title: Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival.
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.
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China; Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: qianyang@fmmu.edu.cn.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Wenming
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: She
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Dou
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
authors.forename: Shao-Hua
authors.initials: SH
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Neurosurgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an, Shaanxi 710038, China.
authors.forename: Guodong
authors.initials: G
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: zmao@pharm.emory.edu.
authors.forename: Zixu
authors.initials: Z
authors.lastname: Mao
mesh_terms: D021581:Active Transport, Cell Nucleus; D002470:Cell Survival; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013312:Stress, Physiological; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: C474043:DGCR8 protein, human; D016601:RNA-Binding Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C517918:DROSHA protein, human; D043244:Ribonuclease III