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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression
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Role of AMP-activated protein kinase in the regulation by glucose of islet beta cell gene expression

机译：AMP激活的蛋白激酶在胰岛β细胞基因表达的葡萄糖调节中的作用

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Elevated glucose concentrations stimulate the transcription of the pre-proinsulin (PPI), L-type pyruvate kinase (L-PK), and other genes in islet beta cells. In liver cells, pharmacological activation by 5-amino-4-imidazolecarboxamide riboside (AlCAR) of AMP- adivated protein kinase (AMPK), the mammalian homologue of the yeast SNF1 kinase complex, inhibits the effects of glucose, suggesting a key signaling role for this kinase. Here, we demon- strate that AMPK activity is inhibited by elevated glucose concen- trations in MlN6 beta cells and that activation of the enzyme with AlCAR prevents the activation of the L-PK gene by elevated glucose. Furthermore, microinjection of antibodies to the α2- (catalytic) or β2-subunits of AMPK complex, but not to the α1- subunit or extracellular stimulus-regulated kinase, mimics the effeCts of elevated glucose on the L-PK and PPl promoter activities as assessed by single-cell imaging of promoter luciferase con- Structs. In each case. injection of antibodies into the nucleus and Cytosol, but not the nucleus alone. was necessary, indicating the importance of either a cytosolic phosphorylation event or the subcellular localization of the α2-subunits. incubation with AlCAR diminished. but did not abolish. the effect of glucose on PPl transcription. These data suggest that glucose-induced changes in AMPK activity are necessary and sufficient for the regulation of the L-PK gene by the sugar and also play an important role in the regulation of the PPI promoter.
机译：升高的葡萄糖浓度刺激胰岛β细胞中胰岛素原（PPI），L型丙酮酸激酶（L-PK）和其他基因的转录。在肝细胞中，5-氨基-4-咪唑甲酰胺核糖核苷（AlCAR）对AMP Sdiv1蛋白激酶（AMPK）的哺乳动物同源物的药理学激活抑制了葡萄糖的作用，这提示了其关键的信号传导作用。这种激酶。在这里，我们证明AMPK活性受到MlN6β细胞中葡萄糖浓度升高的抑制，而AlCAR激活酶阻止了葡萄糖升高对L-PK基因的激活。此外，对AMPK复合物的α2-（催化）或β2-亚基而不是α1-亚基或细胞外刺激调节激酶的微注射抗体模拟了葡萄糖升高对L-PK和PP1启动子活性的影响，如下所示：通过启动子荧光素酶结构的单细胞成像评估。在每种情况下。将抗体注射到细胞核和胞质溶胶中，但不能单独注射细胞核。是必需的，表明胞质磷酸化事件或α2-亚基亚细胞定位的重要性。与AlCAR的孵育减少了。但并没有废除。葡萄糖对PP1转录的影响。这些数据表明葡萄糖诱导的AMPK活性的改变对于糖对L-PK基因的调节是必要和充分的，并且在PPI启动子的调节中也起重要作用。

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