A Common Set of Immediate–Early Response Genes in Liver Regeneration and Hyperplasia

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Abstract
Partial hepatectomy (PH) and some tumor–promoting agents stimulate hepatocyte cell proliferation, but each treatment acts through distinct transcription factors. We compared mouse immediate–early gene expression changes after PH with those induced by 1,4–bis[2–(3,5–dichoropyridyloxy)]benzene (TCPOBOP), a tumor–promoting liver mitogen. PH activates nuclear factor κB (NF–κB) and Stat3, whereas TCPOBOP is a ligand for the nuclear receptor, constitutive androstane receptor (CAR). RNA from 1 and 3 hours after each treatment was hybridized to a 9,000 complementary DNA (cDNA) microarray. Of about 6,000 messenger RNAs that had detectable expression, 127 showed reproducible up–regulation or down–regulation at a significant level. The TCPOBOP response was more discrete than the PH response; they amounted to 1% and 1.9% of positive hybridizations, respectively. Twenty–three genes were regulated only by TCPOBOP, 57 only by PH, and 59 by both treatments. More detailed analysis defined 16 clusters with common patterns of expression. These patterns and quantification of hybridization levels on the array were confirmed by Northern blots. TCPOBOP selectively activated expression of a number of detoxification enzymes. In conclusion, the genes that were regulated by both treatments suggest down–regulation of apoptosis, altered signal transduction, and early biogenesis of critical cell components.