Zonation of heme synthesis enzymes in mouse liver and their regulation by beta-catenin and Ha-ras.
Summary of "Zonation of heme synthesis enzymes in mouse liver and their regulation by beta-catenin and Ha-ras."
Abstract Cytochrome P450 (CYP) hemoproteins play an important role in hepatic biotransformation. Recently, beta-catenin and Ha-ras signaling have been established as new players controlling transcription of various CYP genes in mouse liver. The present study was aimed to analyze the role of beta-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 beta-catenin or Ha-ras, and in hepatomas. Regulation of the aminolevulinate synthase promoter was studied in vitro. Elevated expression of mRNAs and proteins involved in heme biosynthesis was linked to beta-catenin activation in perivenous hepatocytes, in transgenic hepatocytes, and in hepatocellular tumors. Stimulation of the aminolevulinate dehydratase promoter by beta-catenin was independent of the beta-catenin/T-cell-specific transcription factor dimer. By contrast, activation of Ha-ras repressed heme synthesis-related gene expression. The present data suggest that beta-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 beta-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.
Institute of Experimental and Clinical Pharmacology and Toxicology, Department of Toxicology, University of Tübingen, Wilhelmstr. 56, D-72074 Tübingen, Germany.
This article was published in the following journal.
Name: Biological chemistry
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/20707599
- DOI: http://dx.doi.org/10.1515/BC.2010.115
Medical and Biotech [MESH] Definitions
A trace element with atomic symbol Mn, atomic number 25, and atomic weight 54.94. It is concentrated in cell mitochondria, mostly in the pituitary gland, liver, pancreas, kidney, and bone, influences the synthesis of mucopolysaccharides, stimulates hepatic synthesis of cholesterol and fatty acids, and is a cofactor in many enzymes, including arginase and alkaline phosphatase in the liver. (From AMA Drug Evaluations Annual 1992, p2035)
A 4-hydroxylated metabolite of AFLATOXIN B1, one of the MYCOTOXINS from ASPERGILLUS tainted food. It is associated with LIVER damage and cancer resulting from its P450 activation to the epoxide which alkylates DNA. Toxicity depends on the balance of liver enzymes that activate it (CYTOCHROME P-450) and others that detoxify it (GLUTATHIONE S TRANSFERASE) (Pharmac Ther 50.443 1991). Primates & rat are sensitive while mouse and hamster are tolerant (Canc Res 29.236 1969).
An enzyme of the transferase class that catalyzes condensation of the succinyl group from succinyl coenzyme A with glycine to form delta-aminolevulinate. It is a pyridoxyal phosphate protein and the reaction occurs in mitochondria as the first step of the heme biosynthetic pathway. The enzyme is a key regulatory enzyme in heme biosynthesis. In liver feedback is inhibited by heme. EC 22.214.171.124.
An autosomal dominant porphyria that is due to a deficiency of FERROCHELATASE (heme synthetase) in both the LIVER and the BONE MARROW, the last enzyme in the 8-enzyme biosynthetic pathway of HEME. Clinical features include mainly neurological symptoms, rarely cutaneous lesions, and elevated levels of protoporphyrin and COPROPORPHYRINS in the feces.
A diverse group of metabolic diseases characterized by errors in the biosynthetic pathway of HEME in the LIVER, the BONE MARROW, or both. They are classified by the deficiency of specific enzymes, the tissue site of enzyme defect, or the clinical features that include neurological (acute) or cutaneous (skin lesions). Porphyrias can be hereditary or acquired as a result of toxicity to the hepatic or erythropoietic marrow tissues.
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