AMP-activated protein kinase regulates PEPCK gene expression by direct phosphorylation of a novel zinc finger transcription factor.
AMP-activated protein kinase regulates PEPCK gene expression by direct phosphorylation of a novel zinc finger transcription factor.
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DOI：
10.1016/j.bbrc.2006.10.124
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发表时间：
2006-12
影响因子：
3.1
通讯作者：
Erina Inoue;J. Yamauchi
中科院分区：
文献类型：
--
作者：
Erina Inoue;J. Yamauchi
AMP活化蛋白激酶(AMPK)是维持能量平衡的细胞内感受器。AMPK的激活开启了ATP的生成过程，而关闭了ATP的消耗过程。它通过下游代谢酶的磷酸化来实现这些效果。已有研究提出，AMPK还通过某些转录因子的磷酸化来调节基因表达，但其分子机制尚不完全清楚。在这里，我们展示了一种新的锌指转录因子AREBP的克隆和鉴定。AREBP在Ser470位被AMPK磷酸化。磷酸化会降低AREBP的DNA结合活性。瞬时转染实验表明，野生型AREBP，而不是Ser470到Ala470替代的非磷酸化突变体，抑制了糖异生的关键酶--磷酸烯醇式丙酮酸羧激酶(PEPCK)的基因表达。RNA干扰介导的内源性AREBP表达下调可减弱AMPK诱导的PEPCK下调。这些结果表明，AREBP是AMPK调控PEPCK基因表达的一个新的关键调控因子。
AMP-activated protein kinase (AMPK) acts as an intracellular sensor for maintaining the energy balance. Activation of AMPK switches on ATP-generating process while switches off ATP-consuming process. It achieves these effects by phosphorylation of downstream metabolic enzymes. It has been proposed that AMPK also regulates gene expression through phosphorylation of certain transcription factors; however its molecular mechanism is not fully understood. Here we show the cloning and characterization of a novel zinc finger transcription factor referred to as AREBP. AREBP is phosphorylated at Ser470by AMPK. Phosphorylation reduces the DNA-binding activity of AREBP. Transient transfection experiments indicate that wild-type AREBP, but not Ser470to Ala470substituted non-phosphorylating mutant, represses gene expression of the phosphoenolpyruvate carboxykinase (PEPCK), a key enzyme of gluconeogenesis. RNA interference-mediated reduction of endogenous AREBP expression attenuates AMPK-induced PEPCK down-regulation. These results implicate AREBP as a novel key modulator of PEPCK gene expression regulated by AMPK.