THE ROLE OF NEDD4-1 IN IGF-1R SIGNALING

NEDD4-1 在 IGF-1R 信号转导中的作用

基本信息

  • 批准号:
    8847292
  • 负责人:
  • 金额:
    $ 32.58万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2011
  • 资助国家:
    美国
  • 起止时间:
    2011-08-08 至 2016-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): NEDD4-1 is an E3 ubiquitination ligase that is frequently over-expressed in human cancers. NEDD4-1 plays an important role in tumorigenesis. Although it has been suggested that NEDD4-1 functions as an oncogenic protein by facilitation of Akt activation, the molecular mechanisms by which NEDD4-1 activates Akt remain largely unknown. We found that NEDD4-1 activates Akt via regulation of IGF-1R signaling. Strikingly, we also found that activation of Akt by NEDD4-1 is negatively regulated by replication protein A (RPA), a single strand DNA (ssDNA) binding protein which is generally believed to play a critical role in DNA metabolism. Thus, we are proposing a study to test the central hypothesis that NEDD4-1 plays a role in cell proliferation via activation of IGF-1R signaling and this pathway is inhibited by RPA. Therefore, growth of cells overexpressing NEDD4-1 is specifically suppressed by IGF-1R inhibition through IGF-1R antibody and/or RPA. Three interrelated specific aims are proposed to test our hypothesis. Aim 1 will identify the role of NEDD4-1 in cell proliferation via regulation of IGF-1R signaling. Aim 2 will delineate how NEDD4-1 dependent IGF-1R signaling is regulated by RPA. Aim 3 will determine the antitumor activity of blocking IGF-1R signaling in cells over-expressing NEDD4-1. We anticipate to (1) define the molecular mechanisms by which NEDD4-1 promotes cell proliferation via regulation of IGF-1R signaling; (2) identify a novel function of RPA in suppression of IGF-1R signaling via interaction with NEDD4-1; (3) find that the growth of cancer cells over-expressing NEDD4-1 can be specifically targeted by IGF-1R inhibition through RPA and/or IGF-1R antibody. The expected results will fundamentally advance our understanding of the molecular mechanism underlying NEDD4-1 associated cancer development. In addition, identification of a novel function of RPA in suppression of IGF-1R signaling will facilitate the development of novel drugs targeting NEDD4-1 or IGF-1R. Moreover, the expected result will improve guidance for cancer treatment plans based on better predictions of tumor response to IGR-1R inhibition by identification of cancer patients with NEDD4-1 over-expression.
描述(由申请人提供):NEDD 4 -1是一种E3泛素化连接酶,经常在人类癌症中过表达。NEDD 4 -1在肿瘤发生中起重要作用。尽管已经表明NEDD 4 -1通过促进Akt活化而作为致癌蛋白发挥功能,但NEDD 4 -1活化Akt的分子机制仍然很大程度上未知。我们发现NEDD 4 -1通过调节IGF-1 R信号通路激活Akt。引人注目的是,我们还发现NEDD 4 -1对Akt的激活受复制蛋白A(RPA)负调控,RPA是一种单链DNA(ssDNA)结合蛋白,通常认为其在DNA代谢中起关键作用。因此,我们提出了一项研究,以测试核心假设,即NEDD 4 -1通过激活IGF-1 R信号传导在细胞增殖中发挥作用,并且该途径被RPA抑制。因此,通过IGF-1 R抗体和/或RPA的IGF-1 R抑制特异性抑制过表达NEDD 4 -1的细胞的生长。提出了三个相互关联的具体目标来检验我们的假设。目的1研究NEDD 4 -1通过调节IGF-1 R信号通路在细胞增殖中的作用。目的2将描述RPA如何调节NEDD 4 -1依赖性IGF-1 R信号转导。目的3将确定在过表达NEDD 4 -1的细胞中阻断IGF-1 R信号传导的抗肿瘤活性。我们期望(1)确定NEDD 4 -1通过调节IGF-1 R信号促进细胞增殖的分子机制;(2)鉴定RPA通过与NEDD 4 -1相互作用抑制IGF-1 R信号的新功能;(3)发现通过RPA和/或IGF-1 R抗体抑制IGF-1 R可以特异性靶向过表达NEDD 4 -1的癌细胞的生长。预期的结果将从根本上推进我们对NEDD 4 -1相关癌症发展的分子机制的理解。此外,RPA在抑制IGF-1 R信号传导中的新功能的鉴定将促进靶向NEDD 4 -1或IGF-1 R的新型药物的开发。此外,预期的结果将通过识别NEDD 4 -1过表达的癌症患者,基于更好地预测肿瘤对IGR-1 R抑制的反应,改善癌症治疗计划的指导。

项目成果

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Junran Zhang其他文献

Junran Zhang的其他文献

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{{ truncateString('Junran Zhang', 18)}}的其他基金

Targeting cholesterol metabolism and replication stress response in cancer therapy
癌症治疗中针对胆固醇代谢和复制应激反应
  • 批准号:
    10328961
  • 财政年份:
    2021
  • 资助金额:
    $ 32.58万
  • 项目类别:
Targeting cholesterol metabolism and replication stress response in cancer therapy
癌症治疗中针对胆固醇代谢和复制应激反应
  • 批准号:
    10548830
  • 财政年份:
    2021
  • 资助金额:
    $ 32.58万
  • 项目类别:
B55 alpha deficiency as a therapeutic target in cancer
B55 α 缺乏症作为癌症的治疗靶点
  • 批准号:
    9981116
  • 财政年份:
    2020
  • 资助金额:
    $ 32.58万
  • 项目类别:
Interruption of cholesterol metabolism and replication stress response in cancer therapy
癌症治疗中胆固醇代谢和复制应激反应的中断
  • 批准号:
    10044013
  • 财政年份:
    2020
  • 资助金额:
    $ 32.58万
  • 项目类别:
B55 alpha deficiency as a therapeutic target in cancer
B55 α 缺乏症作为癌症的治疗靶点
  • 批准号:
    10162546
  • 财政年份:
    2020
  • 资助金额:
    $ 32.58万
  • 项目类别:
B55 alpha deficiency as a therapeutic target in cancer
B55 α 缺乏症作为癌症的治疗靶点
  • 批准号:
    10659238
  • 财政年份:
    2020
  • 资助金额:
    $ 32.58万
  • 项目类别:
Interruption of squalene epoxidase and DNA damage response in cancer therapy
癌症治疗中角鲨烯环氧酶和 DNA 损伤反应的中断
  • 批准号:
    10066331
  • 财政年份:
    2019
  • 资助金额:
    $ 32.58万
  • 项目类别:
THE ROLE OF NEDD4-1 IN IGF-1R SIGNALING
NEDD4-1 在 IGF-1R 信号转导中的作用
  • 批准号:
    8316173
  • 财政年份:
    2011
  • 资助金额:
    $ 32.58万
  • 项目类别:
THE ROLE OF NEDD4-1 IN IGF-1R SIGNALING
NEDD4-1 在 IGF-1R 信号转导中的作用
  • 批准号:
    8693962
  • 财政年份:
    2011
  • 资助金额:
    $ 32.58万
  • 项目类别:
THE ROLE OF NEDD4-1 IN IGF-1R SIGNALING
NEDD4-1 在 IGF-1R 信号转导中的作用
  • 批准号:
    8537123
  • 财政年份:
    2011
  • 资助金额:
    $ 32.58万
  • 项目类别:

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