
  • 财政年份:
    2005
  • 资助金额:
    $ 45.23万
  • 项目类别:
Core B
核心B
  • 批准号:
    8744397
  • 财政年份:
    2005
  • 资助金额:
    $ 45.23万
  • 项目类别:
Core B
核心B
  • 批准号:
    8744375
  • 财政年份:
    2005
  • 资助金额:
    $ 45.23万
  • 项目类别:
Signaling and Progression in Prostate Cancer
前列腺癌的信号传导和进展
  • 批准号:
    7284160
  • 财政年份:
    2005
  • 资助金额:
    $ 45.23万
  • 项目类别:
Project 1
项目1
  • 批准号:
    8916609
  • 财政年份:
    2005
  • 资助金额:
    $ 45.23万
  • 项目类别:

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前瞻性纵向队列中不同种族和民族的育龄女性雄激素和卵巢标志物的异常
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Nonalcoholic Fatty Liver Disease (NAFLD) in Polycystic Ovary Syndrome: The Role of Androgens on Liver Injury and NAFLD Progression
多囊卵巢综合征中的非酒精性脂肪肝 (NAFLD):雄激素在肝损伤和 NAFLD 进展中的作用
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  • 批准号:
    10418461
  • 财政年份:
    2022
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  • 批准号:
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  • 财政年份:
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    $ 45.23万
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桩蛋白和雄激素在卵巢卵泡发育调节中的作用
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使用新型 11-含氧雄激素提高多囊卵巢综合征的诊断准确性和治疗效果
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Paxillin and Androgens in the Regulation of Ovarian Follicle Development
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