PEROXISOME PROLIFERATORS AND THE CELL CYCLE

过氧化物酶体增殖剂和细胞周期

• 批准号: 6350750
• 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/6350750
• 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（改编自候选人摘要） 人类暴露于过氧化物酶体增殖物是广泛的，并可能发生在一个 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类动物致癌物， 人类是不确定的，因为其影响的分子机制是 未知 过氧化物酶体增殖物的生物学效应似乎是 通过与激活的过氧化物酶体增殖物直接相互作用介导 受体α（PPAR-alpha），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。 的小鼠 缺乏这种受体不能显示典型的肝细胞改变， 对过氧化物酶体增殖剂如过氧化物酶体治疗的反应 增殖，肝肿大，DNA合成增加， PPAR-alpha调控基因与肝癌发生 总体目标 这项建议的目的是表征一种新的PPAR-alpha相互作用蛋白 （克隆D 7），并确定核受体共激活因子在PPAR-γ表达中的作用。 α介导的细胞周期破坏。 目前认为 受调节的转录因子（如PPAR-alpha和肿瘤抑制因子） 蛋白p53）利用一组共同的共激活蛋白， 在细胞中以有限的量表达。 因此，有可能慢性 过氧化物酶体增殖物激活的PPAR-alpha可以隔离 在多个PPAR-alpha靶基因启动子处的共激活子，从而 通过p300干扰p53信号传导。 具体的假设是 核受体相关辅激活蛋白（如p300） 在基本机制中发挥不可或缺的重要作用 过氧化物酶体增殖物通过对特异性 细胞周期的各个阶段。 为了实现这一目标， （1）表征PPAR-alpha与新的 转录共激活蛋白（克隆D 7）在存在和不存在 过氧化物酶体增殖物，并确定蛋白质 D 7编码的蛋白可能在PPAR-alpha信号通路中起作用;（2）建立 过氧化物酶体增殖物影响细胞复制的速率， 使用Hepa细胞作为细胞周期的各个阶段， 模型，和（3）测试假设，PPAR-alpha相互作用蛋白（如 如p300和克隆D 7）在介导细胞周期变化中起关键作用 是对过氧化物酶体增殖物的反应 总的来说，希望 这些研究将增加我们对 非遗传毒性物质诱导的细胞增殖和肝癌发生 致癌物质。