Helicobacter pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3beta phosphorylation.
Helicobacter pylori activate epidermal growth factor receptor- and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3beta phosphorylation.
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DOI：
10.1111/j.1462-5822.2008.01237.x
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发表时间：
2009-01
影响因子：
3.4
通讯作者：
Yamaoka Y
中科院分区：
文献类型：
--
作者：
Tabassam FH;Graham DY;Yamaoka Y
导致幽门螺杆菌诱导的胃癌发生的信号通路仍然知之甚少。我们检验了幽门螺杆菌感染与人胃上皮癌细胞Akt信号激活有关的假设。免疫印迹、免疫荧光和激酶分析表明，幽门螺杆菌感染胃上皮细胞可诱导Akt在Ser473和Thr308位发生磷酸化。幽门螺杆菌毒力因子OIPA突变显著降低Ser473的磷酸化，而CAG致病岛突变主要抑制Thr308的磷酸化。幽门螺杆菌感染作为Akt激活的下游，通过其磷酸化作用使糖原合成酶K3β在Ser9失活。幽门螺杆菌感染作为Akt激活的上游，在Tyr 992处激活了表皮生长因子受体(EGFR)，在Ser241处激活了磷脂酰肌醇3-羟基激酶(PI3K)P85亚基和PI3K依赖的K1。药物抑制剂PI3K或丝裂原活化蛋白激酶、Akt基因敲除和EGFR基因敲除表明，Hp感染可诱导EGFR→、PI3K→、PI3K依赖的激酶1、→Akt→细胞外信号调节激酶信号通路的激活、糖原合成酶3β的失活和白介素8的产生。CAG致病岛和OIPA的联合作用是充分激活各个水平信号的必要条件和充分条件。我们认为激活这些通路是幽门螺杆菌介导的致癌的一种新机制。
The signalling pathways leading to the development of Helicobacter pylori-induced gastric cancer remain poorly understood. We tested the hypothesis that H. pylori infections involve the activation of Akt signalling in human gastric epithelial cancer cells. Immunoblot, immunofluorescence and kinase assays show that H. pylori infection of gastric epithelial cells induced phosphorylation of Akt at Ser 473 and Thr 308. Mutations in the H. pylori virulence factor OipA dramatically reduced phosphorylation of Ser 473, while the cag pathogenicity island mutants predominantly inhibited phosphorylation of Thr 308. As the downstream of Akt activation, H. pylori infection inactivated the inactivation of glycogen synthase kinase 3β at Ser 9 by its phosphorylation. As the upstream of Akt activation, H. pylori infection activated epidermal growth factor receptor (EGFR) at Tyr 992, phosphatidylinositol 3-OH kinase (PI3K) p85 subunit and PI3K-dependent kinase 1 at Ser 241. Pharmacologic inhibitors of PI3K or mitogen-activated protein kinase kinase (MEK), Akt knock-down and EGFR knock-down showed that H. pylori infection induced the activation of EGFR→PI3K→PI3K-dependent kinase 1→Akt→extracellular signal-regulated kinase signalling pathways, the inactivation of glycogen synthase kinase 3β and interleukin-8 production. The combined functions of cag pathogenicity island and OipA were necessary and sufficient for full activation of signalling at each level. We propose activation of these pathways as a novel mechanism for H. pylori-mediated carcinogenesis.
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影响因子：
4.8
作者：
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