PEROXISOME PROLIFERATORS AND THE CELL CYCLE

描述(改编自候选人的摘要) 人类接触到过氧化物体增殖物是很普遍的，可能发生在 各种环境、职业和临床环境。虽然 过氧化物体增殖物是啮齿动物的致癌物，它们构成的危险 人类是不确定的，因为它们影响的分子机制是 未知。过氧化物酶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而介导 受体α(PPAR-α)，是类固醇/甲状腺激素的成员 受体超家族的配体依赖的转录因子。老鼠是 缺乏这种受体的人不能显示典型的肝细胞改变 对过氧化酶体增殖物治疗的反应，如过氧化酶体 增殖，肝肿大，DNA合成增加，表达增加 PPAR-α调控基因与肝癌发生总体目标 是为了表征一种新的PPAR-α相互作用蛋白 (克隆D7)，并确定核受体辅活化子在PPAR- 阿尔法介导的细胞周期中断。目前认为， 受调控的转录因子(如PPAR-α和肿瘤抑制因子 蛋白P53)利用一组共同的共激活蛋白，该共激活蛋白可 在细胞中以有限的数量表达。因此，慢性病有可能 过氧化物酶体增殖物对PPAR-α的激活作用 在多种PPAR-α靶基因启动子上的共激活剂，从而 通过p300干扰P53信号传导。具体的假设是 检测的是核受体相关的辅助激活蛋白(如p300) 在基础性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作用于特定的细胞因子诱导癌变 细胞周期的各个阶段。为了实现这一目标，该提案的具体目标 目的是：(1)表征PPAR-α与一种新的 转录共激活蛋白(克隆D7)的存在和不存在 过氧化物酶体增殖物和确定蛋白质通过其 D7编码可能在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度 利用HEPA细胞对细胞周期的各个阶段施加特定的影响 模型，以及(3)检验PPAR-α相互作用蛋白(如 AS p300和克隆D7)在调节细胞周期变化中起关键作用 是对过氧化物酶增殖物的反应。总的来说，人们希望 这些研究将增加我们对两者关系的理解 非遗传毒性诱导的细胞增殖和肝癌的发生 致癌物质。

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.