Involvement of G proteins of the Rho family in the regulation of Bcl-2-like protein expression and caspase 3 activation by Gastrins
Involvement of G proteins of the Rho family in the regulation of Bcl-2-like protein expression and caspase 3 activation by Gastrins
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DOI：
10.1016/j.cellsig.2007.08.018
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发表时间：
2008-01-01
影响因子：
4.8
通讯作者：
Baldwin, Graham S.
中科院分区：
文献类型：
--
作者：
He, Hong;Yim, Mildred;Baldwin, Graham S.
已知胃泌素，包括酰胺化胃泌素（Gamide）和甘氨酸延伸的胃泌素（Ggly），通过刺激增殖和抑制凋亡来加速胃和结肠直肠癌细胞的生长。Gamide通过调节Bcl-2家族蛋白和通过调节半胱天冬酶的活化来控制细胞凋亡。然而，Ggly与Bcl-2家族蛋白和半胱天冬酶之间的相互作用尚不清楚。由于在其他系统中，Rho家族的G蛋白通过与Bcl-2家族的蛋白相互作用抑制细胞凋亡，导致半胱天冬酶活性的变化，我们比较了Rho家族G蛋白在调节Bcl-2样（Bad/Bax/Bcl-xl）蛋白表达和Ggly和Gamide激活半胱天冬酶3中的作用。在胃上皮细胞系IMGE-5中研究了特异性抑制剂C3（Rho）和Y-27632（ROCK）以及Rac、Cdc 42和PAK的显性阴性突变体的作用。通过血清饥饿诱导细胞凋亡，并通过膜联蛋白V染色和半胱天冬酶3激活来证实。Ggly通过Bcl-2样蛋白介导的途径抑制caspase 3的活化，该途径需要Rho/ROCK和Rac/Cdc 42/PAK的活化。Gamide通过冗余Bcl-2样蛋白介导的途径抑制caspase 3的激活，该途径涉及Rac/Cdc 42/PAK和Rho/ROCK的交替激活。Gamide和Ggly差异性地激活Rho家族G蛋白的成员，其进而调节Bcl-2家族的不同蛋白，导致半胱天冬酶3活性的变化。这些发现为阻断这些胃泌素的生长刺激作用提供了潜在的靶点。(C)2007爱思唯尔公司All rights reserved.
Gastrins, including amidated gastrin (Gamide) and glycine-extended gastrin (Ggly), are known to accelerate the growth of gastric and colorectal cancer cells by stimulation of proliferation and inhibition of apoptosis. Gamide controls apoptosis by regulation of proteins of the Bcl-2 family and by regulation of the activation of caspases. However the interactions between Ggly and proteins of the Bcl-2 family and caspases are not known. Since in other systems G proteins of the Rho family inhibit apoptosis via interaction with proteins of the Bcl-2 family, leading to changes in caspase activities, we have compared the role of Rho family G proteins in regulation of Bcl-2-like (Bad/Bax/Bcl-xl) protein expression and caspase 3 activation by Ggly and Gamide. The effects of the specific inhibitors C3 (for Rho) and Y-27632 (for ROCK), and of dominant negative mutants of Rac, Cdc42 and PAK, were investigated in the gastric epithelial cell line IMGE-5. Apoptosis was induced by serum starvation and confirmed by annexin V staining and caspase 3 activation. Ggly inhibits caspase 3 activation via a Bcl-2-like protein-mediated pathway which requires activation of both Rho/ROCK and Rac/Cdc42/PAK. Gamide inhibits caspase 3 activation via redundant Bcl-2-like protein-mediated pathways which involve alternative activation of Rac/Cdc42/PAK and Rho/ROCK. Gamide and Ggly differentially activate members of Rho family G proteins which in turn regulate different proteins of the Bcl-2 family leading to changes in caspase 3 activity. The findings offer potential targets for blocking the growth-stimulating effects of these gastrins. (C) 2007 Elsevier Inc. All rights reserved.