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Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival.
- Source :
-
Molecular cell [Mol Cell] 2015 Feb 19; Vol. 57 (4), pp. 721-734. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Subjects :
- Active Transport, Cell Nucleus
Cell Survival
HEK293 Cells
Humans
Phosphorylation
Proteolysis
RNA-Binding Proteins genetics
RNA-Binding Proteins metabolism
RNA-Binding Proteins physiology
Ribonuclease III genetics
Ribonuclease III metabolism
p38 Mitogen-Activated Protein Kinases genetics
p38 Mitogen-Activated Protein Kinases metabolism
Ribonuclease III physiology
Stress, Physiological
p38 Mitogen-Activated Protein Kinases physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4164
- Volume :
- 57
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Molecular cell
- Publication Type :
- Academic Journal
- Accession number :
- 25699712
- Full Text :
- https://doi.org/10.1016/j.molcel.2015.01.004