PEROXISOME PROLIFERATORS AND THE CELL CYCLE

过氧化物酶体增殖剂和细胞周期

• 批准号: 2849626
• 负责人: JANE E ISHMAEL
• 金额: $ 10.8万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2849626
• 关键词: carcinogens; cell cycle; peroxisome proliferator activated receptor; tissue /cell culture; transcription factor

DESCRIPTION (Adapted from the Candidate's Abstract) Human exposure to peroxisome proliferators is widespread and may occur in a variety of environmental, occupational and clinical settings. Although peroxisome proliferators are rodent carcinogens the hazard that they pose to humans is uncertain as the molecular mechanism underlying their effects is unknown. The biological effects of peroxisome proliferators appear to be mediated by a direct interaction with peroxisome proliferator activated receptor alpha (PPAR-alpha), which is a member of the steroid/thyroid hormone receptor superfamily of ligand-dependent transcription factors. Mice that are devoid of this receptor fail to show typical hepatocytic alterations in response to treatment with peroxisome proliferators, such as peroxisome proliferation, hepatomegaly, increased DNA synthesis, increased expression of PPAR-alpha regulated genes and hepatocarcinogenesis. The overall objectives of this proposal are to characterize a novel PPAR-alpha interacting protein (clone D7) and to determine the role of nuclear receptor coactivators in PPAR- alpha-mediated disruption of cell cycle. It is currently believed that regulated transcription factors (such as PPAR-alpha and the tumor suppressor protein p53) utilize a common group of coactivator proteins which may be expressed in limited amounts in the cell. Thus, it is possible that chronic activation of PPAR-alpha by peroxisome proliferators could sequester coactivators at a multiplicity of PPAR-alpha target gene promoters and thereby interfere with p53 signaling through p300. The specific hypothesis to be tested is that nuclear receptor-associated coactivator proteins (such as p300) play an integral and essential role in the basic mechanism underlying peroxisome proliferator-induced carcinogenesis by exerting effects on specific stages of the cell cycle. Toward this goal the specific aims of the proposal are to: (1) characterize the interaction of PPAR-alpha with a novel transcriptional coactivator protein (clone D7) in the presence and absence of peroxisome proliferators and to define the mechanism by which the protein encoded by D7 may function in the PPAR-alpha signaling pathway; (2) establish that peroxisome proliferators influence the rate of cell replication by exerting specific effects on stages of the cell cycle using Hepa cells as a model, and (3) test the hypothesis that PPAR-alpha-interacting proteins (such as p300 and clone D7) play a critical role in mediating cell cycle changes that occur in response to peroxisome proliferators. In general it is hoped that these studies will increase our understanding of the relationship between cell proliferation and hepatocarcinogenesis induced by nongenotoxic carcinogens.

描述（改编自候选人的摘要） 人类接触过氧化物酶体增殖物的情况很普遍，并且可能发生在 各种环境、职业和临床环境。 虽然 过氧化物酶体增殖物是啮齿动物致癌物，其危害 人类不确定，因为其作用背后的分子机制是 未知。 过氧化物酶体增殖剂的生物学效应似乎是 通过与激活的过氧化物酶体增殖剂直接相互作用介导 α受体 (PPAR-α)，是类固醇/甲状腺激素的成员 配体依赖性转录因子受体超家族。 老鼠是 缺乏这种受体无法表现出典型的肝细胞改变 对过氧化物酶体增殖剂（例如过氧化物酶体）治疗的反应 增殖，肝肿大，DNA合成增加，表达增加 PPAR-α 调节基因和肝癌发生。 总体目标 该提案的目的是表征一种新型 PPAR-α 相互作用蛋白 （克隆 D7）并确定核受体共激活剂在 PPAR- 中的作用 α介导的细胞周期破坏。 目前认为 调节转录因子（例如 PPAR-α 和肿瘤抑制因子 p53 蛋白）利用一组常见的共激活蛋白，它们可能是 在细胞中以有限的量表达。 因此，有可能是慢性 过氧化物酶体增殖剂激活 PPAR-α 可以隔离 多个 PPAR-α 靶基因启动子上的共激活子，从而 通过 p300 干扰 p53 信号传导。 具体假设为 测试的是核受体相关的共激活蛋白（例如 p300） 在其基本机制中发挥着不可或缺的重要作用 过氧化物酶体增殖物通过作用于特定的细胞而诱导癌变 细胞周期的阶段。 为实现这一目标，提案的具体目标 目的是：（1）表征 PPAR-α 与新型药物的相互作用 转录辅激活蛋白（克隆 D7）在存在和不存在的情况下 过氧化物酶体增殖剂并定义蛋白质的机制 D7 编码的蛋白可能在 PPAR-α 信号通路中发挥作用； (2)建立 过氧化物酶体增殖物通过以下方式影响细胞复制速率 使用 Hepa 细胞作为细胞对细胞周期的各个阶段发挥特定作用 模型，(3) 检验 PPAR-α 相互作用蛋白（例如 p300 和克隆 D7）在介导细胞周期变化中发挥着关键作用 这是对过氧化物酶体增殖物的反应而发生的。 总体来说是希望 这些研究将增加我们对两者之间关系的理解 非基因毒性诱导的细胞增殖和肝癌发生 致癌物质。