c-Myc is required for the glucose-mediated induction of metabolic enzyme genes
c-Myc is required for the glucose-mediated induction of metabolic enzyme genes
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DOI：
10.1074/jbc.m208011200
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发表时间：
2003-02-21
影响因子：
4.8
通讯作者：
Scott, DK
中科院分区：
文献类型：
--
作者：
Collier, JJ;Doan, TTT;Scott, DK
葡萄糖对肝细胞基因转录有强大的影响，其机制尚不完全清楚。c-Myc通过增加糖酵解酶基因转录来调节肝脏糖代谢，同时降低糖异生酶和生酮酶基因表达。然而，c-Myc发挥这些作用的分子机制尚不清楚。在这项研究中，葡萄糖介导的l型丙酮酸激酶和葡萄糖-6-磷酸酶mRNA水平的诱导通过涉及重组腺病毒载体的操作而降低，重组腺病毒载体通过反义表达干扰(i) c-Myc蛋白水平，或（ii）通过显性阴性Max蛋白干扰c-Myc功能。这些结果是在h1c大鼠肝癌细胞和原代大鼠肝细胞中获得的。此外，c-Myc丰度的降低可能通过降低葡萄糖-6-磷酸酶活性降低了h1c细胞的葡萄糖生成。葡萄糖抑制激素激活的磷酸烯醇丙酮酸羧激酶基因转录不受c-Myc水平降低的影响。l -丙酮酸激酶和葡萄糖-6-磷酸酶的基础mRNA水平未被腺病毒处理显著改变。此外，在没有葡萄糖刺激的情况下，腺病毒过表达c-Myc蛋白诱导葡萄糖-6-磷酸酶mRNA。我们得出结论，存在多种机制来传递葡萄糖来源的信号，并且c-Myc在肝脏葡萄糖信号通路中起关键作用。
Glucose exerts powerful effects on hepatocyte gene transcription by mechanisms that are incompletely understood. c-Myc regulates hepatic glucose metabolism by increasing glycolytic enzyme gene transcription while concomitantly decreasing gluconeogenic and ketogenic enzyme gene expression. However, the molecular mechanisms by which c-Myc exerts these effects is not known. In this study, the glucose-mediated induction of L-type pyruvate kinase and glucose-6-phosphatase mRNA levels was diminished by maneuvers involving recombinant adenoviral vectors that interfere with (i) c-Myc protein levels by antisense expression or (ii) c-Myc function through a dominant-negative Max protein. These results were obtained using both HL1C rat hepatoma cells and primary rat hepatocytes. Furthermore, a decrease in c-Myc abundance reduced glucose production in HL1C cells, presumably by decreasing glucose-6-phosphatase activity. The repression of hormone-activated phosphoenolpyruvate carboxykinase gene transcription by glucose was not affected by a reduction in c-Myc levels. The basal mRNA levels for L-pyruvate kinase and glucose-6-phosphatase were not altered to any significant degree by adenoviral treatment. Furthermore, adenoviral overexpression of the c-Myc protein induced glucose-6-phosphatase mRNA in the absence of glucose stimulation. We conclude that multiple mechanisms exist to communicate the glucose-derived signal and that c-Myc has a key role in the hepatic glucose signaling pathway.