Functions of the Maf transcription factors in development and differentiation

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1,c-Maf regulates CTGF gene ; We have previously reported that the c-Maf and MafB transcription factors were specifically expressed in the differentiation process of lens, cartilage, spinal cord and kidney. However the target genes and functions in these tissues are not known. Introduction of the Maf gene into the fibroblast cell line using adenovirus vector induced connective tissue growth factor (CTGF) gene, which has pivotal functions in cartilage development. From the detailed analyses, including EMSA, reporter transfection and ChIP analyses, c-Maf binds to the promoter region and 5'-untranslated regions of CTGF gene and strongly activates this gene. (Biochem Biophys Res Commn 339,1089-1097,2006)2.Identification of c-Maf target genes by DNA micro-array analysis : To identify the target genes of c-Maf, we have performed DNA micro-array analysis using the mouse embryonic fibroblast (MEF) cells from wild and c-maf knock-out mice. We identified several genes, including fibroblast growth factors (Fgf 18 and Fgf 9), which significantly reduced the expression in KO-MEF cells. The detailed analyses on these genes are currently in progress.3,Regulation of glutathione S-transferase (GST-P) gene during hepatocarcinogenesis. GST-P is a tumor marker activated by the Nrf2/MafK hetero-dimers in early stage of carcinogenesis (Biochemical J.380,515-521,2004). Recently, we identified the CAAT enhancer binding protein α (C/EBPα) as a suppressor of this gene in the normal liver. C/EBPα specifically binds to the GPE1,a strong enhancer element of GST-P gene, in vitro and in vivo. C/EBPα expressed in normal liver and strongly inhibited the Nrf2/MafK activity by competing the binding site (GPE1) with the Nrf2/MafK. In the early stage of carcinogenesis, the C/EBPα expression is completely shut-off, and the substitution of GPE1 binding factor from C/EBPα to the Nrf2/MafK lead to the strong induction of GST-P expression. (J.Biol.Chem.in press)