Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module
Glucose-dependent transcriptional regulation by an evolutionarily conserved glucose-sensing module
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DOI：
10.2337/db05-0822
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发表时间：
2006-05-01
期刊：
影响因子：
7.7
通讯作者：
Chan, L
中科院分区：
文献类型：
--
作者：
Li, MV;Chang, B;Chan, L
我们在这里报告了一个新的机制，葡萄糖介导的激活碳水化合物反应元件结合蛋白（ChREBP），一个基本的螺旋-环-螺旋/亮氨酸拉链（bHLH/ZIP）的Mondo家族的转录因子，结合到一些葡萄糖调节基因的启动子中的碳水化合物反应元件，并激活其表达葡萄糖刺激。ChREBP在一个高葡萄糖敏感系统中的结构-功能分析，使用GAL 4-ChREBP融合构建体揭示了一个葡萄糖传感模块（GSM），介导的葡萄糖响应的ChREBP。GSM在Mondo家族成员中是保守的，MondoA是一种功能未知的哺乳动物parasites，并且还发现果蝇同源物的GSM区域是葡萄糖响应性的。GSM由低葡萄糖抑制结构域（LID）和葡萄糖应答激活保守元件（GRACE）组成。我们已经确定了一个新的机制占葡萄糖的响应ChREBP，涉及特定的抑制GRACE的反式激活活性的LID在低葡萄糖浓度和逆转这种抑制葡萄糖在一个方向敏感的方式。葡萄糖的分子内抑制及其释放是一种调节机制，不依赖于亚细胞定位或DNA结合活性的变化，这些事件似乎也参与葡萄糖反应。这种进化上保守的机制可能在葡萄糖响应基因调控中发挥重要作用。
We report here a novel mechanism for glucose-mediated activation of carbohydrate response element binding protein (ChREBP), a basic helix-loop-helix/leucine zipper (bHLH/ZIP) transcription factor of Mondo family that binds to carbohydrate response element in the promoter of some glucose-regulated genes and activates their expression upon glucose stimulation. Structure-function analysis of ChREBP in a highly glucose-sensitive system using GAL4-ChREBP fusion constructs revealed a glucose-sensing module (GSM) that mediates glucose responsiveness of ChREBP. GSM is conserved among Mondo family members-, MondoA, a mammalian paralog of unknown function, and the GSM region of a Drosophila homolog were also found to be glucose responsive. GSM is composed of a low-glucose inhibitory domain (LID) and a glucose-response activation conserved element (GRACE). We have identified a new mechanism accounting for glucose responsiveness of ChREBP that involves specific inhibition of the transactivation activity of GRACE by LID under low glucose concentration and reversal of this inhibition by glucose in an orientation-sensitive manner. The intramolecular inhibition and its release by glucose is a regulatory mechanism that is independent of changes of subcellular localization or DNA binding activity, events that also appear to be involved in glucose responsiveness. This evolutionally conserved mechanism may play an essential role in glucose-responsive gene regulation.