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首页> 外文期刊>American Journal of Physiology >c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells.
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c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells.

机译：c-Myc和ChREBP调节INS-1衍生的832/13细胞中葡萄糖介导的L型丙酮酸激酶基因的表达。

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摘要

Increased glucose flux generates metabolic signals that control transcriptional programs through poorly understood mechanisms. Previously, we demonstrated a necessity in hepatocytes for c-Myc in the regulation of a prototypical glucose-responsive gene, L-type pyruvate kinase (L-PK) (Collier JJ, Doan TT, Daniels MC, Schurr JR, Kolls JK, Scott DK. J Biol Chem 278: 6588-6595, 2003). Pancreatic beta-cells have many features in common with hepatocytes with respect to glucose-regulated gene expression, and in the present study we determined whether c-Myc was required for the L-PK glucose response in insulin-secreting (INS-1)-derived 832/13 cells. Glucose increased c-Myc abundance and association with its heterodimer partner, Max. Manipulations that prevented the formation of a functional c-Myc/Max heterodimer reduced the expression of the L-PK gene. In addition, glucose augmented the binding of carbohydrate response element binding protein (ChREBP), c-Myc, and Max to the promoter of the L-PK gene in situ. The transactivation of ChREBP, but not of c-Myc, was dependent on high glucose concentrations in the contexts of either the L-PK promoter or a heterologous promoter. The glucose-mediated transactivation of ChREBP was independent of mutations that alter phosphorylation sites thought to regulate the cellular location of ChREBP. We conclude that maximal glucose-induced expression of the L-PK gene in INS-1-derived 832/13 cells involves increased c-Myc abundance, recruitment of c-Myc, Max, and ChREBP to the promoter, and a glucose-stimulated increase in ChREBP transactivation.
机译：葡萄糖通量增加产生代谢信号，该信号通过人们不了解的机制来控制转录程序。以前，我们证明了肝细胞中c-Myc在调节典型的葡萄糖反应性基因L型丙酮酸激酶（L-PK）方面的必要性（Collier JJ，Doan TT，Daniels MC，Schurr JR，Kolls JK，Scott DK.J Biol Chem 278：6588-6595，2003）。胰岛β细胞在葡萄糖调节基因表达方面具有与肝细胞相同的许多特征，在本研究中，我们确定了胰岛素分泌（INS-1）-中L-PK葡萄糖应答是否需要c-Myc-衍生的832/13细胞。葡萄糖增加了c-Myc的丰度并与其异二聚体伙伴Max。阻止功能性c-Myc / Max异二聚体形成的操作降低了L-PK基因的表达。此外，葡萄糖增强了碳水化合物反应元件结合蛋白（ChREBP），c-Myc和Max与L-PK基因启动子的结合。 ChREBP的反式激活，而不是c-Myc的反式激活，取决于L-PK启动子或异源启动子的高葡萄糖浓度。葡萄糖介导的ChREBP的反式激活与改变磷酸化位点的突变无关，这些突变被认为可调节ChREBP的细胞定位。我们得出的结论是，INS-1衍生的832/13细胞中L-PK基因的最大葡萄糖诱导表达涉及增加c-Myc丰度，将c-Myc，Max和ChREBP募集到启动子，以及葡萄糖刺激ChREBP反式激活增加。

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