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A Reporter Assay to Analyze Intronic microRNA Maturation in Mammalian Cells
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ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5
Hui-Lung Sun1, Ri Cui2, JianKang Zhou3
1Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH 43210, USA; Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.
Abstract:
MicroRNAs (miRNA) are mostly downregulated in cancer. However, the mechanism underlying this phenomenon and the precise consequence in tumorigenesis remain obscure. Here we show that ERK suppresses pre-miRNA export from the nucleus through phosphorylation of exportin-5 (XPO5) at T345/S416/S497. After phosphorylation by ERK, conformation of XPO5 is altered by prolyl isomerase Pin1, resulting in reduction of pre-miRNA loading. In liver cancer, the ERK-mediated XPO5 suppression reduces miR-122, increases microtubule dynamics, and results in tumor development and drug resistance. Analysis of clinical specimens further showed that XPO5 phosphorylation is associated with poor prognosis for liver cancer patients. Our study reveals a function of ERK in miRNA biogenesis and suggests that modulation of miRNA export has potential clinical implications.
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