Jnk2 deletion disrupts intestinal mucosal homeostasis and maturation by differentially modulating RNA-binding proteins HuR and CUGBP1
Jnk2 deletion disrupts intestinal mucosal homeostasis and maturation by differentially modulating RNA-binding proteins HuR and CUGBP1
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DOI：
10.1152/ajpcell.00093.2014
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发表时间：
2014-06-15
影响因子：
5.5
通讯作者：
Wang, Jian-Ying
中科院分区：
文献类型：
--
作者：
Chung, Hee Kyoung;Rao, Jaladanki N.;Wang, Jian-Ying
哺乳动物肠上皮的稳态和成熟通过严格调节细胞增殖、凋亡和分化来保持，但这一过程的确切机制在很大程度上仍然未知。c-Jun氨基末端激酶2（JNK 2）在肠粘膜中高度表达，其活化在培养的肠上皮细胞（IEC）的增殖中起重要作用，并且还介导凋亡。在这里，我们研究了JNK 2在体内功能的调节肠上皮稳态和成熟，通过使用靶向基因删除的方法。靶向删除jnk 2基因增加了小肠隐窝内的细胞增殖，并破坏了粘膜成熟，如绒毛高度和绒毛与隐窝比率的降低所示。JNK 2缺失也降低了肠上皮细胞对凋亡的敏感性。JNK 2缺陷的肠上皮细胞与RNA结合蛋白HuR水平的增加和CUG结合蛋白1（CUGBP 1）丰度的减少相关。在体外研究中，JNK 2沉默可保护肠上皮细胞-6（IEC-6）细胞免受凋亡，而这种保护作用可通过抑制HuR来阻止。异位过表达CUGBP 1抑制IEC-6细胞增殖，而CUGBP 1沉默促进细胞生长。这些结果表明，JNK 2是必不可少的维持正常的肠上皮稳态和成熟的生物条件下，通过差异调节HuR和CUGBP 1。
Homeostasis and maturation of the mammalian intestinal epithelium are preserved through strict regulation of cell proliferation, apoptosis, and differentiation, but the exact mechanism underlying this process remains largely unknown. c-Jun NH2-terminal kinase 2 (JNK2) is highly expressed in the intestinal mucosa, and its activation plays an important role in proliferation and also mediates apoptosis in cultured intestinal epithelial cells (IECs). Here, we investigated the in vivo function of JNK2 in the regulation of intestinal epithelial homeostasis and maturation by using a targeted gene deletion approach. Targeted deletion of the jnk2 gene increased cell proliferation within the crypts in the small intestine and disrupted mucosal maturation as indicated by decreases in the height of villi and the villus-to-crypt ratio. JNK2 deletion also decreased susceptibility of the intestinal epithelium to apoptosis. JNK2-deficient intestinal epithelium was associated with an increase in the level of the RNA-binding protein HuR and with a decrease in the abundance of CUG-binding protein 1 (CUGBP1). In studies in vitro, JNK2 silencing protected intestinal epithelial cell-6 (IEC-6) cells against apoptosis and this protection was prevented by inhibiting HuR. Ectopic overexpression of CUGBP1 repressed IEC-6 cell proliferation, whereas CUGBP1 silencing enhanced cell growth. These results indicate that JNK2 is essential for maintenance of normal intestinal epithelial homeostasis and maturation under biological conditions by differentially modulating HuR and CUGBP1.