Functions of the Maf transcription factors in development and differentiation

1、c-Maf调控CTGF基因；我们之前报道过c-Maf和MafB转录因子在晶状体、软骨、脊髓和肾脏的分化过程中特异性表达。然而，这些组织中的靶基因和功能尚不清楚。利用腺病毒载体诱导结缔组织生长因子（CTGF）基因将Maf基因导入成纤维细胞系，该基因在软骨发育中起关键作用。从EMSA、报告基因转染、ChIP分析等详细分析来看，c-Maf结合到CTGF基因的启动子区和5′-非翻译区，强烈激活CTGF基因。（生物化学与生物物理，339,1089-1097,2006）通过DNA微阵列分析鉴定c-Maf靶基因：为了鉴定c-Maf的靶基因，我们对野生小鼠和c-Maf敲除小鼠的小鼠胚胎成纤维细胞（MEF）进行了DNA微阵列分析。我们发现了几个基因，包括成纤维细胞生长因子（Fgf 18和Fgf 9），可以显著降低KO-MEF细胞的表达。对这些基因的详细分析目前正在进行中。3、谷胱甘肽s -转移酶（GST-P）基因在肝癌发生中的调控。GST-P是Nrf2/MafK异源二聚体在癌变早期激活的肿瘤标志物（Biochemical J.380,515-521,2004）。最近，我们在正常肝脏中发现CAAT增强子结合蛋白α (C/EBPα)是该基因的抑制因子。C/EBPα在体外和体内特异性结合GPE1， GPE1是GST-P基因的强增强元件。C/EBPα在正常肝脏中表达，并通过与Nrf2/MafK竞争结合位点（GPE1），强烈抑制Nrf2/MafK活性。在癌变早期，C/EBPα表达完全关闭，GPE1结合因子从C/EBPα替换为Nrf2/MafK，导致GST-P表达强烈诱导。(J.Biol.Chem。在出版社)

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)