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ERK Activation Globally Downregulates miRNAs through Phosphorylating Exportin-5.

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.
AuthorsHui-Lung Sun, Ri Cui, JianKang Zhou, Kun-Yu Teng, Yung-Hsuan Hsiao, Kotaro Nakanishi, Matteo Fassan, Zhenghua Luo, Guqin Shi, Esmerina Tili, Huban Kutay, Francesca Lovat, Caterina Vicentini, Han-Li Huang, Shih-Wei Wang, Taewan Kim, Nicola Zanesi, Young-Jun Jeon, Tae Jin Lee, Jih-Hwa Guh, Mien-Chie Hung, Kalpana Ghoshal, Che-Ming Teng, Yong Peng, Carlo M Croce
JournalCancer cell (Cancer Cell) Vol. 30 Issue 5 Pg. 723-736 (Nov 14 2016) ISSN: 1878-3686 [Electronic] United States
PMID27846390 (Publication Type: Journal Article)
CopyrightCopyright © 2016 Elsevier Inc. All rights reserved.
Chemical References
  • Karyopherins
  • MIRN122 microRNA, human
  • MicroRNAs
  • NIMA-Interacting Peptidylprolyl Isomerase
  • XPO5 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • PIN1 protein, human
Topics
  • Carcinoma, Hepatocellular (genetics, metabolism, pathology)
  • Down-Regulation
  • Drug Resistance, Neoplasm
  • Extracellular Signal-Regulated MAP Kinases (metabolism)
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Karyopherins (chemistry, metabolism)
  • Liver Neoplasms (genetics, metabolism, pathology)
  • MicroRNAs (genetics)
  • NIMA-Interacting Peptidylprolyl Isomerase (metabolism)
  • Phosphorylation
  • Prognosis
  • Protein Conformation

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