title: Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary microRNAs.
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 Ser(197) 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 Ser(197). 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA. shuang@gru.edu
authors.forename: Sungguan
authors.initials: S
authors.lastname: Hong
authors.forename: Hyangsoon
authors.initials: H
authors.lastname: Noh
authors.forename: Haoming
authors.initials: H
authors.lastname: Chen
authors.forename: Ravi
authors.initials: R
authors.lastname: Padia
authors.forename: Zhixing K
authors.initials: ZK
authors.lastname: Pan
authors.forename: Shi-Bing
authors.initials: SB
authors.lastname: Su
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.forename: Han-Fei
authors.initials: HF
authors.lastname: Ding
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D010766:Phosphorylation; D012323:RNA Processing, Post-Transcriptional; D015398:Signal Transduction; D013379:Substrate Specificity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; D048051:p38 Mitogen-Activated Protein Kinases