Epidermal growth factor receptor signaling modulates apoptosis via p38α MAPK-dependent activation of Bax in intestinal epithelial cells
Epidermal growth factor receptor signaling modulates apoptosis via p38α MAPK-dependent activation of Bax in intestinal epithelial cells
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DOI：
10.1152/ajpgi.00182.2007
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发表时间：
2007-09-01
影响因子：
4.5
通讯作者：
Warner, Brad W.
中科院分区：
文献类型：
--
作者：
Sheng, George;Guo, Jun;Warner, Brad W.
先前的研究已经证明，促凋亡蛋白Bax在大量小肠切除术（SBR）的肠道适应性反应期间发生的肠细胞凋亡升高中起重要作用。此外，表皮生长因子受体（EGFR）的激活防止SBR诱导的肠上皮细胞凋亡。本研究旨在阐明EGFR活性与肠上皮细胞凋亡的关系。用选择性EGFR抑制剂（ZD 1839）和EGFR小干扰RNA敲低治疗模型肠上皮细胞（RIEC-18）导致凋亡急剧增加，伴随着p38 α的快速磷酸化。与此同时，Bax经历了与激活一致的构象变化并移位到线粒体。相反，EGF刺激通过减弱p38 α磷酸化、Bax构象变化、线粒体运输和凋亡来增强细胞存活。这些结果表明，EGFR活性的降低通过肠上皮细胞中p38 α依赖性Bax激活启动了细胞凋亡的内在途径。这些发现为EGFR信号传导在大量肠损失后肠上皮细胞凋亡的调节中所起的作用提供了机制性见解。
Previous studies have demonstrated that the proapoptotic protein Bax plays an important role in the elevated enterocyte apoptosis that occurs during the intestinal adaptation response to massive small bowel resection ( SBR). Additionally, epidermal growth factor receptor ( EGFR) activation prevents SBRinduced enterocyte apoptosis. The present study aims to delineate the relationship between EGFR activity and intestinal epithelial cell apoptosis. Treatment of model intestinal epithelial cells ( RIEC-18) with both a selective EGFR inhibitor ( ZD1839) and EGFR small interfering RNA knockdown resulted in a dramatic increase in apoptosis, accompanied by rapid phosphorylation of p38 alpha. Concurrently, Bax underwent conformational changes consistent with activation and translocated to mitochondria. In contrast, EGF stimulation enhanced cell survival by attenuating p38 alpha phosphorylation, Bax conformational change, mitochondrial trafficking, and apoptosis. These results demonstrate that that diminished EGFR activity initiates the intrinsic pathway of apoptosis through p38 alpha-dependent Bax activation in intestinal epithelial cells. These finding provide mechanistic insight into the role that EGFR signaling plays in the regulation of enterocyte apoptosis following massive intestinal loss.