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Comprehensive Gene Expression Analysis of Peroxisome Proliferator-treated Immortalized Hepatocytes

Identification of Peroxisome Proliferator-activated Receptor -dependent Growth Regulatory Genes¹

Department of Veterinary Science, Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802

Chemicals known as peroxisome proliferators (PPs) are the subject of intense study because of their ability to cause hepatocellular carcinoma in laboratory rodents. These chemicals act through a family of proteins termed the peroxisome proliferator-activated receptors (PPARs), in particular PPAR. It has become increasingly apparent that the role of the PPs in the development of cancer encompasses many different aspects of cell growth regulation. Immortalized hepatocytes from wild-type (PPAR^+/+) and PPAR^-/- mice were generated using a temperature-sensitive SV40 virus. Characterization of the murine SV40 hepatocytes (MuSH) generated from both genotypes (MuSH^+/+, MuSH^-/-) show markers of differentiation such as albumin expression, but is devoid of Kupffer cell contamination. Hallmark PPAR-mediated responses such as induction of acyl-CoA oxidase mRNA by PPs are present in the MuSH^+/+ but are absent in MuSH^-/- cells. In contrast to most cell culture systems, the wild-type MuSH hepatocytes retain the mitogenic activity of PPs, whereas the MuSH^-/- does not respond in this manner, thus making this cell culture system an ideal tool to examine growth regulatory gene expression affected by PPs. Microarray experiments performed on both cell types identified many genes in which regulation is dependent on the presence of PPAR, and these changes were verified with reverse transcriptase-PCR. Genes involved in carcinogenesis and control of the cell cycle that are regulated by PPs in a PPAR-dependent manner include ubiquitin COOH-terminal hydrolase 37 (also known as UCT-L5) and cyclin T1. These results show that MuSH cells reflect the biological properties of both the wild-type and PPAR-null animals and can be used to identify novel PPAR-regulated genes that could be involved in regulation of the cell cycle and carcinogenesis.

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