Glucose-6-phosphate mediates activation of the carbohydrate responsive binding protein (ChREBP).
Glucose-6-phosphate mediates activation of the carbohydrate responsive binding protein (ChREBP).
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DOI：
10.1016/j.bbrc.2010.04.028
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发表时间：
2010-05-07
影响因子：
3.1
通讯作者：
Chan, Lawrence
中科院分区：
文献类型：
--
作者：
Li, Ming V.;Chen, Weiqin;Harmancey, Romain N.;Nuotio-Antar, Alli M.;Imamura, Minako;Saha, Pradip;Taegtmeyer, Heinrich;Chan, Lawrence
关键词：
碳水化合物反应元件结合蛋白（ChREBP）是Mondo家族转录因子，其响应于葡萄糖刺激而激活许多糖酵解和脂肪生成基因。我们以前曾报道，高葡萄糖可以激活ChREBP的转录活性独立于蛋白磷酸酶2A（PP 2A）介导的增加核进入和DNA结合。在这里，我们发现葡萄糖-6-磷酸（G-6-P）的形成是必不可少的葡萄糖激活ChREBP。GAL 4-ChREBP的葡萄糖反应被D-甘露庚酮糖（一种有效的己糖激酶抑制剂）以及葡萄糖-6-磷酸酶（G6 β）的过表达减弱; GAL 4-ChREBP的激活动力学可以被外源表达的GCK修饰。G-6-P通过糖酵解和戊糖磷酸途径这两个主要葡萄糖代谢途径的进一步代谢不是ChREBP激活所必需的;葡萄糖-6-磷酸脱氢酶（G6 PD）的过表达减少，而该酶的RNAi敲低分别增强GAL 4-ChREBP的葡萄糖响应。此外，葡萄糖类似物2-脱氧葡萄糖（2-DG），这是磷酸化的己糖激酶，但不进一步代谢，有效地上调ChREBP的转录活性。此外，磷酸果糖激酶（PFK）1和2的过表达，协同减少GAL 4-ChREBP的葡萄糖反应。这些多方面的证据支持G-6-P介导ChREBP激活的结论。
Carbohydrate Response Element Binding Protein (ChREBP) is a Mondo family transcription factor that activates a number of glycolytic and lipogenic genes in response to glucose stimulation. We have previously reported that high glucose can activate the transcriptional activity of ChREBP independent of the protein phosphatase 2A (PP2A)-mediated increase in nuclear entry and DNA binding. Here we found that formation of glucose-6-phosphate (G-6-P) is essential for glucose activation of ChREBP. The glucose response of GAL4-ChREBP is attenuated by D-mannoheptulose, a potent hexokinase inhibitor, as well as over-expression of glucose-6-phosphatase (G6Pase); kinetics of activation of GAL4-ChREBP can be modified by exogenously expressed GCK. Further metabolism of G-6-P through the two major glucose metabolic pathways, glycolysis and pentose phosphate pathway, is not required for activation of ChREBP; over-expression of glucose-6-phosphate dehydrogenase (G6PD) diminishes, whereas RNAi knockdown of the enzyme enhances, the glucose response of GAL4-ChREBP, respectively. Moreover, the glucose analogue 2-deoxyglucose (2-DG), which is phosphorylated by hexokinase, but not further metabolized, effectively upregulates the transcription activity of ChREBP. In addition, over-expression of phosphofructokinase (PFK) 1 and 2, synergistically diminishes the glucose response of GAL4-ChREBP. These multiple lines of evidence support the conclusion that G-6-P mediates the activation of ChREBP.
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影响因子：
7.7
作者：
Li, MV;Chang, B;Chan, L
通讯作者：
Chan, L
影响因子：
4.1
作者：
HEDESKOV, CJ;CAPITO, K
通讯作者：
CAPITO, K
DOI：
10.1016/j.bbrc.2005.12.029
发表时间：
2006-02-10
影响因子：
3.1
作者：
Tsatsos, NG;Towle, HC
通讯作者：
Towle, HC
DOI：
10.1073/pnas.161284298
发表时间：
2001-07-31
影响因子：
11.1
作者：
Yamashita, H;Takenoshita, M;Uyeda, K
通讯作者：
Uyeda, K
DOI：
10.1073/pnas.231370798
发表时间：
2001-11-20
影响因子：
11.1
作者：
Kawaguchi, T;Takenoshita, M;Uyeda, K
通讯作者：
Uyeda, K