Peroxisomes contain more than 50 proteins, and more than half of these participate in lipid metabolism. The objective of our studies is to characterize cellular, and molecular aspects of the phenomenon of peroxisome proliferation induced by structurally diverse compounds and delineate mechanisms of peroxisome proliferator- induced pleiotropic responses, including development of liver tumors. While the role of peroxisome proliferator-activated receptors (PPARs) in the transcriptional activation of responsive genes, and that sustained induction of massive peroxisome proliferation in hepatocytes is carcinogenic appear well established, there are critical gaps in our understanding of the: a) mechanisms by which PPARs participate in gene activation in a cell and species specific manner; and b) role of sustained transcriptional activation ofH2O2-generating peroxisomal fatty acid-oxidation, as well as the nature of downstream events that occur as a result of increased by generation of H2O2 by peroxisomal oxidases in the development of peroxisome proliferator-induced tumors. We now propose to focus on generating fundamental information, which can provide insights into the molecular complexity of unique pleiotropic responses induced by peroxisome proliferators.
Our specific aims are to: l) Analyze the differences in the expression, developmental regulation and transcriptional activation of peroxisomal beta-oxidation system, employing the peroxisomal fatty acyl-CoA oxidase gene (ACOX) promoter to direct E. coli beta-galactosidase, or urate oxidase in transgenic mice; 2) Explore the role of H202-generating peroxisomal oxidases in carcinogenesis using the in vitro/in vivo molecular approaches and delineate the mechanism by which H202 initiates the cascade of events leading to neoplastic transformation; 3) Investigate the natural course and full potential of mice with disrupted ACOX gene, and other gene(s) of the -oxidation system, and delineate the reasons for the susceptibility of ACOX-/- mice to liver tumor development; 4) Evaluate the functional role of rat deoxyuridine triphosphatase (dUTPase), which interacts with and inhibits PPARalpha:, and determine whether the extra 62 N- terminal amino acid PPARalpha-interacting portion present in rat dUTPase, but lacking in human dUTPase has any fictional significance; and 5) Identify and characterize proteins interacting with PPARs in order to understand the differential and cell specific control and activation of gene expression by structurally diverse peroxisome proliferators.
Showing the most recent 10 out of 104 publications
