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 language | English (US) |
|---|---|
| Journal | Science Signaling |
| Volume | 6 |
| Issue number | 266 |
| DOIs | |
| State | Published - Mar 12 2013 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary MicroRNAs. / Hong, Sungguan; Noh, Hyangsoon; Chen, Haoming; Padia, Ravi; Pan, Zhixing K.; Su, Shi Bing; Jing, Qing; Ding, Han Fei; Huang, Shuang.
In: Science Signaling, Vol. 6, No. 266, 12.03.2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Signaling by p38 MAPK stimulates nuclear localization of the microprocessor component p68 for processing of selected primary MicroRNAs
AU - Hong, Sungguan
AU - Noh, Hyangsoon
AU - Chen, Haoming
AU - Padia, Ravi
AU - Pan, Zhixing K.
AU - Su, Shi Bing
AU - Jing, Qing
AU - Ding, Han Fei
AU - Huang, Shuang
PY - 2013/3/12
Y1 - 2013/3/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84875199337&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84875199337&partnerID=8YFLogxK
U2 - 10.1126/scisignal.2003706
DO - 10.1126/scisignal.2003706
M3 - Article
C2 - 23482664
AN - SCOPUS:84875199337
VL - 6
JO - Science Signaling
JF - Science Signaling
SN - 1937-9145
IS - 266
ER -