Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary MicroRNAs

Sungguan Hong, Hyangsoon Noh, Haoming Chen, Ravi Padia, Zhixing K. Pan, Shi Bing Su, Qing Jing, Han Fei Ding, Shuang Huang

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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 kinaseMAPK-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 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-miRNAprocessing occurs in the nucleus, our findings suggest that the p38 MAPK-MK2 signaling pathway promotes miRNA biogenesis by facilitating the nuclear localization of p68.

Original languageEnglish (US)
JournalScience Signaling
Volume6
Issue number266
DOIs
StatePublished - Mar 12 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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