Molecular basis of arsenic-induced cell transformation

砷诱导细胞转化的分子基础

基本信息

  • 批准号:
    7172311
  • 负责人:
  • 金额:
    $ 28.28万
  • 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:
    2005-02-01 至 2008-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Arsenic is a well-documented human carcinogen. Our goal is to address the central hypothesis that MAP kinases, p90 S6 kinases, and histone H3 are mediators of arsenic-induced signal transduction and cell transformation. The Specific Aims are: Specific Aim 1, to determine whether arsenic-induced p38 kinase is required for arsenic-induced cell transformation; Specific Aim 2, to determine the role of c-Jun N-terminal kinases (JNKs) in arsenic-induced cell transformation and apoptosis; Specific Aim 3, to determine whether activation of p90 S6 kinase/MAPKAP-K1 (p90RSK) is involved in arsenic-induced signal transduction and cell transformation; and Specific Aim 4, to determine the role of p38 kinase, JNKs, and p90RSK in arsenic-induced phosphorylation of histone H3 and the role of phosphorylation of histone H3 in cell transformation. The strategy for Specific Aim 1 is to use p38 kinase inhibitors or dominant negative mutants or siRNA to inhibit p38 kinase activation. For Specific Aim 2, we will (1) test whether inactivation of JNK phosphorylation is required for development of resistant phenotype to arsenic; (2) test whether inhibition of JNK phosphorylation/activation will cause inhibition of arsenite-induced cell transformation or apoptosis; (3) test whether introduction of an active JNK mutant into arsenic resistant cells will cause the rescue of the apoptosis-resistant phenotype. For Specific Aim 3, we will inhibit p90RSK using cell lines expressing a dominant negative mutant or siRNA of p90RSK and cell lines which are deficient in p90RSK. For Specific Aim 4, we will (1) block the activation of JNK, p38, and p90RSK by specific inhibitors, dominant negative mutants, siRNA, or gene knockout cell lines; (2) use cell lines expressing siRNA of histone H3, dominant negative mutants (histone H3 S10 mutated to A10, H3 S28 mutated to A28) and histone H3 wild-type to study the role of histone H3 in arsenic-induced cell transformation. Such knowledge will facilitate the design of more effective and specific strategies with fewer side effects for chemoprevention of arsenic-induced cancer.
描述(由申请方提供):砷是一种有充分记录的人类致癌物。我们的目标是解决的核心假设,MAP激酶,p90 S6激酶,组蛋白H3的介质砷诱导的信号转导和细胞转化。具体目标是:具体目的1:确定砷诱导的p38激酶是否是砷诱导的细胞转化所必需的;具体目的2:确定c-Jun N-末端激酶(JNKs)在砷诱导的细胞转化和凋亡中的作用;具体目的3:确定p90 S6激酶/MAPKAP-K1(p90 RSK)的激活是否参与砷诱导的信号转导和细胞转化;和特异性目的4,以确定p38激酶,JNKs,和p90 RSK在砷诱导的组蛋白H3磷酸化中的作用,以及组蛋白H3磷酸化在细胞转化中的作用。具体目标1的策略是使用p38激酶抑制剂或显性失活突变体或siRNA来抑制p38激酶活化。对于特定目标2,我们将(1)测试JNK磷酸化的失活是否是砷抗性表型发展所必需的;(2)测试JNK磷酸化/活化的抑制是否会导致亚砷酸盐诱导的细胞转化或细胞凋亡的抑制;(3)测试将活性JNK突变体引入砷抗性细胞是否会导致砷抗性表型的拯救。对于特异性目标3,我们将使用表达p90 RSK的显性失活突变体或siRNA的细胞系和p90 RSK缺陷的细胞系抑制p90 RSK。对于特定目标4,我们将(1)通过特异性抑制剂、显性失活突变体、siRNA或基因敲除细胞系阻断JNK、p38和p90 RSK的活化;(2)使用表达组蛋白H3的siRNA的细胞系,显性失活突变体(组蛋白H3 S10突变为A10,H3 S28突变为A28)和组蛋白H3野生型以研究组蛋白H3在砷诱导的细胞转化中的作用。这些知识将有助于设计更有效和更具体的策略,减少副作用的砷诱导的癌症的化学预防。

项目成果

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Zigang Dong其他文献

Zigang Dong的其他文献

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{{ truncateString('Zigang Dong', 18)}}的其他基金

Chemoprevention of colon cancer by targeting the Wnt/beta-catenin pathway
通过靶向 Wnt/β-catenin 通路化学预防结肠癌
  • 批准号:
    9035378
  • 财政年份:
    2015
  • 资助金额:
    $ 28.28万
  • 项目类别:
Prevention of solar UV-induced skin cancer by targeting LTA4H
通过靶向 LTA4H 预防太阳紫外线诱发的皮肤癌
  • 批准号:
    9301501
  • 财政年份:
    2015
  • 资助金额:
    $ 28.28万
  • 项目类别:
Chemoprevention of colon cancer by targeting the Wnt/beta-catenin pathway
通过靶向 Wnt/β-连环蛋白途径化学预防结肠癌
  • 批准号:
    9249395
  • 财政年份:
    2015
  • 资助金额:
    $ 28.28万
  • 项目类别:
Prevention of solar UV-induced skin cancer by targeting LTA4H
通过靶向 LTA4H 预防太阳紫外线诱发的皮肤癌
  • 批准号:
    9114539
  • 财政年份:
    2015
  • 资助金额:
    $ 28.28万
  • 项目类别:
Molecular Mechanisms and Targets of Soy Compounds in the Prevention of Colon Canc
大豆化合物预防结肠癌的分子机制和靶点
  • 批准号:
    8422792
  • 财政年份:
    2013
  • 资助金额:
    $ 28.28万
  • 项目类别:
Developing new ornithine decarboxylase inhibitors to prevent skin & colon cancer
开发新型鸟氨酸脱羧酶抑制剂预防皮肤病
  • 批准号:
    9194388
  • 财政年份:
    2013
  • 资助金额:
    $ 28.28万
  • 项目类别:
Developing new ornithine decarboxylase inhibitors to prevent skin & colon cancer
开发新型鸟氨酸脱羧酶抑制剂预防皮肤病
  • 批准号:
    8596803
  • 财政年份:
    2013
  • 资助金额:
    $ 28.28万
  • 项目类别:
Developing new ornithine decarboxylase inhibitors to prevent skin & colon cancer
开发新型鸟氨酸脱羧酶抑制剂预防皮肤病
  • 批准号:
    8434732
  • 财政年份:
    2013
  • 资助金额:
    $ 28.28万
  • 项目类别:
Developing new ornithine decarboxylase inhibitors to prevent skin & colon cancer
开发新型鸟氨酸脱羧酶抑制剂预防皮肤病
  • 批准号:
    8785101
  • 财政年份:
    2013
  • 资助金额:
    $ 28.28万
  • 项目类别:
The role of histone phosphorylation in arsenic-induced cell transformation and sk
组蛋白磷酸化在砷诱导的细胞转化和皮肤病中的作用
  • 批准号:
    8215643
  • 财政年份:
    2008
  • 资助金额:
    $ 28.28万
  • 项目类别:

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