Stress induces p38 MAPK-mediated phosphorylation and inhibition of drosha-dependent cell survival

Qian Yang, Wenming Li, Hua She, Juan Dou, Duc M. Duong, Yuhong Du, Shaohua Yang, Nicholas T. Seyfried, Haian Fu, Guodong Gao, Zixu Mao

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)

Abstract

MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival.

Original languageEnglish
Pages (from-to)721-734
Number of pages14
JournalMolecular Cell
Volume57
Issue number4
DOIs
StatePublished - 19 Feb 2015

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p38 Mitogen-Activated Protein Kinases
MicroRNAs
Cell Survival
Phosphorylation
Ribonuclease III
DiGeorge Syndrome
Calpain
Cell Nucleus Active Transport
Messenger RNA
Enzymes
Genes

Cite this

Yang, Qian ; Li, Wenming ; She, Hua ; Dou, Juan ; Duong, Duc M. ; Du, Yuhong ; Yang, Shaohua ; Seyfried, Nicholas T. ; Fu, Haian ; Gao, Guodong ; Mao, Zixu. / Stress induces p38 MAPK-mediated phosphorylation and inhibition of drosha-dependent cell survival. In: Molecular Cell. 2015 ; Vol. 57, No. 4. pp. 721-734.
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abstract = "MicroRNAs (miRNAs) regulate the translational potential of their mRNA targets and control many cellular processes. The key step in canonical miRNA biogenesis is the cleavage of the primary transcripts by the nuclear RNase III enzyme Drosha. Emerging evidence suggests that the miRNA biogenic cascade is tightly controlled. However, little is known whether Drosha is regulated. Here, we show that Drosha is targeted by stress. Under stress, p38 MAPK directly phosphorylates Drosha at its N terminus. This reduces its interaction with DiGeorge syndrome critical region gene 8 and promotes its nuclear export and degradation by calpain. This regulatory mechanism mediates stress-induced inhibition of Drosha function. Reduction of Drosha sensitizes cells to stress and increases death. In contrast, increase in Drosha attenuates stress-induced death. These findings reveal a critical regulatory mechanism by which stress engages p38 MAPK pathway to destabilize Drosha and inhibit Drosha-mediated cellular survival.",
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Yang, Q, Li, W, She, H, Dou, J, Duong, DM, Du, Y, Yang, S, Seyfried, NT, Fu, H, Gao, G & Mao, Z 2015, 'Stress induces p38 MAPK-mediated phosphorylation and inhibition of drosha-dependent cell survival', Molecular Cell, vol. 57, no. 4, pp. 721-734. https://doi.org/10.1016/j.molcel.2015.01.004

Stress induces p38 MAPK-mediated phosphorylation and inhibition of drosha-dependent cell survival. / Yang, Qian; Li, Wenming; She, Hua; Dou, Juan; Duong, Duc M.; Du, Yuhong; Yang, Shaohua; Seyfried, Nicholas T.; Fu, Haian; Gao, Guodong; Mao, Zixu.

In: Molecular Cell, Vol. 57, No. 4, 19.02.2015, p. 721-734.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Li, Wenming

AU - She, Hua

AU - Dou, Juan

AU - Duong, Duc M.

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AU - Yang, Shaohua

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AU - Mao, Zixu

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