MAFA controls genes implicated in insulin biosynthesis and secretion
MAFA controls genes implicated in insulin biosynthesis and secretion
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DOI：
10.1007/s00125-006-0490-2
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发表时间：
2007-02-01
期刊：
影响因子：
8.2
通讯作者：
Wollheim, C. B.
中科院分区：
文献类型：
--
作者：
Wang, H.;Brun, T.;Wollheim, C. B.
目的/假设研究转录因子v-maf musculoaponeurotic fibrosarcoma coconcene homologue A（MAFA）对β细胞基因表达和功能的调节作用。材料与方法建立了可诱导该转录因子上调或下调的INS-1稳定细胞系。结果MAFA过量表达增强，其显性负突变体（DN-MAFA）表达增强，其显性负突变体（DN-MAFA）表达增强。该因子与胰岛素启动子的结合减少，与胰岛素mRNA水平和细胞蛋白含量相关。MAFA促进葡萄糖刺激的胰岛素分泌，DN-MAFA使其减弱。这部分是由于葡萄糖激酶产生的改变，β细胞的葡萄糖传感器。此外，重要的β细胞基因的表达，例如编码溶质载体家族2的那些，（葡萄糖易化转运蛋白），成员2（以前称为GLUT 2）、胰腺和十二指肠同源框因子1（PDX 1）、NK 6转录因子相关基因座1（NKX 6 -1）、胰高血糖素样肽1受体（GLP 1 R）、激素原转化酶1/3（PCSK 1）和丙酮酸羧化酶（PC），正调节MAFA和负DN-MAFA。结论/解释的数据表明，MAFA不仅是一个关键的胰岛素转录激活剂，但也是一个主调节器的基因参与维持β细胞功能，特别是代谢分泌耦合，胰岛素原加工和GLP 1 R信号。我们的体外研究提供了分子靶点，解释了最近报道的Mafa缺失小鼠的表型。我们还证明了MAFA是在人类胰岛的β细胞中特异性产生的。葡萄糖以钟形方式影响大鼠胰岛MAFA的DNA结合活性。因此，MAFA有资格作为β细胞特异性基因表达和功能的主要调节剂。
Aims/hypothesis Effects of the transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) on the regulation of beta cell gene expression and function were investigated.Materials and methods INS-1 stable cell lines permitting inducible up- or downregulation of this transcription factor were established.Results MAFA overproduction enhanced and its dominant-negative mutant (DN-MAFA) diminished binding of the factor to the insulin promoter, correlating with insulin mRNA levels and cellular protein content. Glucose-stimulated insulin secretion was facilitated by MAFA and blunted by DN-MAFA. This is partly due to alterations in glucokinase production, the glucose sensor of beta cells. In addition, the expression of important beta cell genes, e.g. those encoding solute carrier family 2 (facilitated glucose transporter), member 2 (formerly known as GLUT2), pancreatic and duodenal homeobox factor 1 (PDX1), NK6 transcription factor-related, locus 1 (NKX6-1), glucagon-like peptide 1 receptor (GLP1R), prohormone convertase 1/3 (PCSK1) and pyruvate carboxylase (PC), was regulated positively by MAFA and negatively by DN-MAFA.Conclusions/interpretations The data suggest that MAFA is not only a key activator of insulin transcription, but also a master regulator of genes implicated in maintaining beta cell function, in particular metabolism-secretion coupling, proinsulin processing and GLP1R signalling. Our in vitro study provides molecular targets that explain the phenotype of recently reported Mafa-null mice. We also demonstrate that MAFA is produced specifically in beta cells of human islets. Glucose influenced DNA-binding activity of MAFA in rat islets in a bell-shaped manner. MAFA thus qualifies as a master regulator of beta-cell-specific gene expression and function.