DNA polymerase iota as a putative tumor suppressor

DNA 聚合酶 iota 作为假定的肿瘤抑制因子

基本信息

  • 批准号:
    7777312
  • 负责人:
  • 金额:
    $ 7.4万
  • 依托单位:
  • 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:
    2009-03-01 至 2012-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Recent advances implicate error-prone DNA polymerases in the generation of virtually all mutations induced by environmental carcinogens in higher eukaryotic cells. These data have supported the promise of cancer chemoprevention based on the selective modulation of the activity of these proteins, based on the assumption that reducing the mutant frequency will reduce the incidence of cancer. However, carcinogenesis studies using newly-developed mouse models in which one or another of these polymerases is deficient have yielded unexpected results. Specifically, the deficiency of one such polymerase, termed DNA polymerase iota (pol iota), resulted in greatly decreased mutation frequencies induced by ultraviolet (UV) radiation in an endogenous reporter gene. These results would predict a protective effect against the carcinogenic effects of UV. However, pol iota-deficient animals exhibited a highly accelerated development of aggressive skin cancer. This unexpected result is not consistent with the somatic mutation hypothesis of carcinogenesis, and highlights the fact that there are critical gaps in our knowledge of the cellular function of this universe of polymerases. This application proposes to examine the putative tumor suppressor function of pol iota, and is directly responsive to the current Program Announcement since modulation of the activity of enzymes in this pathway has been proposed as a potential antimutator strategy. This application addresses the overall hypothesis that DNA polymerase iota acts as a tumor suppressor by a mechanism that is distinct from its activity as an error-prone polymerase. To examine this, we propose a pilot project that will consist of two Specific Aims. In Aim 1, we propose to examine the effect of polymerase iota deficiency on UV-induced changes in gene expression and on damage-induced cell cycle checkpoints in murine and human cells. In Aim 2, we will examine the effect of polymerase iota deficiency in UV carcinogenesis studies that employ novel murine models. This application will fill critical gaps in our knowledge of how cancer is initiated by the most ubiquitous environmental carcinogen. The ultimate goal of this research is to understand how carcinogens cause cancer in order to design strategies to prevent the disease.
描述(由申请人提供):最近的进展表明,在高等真核细胞中,环境致癌物诱导的几乎所有突变的产生中都涉及易错DNA聚合酶。这些数据支持了基于这些蛋白质活性的选择性调节的癌症化学预防的前景,基于降低突变频率将降低癌症发病率的假设。然而,使用这些聚合酶中的一种或另一种缺乏的新开发的小鼠模型进行的致癌研究产生了意想不到的结果。具体而言,一种这样的聚合酶,称为DNA聚合酶iota(pol iota)的缺乏导致由紫外线(UV)辐射在内源性报告基因中诱导的突变频率大大降低。这些结果将预测对紫外线致癌作用的保护作用。然而,缺乏多聚酶的动物表现出高度加速的侵袭性皮肤癌的发展。这一意外的结果与致癌的体细胞突变假说不一致,并突出了这样一个事实,即我们对聚合酶的细胞功能的认识存在重大差距。本申请提出检查pol iota的推定肿瘤抑制功能,并且直接响应于当前的计划公告,因为已经提出调节该途径中的酶的活性作为潜在的抗突变剂策略。本申请解决了DNA聚合酶iota通过与其作为易错聚合酶的活性不同的机制充当肿瘤抑制因子的总体假设。为了检验这一点,我们提出了一个试点项目,该项目将包括两个具体目标。在目的1中,我们建议检查聚合酶iota缺乏对小鼠和人细胞中的紫外线诱导的基因表达变化和损伤诱导的细胞周期检查点的影响。在目标2中,我们将研究聚合酶iota缺乏在采用新型小鼠模型的UV致癌研究中的作用。这一应用将填补我们对癌症如何由最普遍存在的环境致癌物引发的知识的关键空白。这项研究的最终目标是了解致癌物质是如何导致癌症的,以便设计预防这种疾病的策略。

项目成果

期刊论文数量(0)
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WILLIAM G MCGREGOR其他文献

WILLIAM G MCGREGOR的其他文献

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{{ truncateString('WILLIAM G MCGREGOR', 18)}}的其他基金

DNA polymerase iota as a putative tumor suppressor
DNA 聚合酶 iota 作为假定的肿瘤抑制因子
  • 批准号:
    7846524
  • 财政年份:
    2009
  • 资助金额:
    $ 7.4万
  • 项目类别:
DNA polymerase iota as a putative tumor suppressor
DNA 聚合酶 iota 作为假定的肿瘤抑制因子
  • 批准号:
    7662857
  • 财政年份:
    2009
  • 资助金额:
    $ 7.4万
  • 项目类别:
Novel strategies to prevent lung cancer
预防肺癌的新策略
  • 批准号:
    7086183
  • 财政年份:
    2005
  • 资助金额:
    $ 7.4万
  • 项目类别:
Novel strategies to prevent lung cancer
预防肺癌的新策略
  • 批准号:
    7002476
  • 财政年份:
    2005
  • 资助金额:
    $ 7.4万
  • 项目类别:
Mutagenesis as a novel target for cancer prevention
诱变作为癌症预防的新靶点
  • 批准号:
    7031572
  • 财政年份:
    2005
  • 资助金额:
    $ 7.4万
  • 项目类别:
Mutagenesis as a novel target for cancer prevention
诱变作为癌症预防的新靶点
  • 批准号:
    7215263
  • 财政年份:
    2005
  • 资助金额:
    $ 7.4万
  • 项目类别:
Mutagenesis as a novel target for cancer prevention
诱变作为癌症预防的新靶点
  • 批准号:
    6856964
  • 财政年份:
    2005
  • 资助金额:
    $ 7.4万
  • 项目类别:
Mutagenesis as a novel target for cancer prevention
诱变作为癌症预防的新靶点
  • 批准号:
    7356396
  • 财政年份:
    2005
  • 资助金额:
    $ 7.4万
  • 项目类别:
MECHANISMS OF MUTAGENIC PROCESSING OF DNA DAMAGE
DNA 损伤的诱变处理机制
  • 批准号:
    2011984
  • 财政年份:
    1997
  • 资助金额:
    $ 7.4万
  • 项目类别:
MECHANISMS OF MUTAGENIC PROCESSING OF DNA DAMAGE
DNA 损伤的诱变处理机制
  • 批准号:
    2895905
  • 财政年份:
    1997
  • 资助金额:
    $ 7.4万
  • 项目类别:

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