全反式维甲酸通过抑制ERK和激活p38 MAPK信号诱导KLF4基因表达  

ATRA Induces KLF4 Expression via Inhibiting ERK Signaling and Activating p38 MAPK Signaling

作　　者：马国燕[1] 史建红[1] 郑斌[1] 陈斯[1] 温进坤[1] 

机构地区：[1]河北医科大学生物化学与分子生物学研究室,石家庄050017

出　　处：《中国生物化学与分子生物学报》2011年第11期1025-1031,共7页Chinese Journal of Biochemistry and Molecular Biology

基　　金：河北省自然科学基金资助(No.C2009001541)项目~~

摘　　要：全反式维甲酸(all-trans retinoic acid,ATRA)诱导细胞分化与上调转录因子Krüppel样因子4(KLF4)表达有关,但目前对ATRA诱导KLF4表达的分子机制尚不清楚.为了研究ATRA在血管平滑肌细胞(VSMC)中诱导KLF4表达的分子机制,本研究观察ATRA对视黄酸受体α(retinoicacid receptorα,RARα)和KLF4表达的影响及RARα介导ATRA诱导KLF4表达所依赖的信号转导途径.实验结果显示,ATRA可显著诱导RARα和KLF4表达,用RARα拮抗剂Ro 41-5253阻断ATRA与受体相互作用后,ATRA诱导的KLF4表达受到显著抑制.用p38 MAPK、ERK和Akt抑制剂阻断ATRA与RARα相互作用所激活的信号转导途径后,发现阻断p38 MAPK信号途径显著抑制ATRA诱导的KLF4表达,抑制ERK信号途径使ATRA对KLF4表达的诱导作用明显增强,抑制Akt信号途径不影响KLF4基因表达.表明RARα介导ATRA对KLF4表达的诱导作用,ATRA通过抑制ERK和激活p38 MAPK信号途径发挥其对KLF4基因表达的诱导作用.The Krüppel-like factor 4（KLF4） expression is induced by all-trans retinoic acid（ATRA） and involved in cell differentiation,but the underlining molecular mechanism has not been well characterized.Using vascular smooth muscle cell（VSMC） as the model,we investigated the effect of ATRA on retinoic acid receptor α（RARα） and KLF4 expression and the signal pathways involving ATRA and the activation of RARα.The results showed that ATRA significantly induces the expression of RARα and KLF4.When VSMCs were treated with RARα inhibitor Ro 41-5253 to block the interaction of ATRA with its receptor,ATRA-induced KLF4 expression was abrogated.Furthermore,ERK and p38 activated MAPK signaling appeared to be responsible for ATRA/RARα-mediated KLF4 expression as demonstrated by pretreating VSMCs with different pharmacological inhibitors.

关 键 词：Krüppel样因子4(KLF4) 视黄酸受体α(RARα) 全反式维甲酸 血管平滑肌细胞 信号通路 

分 类 号：Q78[生物学—分子生物学]