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首页> 外文期刊>Cellular Signalling >Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKC-dependent phosphorylation of Sp1 and CREB
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Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKC-dependent phosphorylation of Sp1 and CREB

机译：胃泌素通过MEK-1 / ERK和PKC依赖的Sp1和CREB的磷酸化反导嗜铬粒蛋白A基因

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摘要

Our previous work revealed that gastrin regulates chromogranin A (CgA) transcription through enhanced binding of Sp1, CREB and Egr-1 to a proximal gastrin-responsive promoter element (Gas-RE). Here, we provide a detailed characterization of the signalling pathways transmitting the effect of gastrin on the CgA promoter. Gastrin treatment of gastric AGS-B cells potently stimulated MEK-1 as well as MAP kinases ERK-1/-2, INK and p38 in a time-dependent manner. Interruption of ERK-1/-2/MEK-1 pathways abolished the transactivating effect of gastrin, whereas blockade of JNK or p38 activity was without effect. Functional promoter analysis revealed that the minimal element CgA-85/-64 was sufficient and necessary to confer MEK-1/ERK responsiveness. Analysis of proximal signalling pathways showed that activation of the MEK-1/ERK-1/2 module by gastrin does not require Ras, PI3-kinase or intracellular calcium signals, but depends on activation of kinases of the PKC family. This report demonstrates that a pathway comprising PKCs > Raf-1 > MEK-1 > ERK-1/-2 mediates the effect of gastrin on the CgA promoter, and strongly suggests that enhanced phosphorylation of Sp1 and CREB is crucial for CgA transactivation through the G protein-coupled CCK-B/gastrin receptor. (C) 2007 Elsevier Inc. All rights reserved.
机译：我们以前的工作表明胃泌素通过增强Sp1，CREB和Egr-1与近端胃泌素反应性启动子元件（Gas-RE）的结合来调节嗜铬粒蛋白A（CgA）转录。在这里，我们提供了传递胃泌素对CgA启动子的影响的信号通路的详细表征。胃泌素治疗胃AGS-B细胞以时间依赖性方式有效刺激MEK-1以及MAP激酶ERK-1 / -2，INK和p38。 ERK-1 / -2 / MEK-1途径的中断取消了胃泌素的反式激活作用，而阻断JNK或p38活性则无效。功能启动子分析表明，最小元素CgA-85 / -64足以赋予MEK-1 / ERK反应性。对近端信号通路的分析表明，胃泌素激活MEK-1 / ERK-1 / 2模块不需要Ras，PI3激酶或细胞内钙信号，但取决于PKC家族激酶的激活。该报告表明，包含PKC> Raf-1> MEK-1> ERK-1 / -2的途径介导了胃泌素对CgA启动子的作用，并强烈暗示Sp1和CREB的增强磷酸化对于通过CgA的CgA反式激活至关重要。 G蛋白偶联的CCK-B /胃泌素受体。 （C）2007 Elsevier Inc.保留所有权利。

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