MafA is a glucose-regulated and pancreatic β-cell-specific transcriptional activator for the insulin gene
MafA is a glucose-regulated and pancreatic β-cell-specific transcriptional activator for the insulin gene
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DOI：
10.1074/jbc.m206796200
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发表时间：
2002-12-20
影响因子：
4.8
通讯作者：
Handa, H
中科院分区：
文献类型：
--
作者：
Kataoka, K;Han, SI;Handa, H
胰岛素基因在胰腺胰岛的β细胞中特异性表达，其转录受循环葡萄糖水平调节。先前的报道表明，一种未鉴定的β细胞特异性核因子与一种称为RIPE 3b的保守顺式调节元件结合，并对其葡萄糖调节表达至关重要。基于RIPE 3b元件和Maf家族碱性亮氨酸拉链转录因子的共有结合序列的序列相似性，我们在这里确定了哺乳动物同源的禽MaLA/L-Maf，眼睛特异性成员的Maf家族，作为RIPE 3b结合转录激活因子。逆转录-PCR分析显示，mafA mRNA仅在眼睛和胰腺β细胞中检测到，而在α细胞中未检测到。MafA蛋白及其mRNA受葡萄糖上调，这与β细胞核提取物中MafA与RIPE 3b元件的葡萄糖调节结合一致。在瞬时荧光素酶分析中，我们还发现MafA的表达大大增强了胰岛素启动子的活性，而MafA的显性负性形式抑制了它。因此，MafA是β细胞特异性的和葡萄糖调节的胰岛素基因表达的转录激活剂，因此可能参与β细胞的功能和发育以及糖尿病的发病机制。
The insulin gene is specifically expressed in beta-cells of the Langerhans islets of the pancreas, and its transcription is regulated by the circulating glucose level. Previous reports have shown that an unidentified beta-cell-specific nuclear factor binds to a conserved cis-regulatory element called RIPE3b and is critical for its glucose-regulated expression. Based on the sequence similarity of the RIPE3b element and the consensus binding sequence of the Maf family of basic leucine zipper transcription factors, we here identified mammalian homologue of avian MaLA/L-Maf, an eye-specific member of the Maf family, as the RIPE3b-binding transcriptional activator. Reverse transcription-PCR analysis showed that mafA mRNA is detected only in the eyes and in pancreatic beta-cells and not in alpha-cells. MafA protein as well as its mRNA is up-regulated by glucose, consistent with the glucose-regulated binding of MafA to the RIPE3b element in beta-cell nuclear extracts. In transient luciferase assays, we also showed that expression of MafA greatly enhanced insulin promoter activity and that a dominant-negative form of MafA inhibited it. Therefore, MafA is a beta-cell-specific and glucose-regulated transcriptional activator for insulin gene expression and thus may be involved in the function and development of beta-cells as well as in the pathogenesis of diabetes.