A novel role for villin in intestinal epithelial cell survival and homeostasis
A novel role for villin in intestinal epithelial cell survival and homeostasis
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DOI：
10.1074/jbc.m707962200
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发表时间：
2008-04-04
影响因子：
4.8
通讯作者：
Khurana, Seema
中科院分区：
文献类型：
--
作者：
Wang, Yaohong;Srinivasan, Kamalakkannan;Khurana, Seema
细胞凋亡是肠粘膜正常更新的关键调节因子，与此功能相关的异常与炎症性肠病和结直肠癌有关。尽管如此，对肠上皮细胞凋亡的介导机制知之甚少。绒毛蛋白是一种肌动蛋白调节蛋白，其在肠上皮的每个细胞以及与胃肠道相关的外分泌腺中表达。在这项研究中，我们首次证明绒毛蛋白是一种上皮细胞特异性抗凋亡蛋白。绒毛蛋白缺乏通过促进细胞凋亡使小鼠易患葡聚糖硫酸钠诱导的结肠炎。为了更好地理解绒毛蛋白抗凋亡功能的细胞和分子机制，我们在Madin-Darby犬肾Tet-Off上皮细胞系中过表达绒毛蛋白，以证明绒毛蛋白的表达通过维持线粒体完整性从而抑制caspase-9和caspase-3的活化来保护细胞免于凋亡。此外，我们报告说，绒毛蛋白的抗凋亡反应依赖于激活的促生存蛋白，磷脂酰肌醇3-激酶和磷酸化Akt。我们的研究结果为以前未被认识到的绒毛蛋白在胃肠道上皮细胞凋亡调节中的功能提供了新的线索。
Apoptosis is a key regulator for the normal turnover of the intestinal mucosa, and abnormalities associated with this function have been linked to inflammatory bowel disease and colorectal cancer. Despite this, little is known about the mechanism (s) mediating intestinal epithelial cell apoptosis. Villin is an actin regulatory protein that is expressed in every cell of the intestinal epithelium as well as in exocrine glands associated with the gastrointestinal tract. In this study we demonstrate for the first time that villin is an epithelial cell-specific anti-apoptotic protein. Absence of villin predisposes mice to dextran sodium sulfate-induced colitis by promoting apoptosis. To better understand the cellular and molecular mechanisms of the anti-apoptotic function of villin, we overexpressed villin in the Madin-Darby canine kidney Tet-Off epithelial cell line to demonstrate that expression of villin protects cells from apoptosis by maintaining mitochondrial integrity thus inhibiting the activation of caspase-9 and caspase-3. Furthermore, we report that the anti-apoptotic response of villin depends on activation of the pro-survival proteins, phosphatidylinositol 3-kinase and phosphorylated Akt. The results of our studies shed new light on the previously unrecognized function of villin in the regulation of apoptosis in the gastrointestinal epithelium.