| セッション情報 |
The 4th International Forum
I Drug-associated GI Injury：Advances of the pathogenesis and recent clinical topics 1. Advances of the pathogenesis（a）Mucosal injury and prostaglandins
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| タイトル |
IFI-1a-1：RNA-binding protein HuR and microRNAs in gut epithelial homeostasis and diseases
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| 演者 |
Wang Jian-Ying（Cell Biology Group, Departments of Surgery and Pathology, University of Maryland and BVAMC, USA） |
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| 抄録 |
The intestinal epithelium is a rapidly self-renewing tissue in the body and its homeostasis is preserved through strict regulation of cell proliferation, apoptosis, and differentiation. Emerging data indicate that RNA-binding proteins（RBPs）and microRNAs（miRNAs）play key roles in fundamental cellular processes. The RBP HuR is highly expressed in gut mucosa and modulates the stability and translation of target mRNAs. We investigated the role of HuR in intestinal homeostasis using a genetic model and further defined its target mRNAs. Targeted deletion of HuR in intestinal epithelial cells（IECs）caused mucosal atrophy in the small intestine as indicated by decreased cell proliferation within the crypts and subsequent shrinkages of crypts and villi. The HuR-deficient intestinal epithelium also displayed a decreased expression of the Wnt co-receptor LDL receptor-related protein 6（LRP6）. At the molecular level, HuR was found to bind the Lrp6 mRNA via its 3’-untranslated region and enhanced LRP6 expression by stabilizing Lrp6 mRNA and stimulating its translation. These results indicate that HuR is essential for intestinal mucosal growth by activating Wnt signaling pathway through up-regulation of LRP6 expression. In a separate study, we demonstrated that mucosal growth inhibition and delayed mucosal repair were associated with an increase in expression of several miRNAs including miR-29b, miR-222 and miR-195. miRNA-29b silencing by the systemic delivery of LNA-antimiR-29b not only increased CDK2 but also stimulated small intestinal mucosal growth in mice. Increased levels of miRNA-29b in IEC-6 cells repressed CDK2 expression and caused growth arrest in G1 phase. miR-29b repressed CDK2 translation through direct interaction with the CDK2 mRNA, and point mutation of miR-29b binding-site on the 3’-untranslated region of the CDK2 mRNA prevented miR-29b-induced repression of CDK2 translation. These results indicate that control of HuR and miRNAs such as miRNA-29b are crucial for maintenance of the intestinal epithelial integrity and homeostasis by modulating intestinal mucosal growth and repair after injury. |
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