The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation
The trefoil gene family are coordinately expressed immediate-early genes: EGF receptor- and MAP kinase-dependent interregulation
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DOI：
10.1172/jci3304
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发表时间：
1999-05-01
影响因子：
15.9
通讯作者：
Podolsky, DK
中科院分区：
文献类型：
--
作者：
Taupin, D;Wu, DC;Podolsky, DK
粘液细胞分泌蛋白的三叶基因家族是胃肠道粘膜恢复的关键介质。三叶基因的转录在粘膜修复过程中被诱导，但涉及的调控机制尚不清楚。小鼠在大肠杆菌特异性肽肠三叶因子（ITF），其中结肠的恢复是致命的损害缺陷，表现出减少表达的胃三叶基因SP和pS2，表明三叶肽可以单独调节整个家族的转录。在胃细胞系中，三叶形被证明以一种暗示能够通过顺式作用调节区进行自动和交叉诱导的立即早期基因的方式起作用。三叶草介导的转录调节需要激活Ras/MEK/MAP激酶信号转导通路。EGF受体（EGF-R）的激活也是三叶草自身和交叉诱导所必需的，并且痉挛多肽（SP）和ITF刺激胃细胞系导致EGF-R磷酸化。然而，ITF和ITF-硫氧还蛋白细胞表面结合在4摄氏度共定位不与EGF-R，但与CD 71，这是发现在网格蛋白包被的坑，这表明三叶肽反应的整合可能发生在内化后。由于EGF-R表达本身在粘膜损伤后被强烈诱导，三叶草/EGF-R关系可能在粘膜修复表型的产生和维持中起关键作用。
The trefoil gene family of mucus cell-secreted proteins is a critical mediator of gastrointestinal mucosal restitution. Transcription of trefoil genes is induced during mucosal repair, but the regulatory mechanisms involved are unknown. Mice deficient in the intestine-specific peptide intestinal trefoil factor (ITF), in which colonic restitution is lethally impaired, showed reduced expression of the gastric trefoil genes SP and pS2, suggesting that trefoil peptides may individually regulate transcription of the entire family. In gastric cell lines, the trefoils were shown to act in a manner suggestive of immediate-early genes capable of auto- and cross-induction through cis-acting regulatory regions. Trefoil-mediated transcriptional regulation required activation of the Ras/MEK/MAP kinase signal transduction pathway. EGF receptor (EGF-R) activation was also necessary for trefoil auto- and cross-induction, and both spasmolytic polypeptide (SP) and ITF stimulation of gastric cell lines led to phosphorylation of EGF-R. Nevertheless, ITF and ITF-thioredoxin cell surface binding at 4 degrees C colocalized not with EGF-R, but with CD71, which is found in clathrin-coated pits, suggesting that integration of trefoil peptide responses may occur after internalization. As EGF-R expression is itself strongly induced after mucosal damage, the trefoil/EGF-R relationship may be pivotal in the generation and maintenance of the mucosal repair phenotype.