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Sci. Signal., 12 March 2013
Vol. 6, Issue 266, p. ra16
[DOI: 10.1126/scisignal.2003706]

RESEARCH ARTICLES

Signaling by p38 MAPK Stimulates Nuclear Localization of the Microprocessor Component p68 for Processing of Selected Primary MicroRNAs

Sungguan Hong1*, Hyangsoon Noh1*, Haoming Chen2, Ravi Padia1, Zhixing K. Pan3, Shi-Bing Su4, Qing Jing5, Han-Fei Ding6,7, and Shuang Huang1,4,7{dagger}

1 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
2 State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, Institute of Genetics, College of Life Science, Fudan University, Shanghai 200433, China.
3 Department of Immunology and Medical Microbiology, University of Toledo Health Science Center, Toledo, OH 43606, USA.
4 Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
5 Changhai Hospital, Shanghai 200433, China.
6 Department of Pathology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
7 Cancer Center, Georgia Health Sciences University, Augusta, GA 30912, USA.

* These authors contributed equally to this work.

Abstract: The importance of microRNAs (miRNAs) in biological and disease processes necessitates a better understanding of the mechanisms that regulate miRNA abundance. We showed that the activities of the mitogen-activated protein kinase (MAPK) p38 and its downstream effector kinase MAPK-activated protein kinase 2 (MK2) were necessary for the efficient processing of a subset of primary miRNAs (pri-miRNAs). Through yeast two-hybrid screening, we identified p68 (also known as DDX5), a key component of the Drosha complex that processes pri-miRNAs, as an MK2-interacting protein, and we found that MK2 phosphorylated p68 at Ser197 in cells. In wild-type mouse embryonic fibroblasts (MEFs) treated with a p38 inhibitor or in MK2-deficient (MK2–/–) MEFs, expression of a phosphomimetic mutant p68 fully restored pri-miRNA processing, suggesting that MK2-mediated phosphorylation of p68 was essential for this process. We found that, whereas p68 was present in the nuclei of wild-type MEFs, it was found mostly in the cytoplasm of MK2–/– MEFs. Nuclear localization of p68 depended on MK2-mediated phosphorylation of Ser197. In addition, inhibition of p38 MAPK promoted the growth of wild-type MEFs and breast cancer MCF7 cells by enhancing the abundance of c-Myc through suppression of the biogenesis of the miRNA miR-145, which targets c-Myc. Because pri-miRNA processing occurs in the nucleus, our findings suggest that the p38 MAPK–MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear localization of p68.

{dagger} Corresponding author. E-mail: shuang{at}gru.edu

Citation: S. Hong, H. Noh, H. Chen, R. Padia, Z. K. Pan, S.-B. Su, Q. Jing, H.-F. Ding, S. Huang, Signaling by p38 MAPK Stimulates Nuclear Localization of the Microprocessor Component p68 for Processing of Selected Primary MicroRNAs. Sci. Signal. 6, ra16 (2013).

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