PEROXISOME PROLIFERATORS AND THE CELL CYCLE

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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.