Gastrin and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase promoter through raf-dependent activation of extracellular signal-regulated kinase-related signaling pathways in gastric cancer cells
Gastrin and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase promoter through raf-dependent activation of extracellular signal-regulated kinase-related signaling pathways in gastric cancer cells
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DOI：
10.1074/jbc.272.43.27015
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发表时间：
1997-10-24
影响因子：
4.8
通讯作者：
Wang, TC
中科院分区：
文献类型：
--
作者：
Hocker, M;Henihan, RJ;Wang, TC
胃泌素通过与G蛋白偶联的胆囊收缩素-B/胃泌素受体结合刺激人组氨酸脱羧酶（HDC）基因的转录。我们已经探讨了有丝分裂原活化蛋白激酶级联在胃癌（AGS-B）细胞系中介导胃泌素对转录的影响中发挥作用的可能性。胃泌素和佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）处理AGS-B细胞被发现增加细胞外信号调节激酶（ERK）1和2的酪氨酸残基的磷酸化，并增加ERK活性，如髓磷脂碱性蛋白的体外磷酸化所确定的。报告基因分析也表明，胃泌素和PMA刺激Elk-1和c-Myc依赖的反式激活，与胃泌素和PMA诱导的ERK激活一致。野生型ERK-1和ERK-2的过表达或使用活化的MEK-1（促分裂原活化蛋白激酶激酶或ERK激酶）过表达的内源性ERK的活化以剂量依赖性方式刺激HDC启动子活性。使用激酶缺陷型ERK或ERK特异性磷酸酶（PAC-1）的表达载体阻断ERK相关途径阻断胃泌素和PMA刺激的HDC启动子活性。相比之下，使用干扰显性负性SEK-1（应激活化蛋白激酶/ERK-1）突变体抑制Jun激酶途径不会抑制HDC启动子活性。此外，而胃泌素刺激磷酸化的She蛋白和协会Grb 2，激活的HDC启动子不受显性负Ras（N15或N17）蛋白的表达。然而，胃泌素刺激Raf-1激酶的活性，和激活的HDC启动子被阻断的显性负Raf-1构建体的共表达。总之，这些数据表明，胃泌素调节HDC转录的Raf-dependent，Ras-独立的方式主要通过激活ERK相关的途径。
Gastrin stimulates transcription of the human histidine decarboxylase (HDC) gene through binding to the G-protein-coupled cholecystokinin-B/gastrin receptor. We have explored the possibility that mitogen-activated protein kinase cascades play a role in mediating the effects of gastrin on transcription in a gastric cancer (AGS-B) cell line. Gastrin and phorbol 12-myristate 13-acetate (PMA) treatment of AGS-B cells was found to increase the phosphorylation of tyrosine residues of extracellular signal-regulated kinases (ERKs) 1 and 2 and increase ERK activity as determined by the in vitro phosphorylation of myelin basic protein. Reporter gene assays also demonstrated that gastrin and PMA stimulated Elk-1- and c-Myc-dependent transactivation, consistent with gastrin and PMA-induced activation of ERKs. Overexpression of wild type ERK-1 and ERK-2 or activation of endogenous ERKs using activated MEK-1 (mitogen-activated protein kinase kinase or ERK kinase) overexpression stimulated HDC promoter activity in a dose-dependent fashion. Interruption of the ERK-related pathway using expression vectors for kinase-deficient ERKs or an ERK-specific phosphatase (PAC-1) blocked gastrin and PMA-stimulated HDC promoter activity. In contrast, inhibition of the Jun kinase pathway using an interfering dominant negative SEK-1 (stress-activated protein kinase/ERK-1) mutant did not inhibit HDC promoter activity. Furthermore, whereas gastrin stimulated phosphorylation of She proteins and association with Grb2, activation of the HDC promoter was not influenced by expression of dominant negative Ras (N15 or N17) proteins. However, gastrin stimulated Raf-1 kinase activity, and activation of the HDC promoter was blocked by coexpression of a dominant negative Raf-1 construct. Overall, these data demonstrate that gastrin regulates HDC transcription in a Raf-dependent, Ras-independent fashion predominantly through activation of the ERK-related pathway.