Zonation of heme synthesis enzymes in mouse liver and their regulation by β-catenin and Ha-ras.
Cytochrome P450 (CYP) hemoproteins play an important role in hepatic biotransformation. Recently, β-catenin and Ha-ras signaling have been identified as players controlling transcription of various CYP genes in mouse liver. The aim of the present study was to analyze the role of β-catenin and Ha-ras in the regulation of heme synthesis. Heme synthesis-related gene expression was analyzed in normal liver, in transgenic mice expressing activated β-catenin or Ha-ras, and in hepatomas. Regulation of the aminolevulinate dehydratase promoter was studied in vitro. Elevated expression of mRNAs and proteins involved in heme biosynthesis was linked to β-catenin activation in perivenous hepatocytes, in transgenic hepatocytes, and in hepatocellular tumors. Stimulation of the aminolevulinate dehydratase promoter by β-catenin was independent of the β-catenin/T-cell-specific transcription factor dimer. By contrast, activation of Ha-ras repressed heme synthesis-related gene expression. The present data suggest that β-catenin enhances the expression of both CYPs and heme synthesis-related genes, thus coordinating the availability of CYP apoprotein and its prosthetic group heme. The reciprocal regulation of heme synthesis by β-catenin and Ha-ras-dependent signaling supports our previous hypothesis that antagonistic action of these pathways plays a major role in the control of zonal gene expression in healthy mouse liver and aberrant expression patterns in hepatocellular tumors.
Braeuning
Albert
A
Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstrasse 56, Tübingen, Germany. albert.braeuning@uni-tuebingen.de
Schwarz
Michael
M
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic; D011905:Genes, ras / Q000235:genetics; D006418:Heme / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D051176:beta Catenin; D006418:Heme; D003577:Cytochrome P-450 Enzyme System