@article{20cf4f2df7a84dc085021b762374285e,
title = "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.",
keywords = "ERK, Exportin-5, Pin1, drug resistance, global downregulation, liver cancer, miR-122, miRNA, microtubule, nuclear export",
author = "Sun, {Hui Lung} and Ri Cui and Zhou, {Jian Kang} and Teng, {Kun yu} and Hsiao, {Yung Hsuan} and Kotaro Nakanishi and Matteo Fassan and Zhenghua Luo and Guqin Shi and Esmerina Tili and Huban Kutay and Francesca Lovat and Caterina Vicentini and Huang, {Han Li} and Wang, {Shih Wei} and Taewan Kim and Nicola Zanesi and Jeon, {Young Jun} and Lee, {Tae Jin} and Guh, {Jih Hwa} and Hung, {Mien Chie} and Kalpana Ghoshal and Teng, {Che Ming} and Yong Peng and Croce, {Carlo M.}",
note = "Funding Information: We thank the Ohio State University Comprehensive Cancer Center microscopy, genomics, nucleic acids, flow cytometry, mass spectrometry, and comparative pathology core facility. We thank Dr. M.-C. Hung, J. Dahlberg, P. Sarnow, A. Deiters, Y. Zheng, C.-S. Chen, and T. Williams for providing reagents; Dr. K. Huebner, W.-L. Shih, and T. Banh for editing; Dr. P. Fadda for NanoString profiling technical support; Dr. S. Palko and Dr. D. Wernicke-Jameson for administrative support. This study was supported by the US NIH (R35CA197706 to C.-M.C.; R01CA193244 to K.G.); Taiwan Ministry of Science and Technology (NSC99-2320-B400-008-MY3 and NSC 99-2628-B002-024-MY3 to C.-M.T.; 101-2917-I-564-052 to H.-L.S.; MOST 105-2632-B-715-001 and MOST 104-2320-B-715-002 to S.-W.W.); Pelotonia Graduate Student Fellowship (to K.-Y.T.); National Key Research & Development Program of China (2016YFA0502204) and National Natural Science Foundation of China (81572739) to (Y.P.); American Cancer Society (IRG-67-003-50) to E.T. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = nov,
day = "14",
doi = "10.1016/j.ccell.2016.10.001",
language = "English",
volume = "30",
pages = "723--736",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}