Peroxisome proliferators are a large group of non-genotoxic carcinogens whose effects are tissue-and species-specific. The mechanism of carcinogenesis in rodents is not completely understood but is thought to involve (i) increased proliferation of hepatocytes; (ii) activation of nuclear receptor PPARa and proliferation of peroxisomes; (iii) production of reactive oxygen species and damage to DNA; and (iv) oxidant-mediated activation of mitogen production by Kupffer cells. This proposal is designed not only to fill in the gaps in specific signaling mechanisms induced by peroxisome proliferators, but also to elucidate how individual cellular and molecular pathways interact to bring about the changes that lead to cancer. Specifically, we hypothesize that peroxisome proliferators activate Kupffer cells to generate oxidants, which increase mitogenic cytokines that require PPARa in parenchymal cells to stimulate cell proliferation maximally. A number of pivotal questions remain unanswered. First, what is the role of oxidant production in long-term effects of peroxisome proliferators? Here we will test the hypothesis that oxidant production by Kupffer cells is critical for the effects on cell proliferation; that WY,14643, but not DEHP, is able to cause a sustained activation of Kupffer cells; and that this phenomenon is important for liver carcinogenesis. Second, which signaling mechanisms are responsible for activation of Kupffer cells by peroxisome proliferators? We will test the hypothesis that peroxisome proliferators, highly lipophilic compounds, form lipid-like particles and bind to the receptors on the Kupffer cell membrane in a non-specific """"""""particle-mediated"""""""" manner, leading to increases in intracellular calcium and activation of kinase cascades. This results in activation of NADPH oxidase via phosphorylation of its subunits leading to oxidant production, which stimulates NF-KB. As a result, cytokine production by Kupffer cells is increased and stimulates cell proliferation in parenchymal cells where PPARa-dependent signaling events warrant specificity of peroxisome proliferator-induced responses. Third, what are the molecular events in hepatocytes that are involved in increased cell proliferation in hepatocytes by mitogenic cytokines and PPARa-activators and how do these pathways interact? We will test the hypothesis that maximal stimulation of parenchymal cell proliferation by mitogenic cytokines from Kupffer cells is potentiated by the actions of peroxisome proliferators on PPARa in parenchymal cells. Specifically, activation of PPARa leads to an increase in the pool of prenyl isoprenoids available for post-translational modification of Ras and thereby promotes its translocation to the membrane where it can be activated. This results in a """"""""potentiation"""""""" of a non-specific mitogen release from Kupffer cells activated by lipid-like peroxisome proliferator particles, thus accounting for a characteristic burst of proliferation in the liver.
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