Gastrin transactivates the chromogranin A gene through MEK-1/ERK- and PKC-dependent phosphorylation of Sp1 and CREB

被引：27

作者：

Cramer, Thorsten ^{[1
,2
]}

Juettner, Stefan ^{[1
]}

Plath, Thomas ^{[2
]}

Mergler, Stefan ^{[2
]}

Seufferlein, Thomas ^{[3
]}

Wang, Timothy C. ^{[4
]}

Merchant, Juanita ^{[5
,6
]}

Hoecker, Michael ^{[1
]}

机构：

[1] Charite Univ Med Berlin, Lab Angiogenesis & Tumor Metastasis, Berlin, Germany

[2] Charite Univ Med Berlin, Med Klin Schwerpunkt Hepatol & Gastroenterol, Berlin, Germany

[3] Univ Ulm Klinikum, Med Klin 1, Ulm, Germany

[4] UMass Mem Med Ctr, Div Digest Dis & Nutr, Worcester, MA USA

[5] Univ Michigan, Dept Med, Ann Arbor, MI 48109 USA

[6] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA

来源：

CELLULAR SIGNALLING | 2008年 / 20卷 / 01期

关键词：

chromogranin A; signal transduction; MEK-1; extracellular-regulated kinases; Sp1; CREB;

D O I：

10.1016/j.cellsig.2007.08.016

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

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.

引用

页码：60 / 72

页数：13

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