Document Detail


Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation.
MedLine Citation:
PMID:  23048029     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Mutations in LMNA gene cause cardiomyopathy, for which mechanistic insights are lacking.
RESULTS: Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy.
CONCLUSIONS: Dusp4 causes cardiac dysfunction and may contribute to the development of LMNA cardiomyopathy.
SIGNIFICANCE: Revealing pathogenic mechanisms of LMNA cardiomyopathy is essential for the development of mechanism-based therapies. Mutations in the lamin A/C gene (LMNA) cause a diverse spectrum of diseases, the most common of which is dilated cardiomyopathy often with skeletal muscular dystrophy. Lamin A and C are fundamental components of the nuclear lamina, a dynamic meshwork of intermediate filaments lining the nuclear envelope inner membrane. Prevailing evidence suggests that the nuclear envelope functions as a signaling node and that abnormality in the nuclear lamina leads to dysregulated signaling pathways that underlie disease pathogenesis. We previously showed that activated ERK1/2 in hearts of a mouse model of LMNA cardiomyopathy (Lmna(H222P/H222P) mice) contributes to disease, but the complete molecular pathogenesis remains poorly understood. Here we uncover a pathogenic role of dual specificity phosphatase 4 (Dusp4), which is transcriptionally induced by ERK1/2. Dusp4 is highly expressed in the hearts of Lmna(H222P/H222P) mice, and transgenic mice with cardiac-selective overexpression of Dusp4 display heart dysfunction similar to LMNA cardiomyopathy. In both primary tissue and cell culture models, overexpression of Dusp4 positively regulates AKT-mTOR signaling, resulting in impaired autophagy. These findings identify a pathogenic role of Dusp4 in LMNA cardiomyopathy.
Authors:
Jason C Choi; Wei Wu; Antoine Muchir; Shinichi Iwata; Shunichi Homma; Howard J Worman
Related Documents :
23717599 - In vivo monitoring of multi-unit neural activity in the suprachiasmatic nucleus reveals...
23851679 - Oat β-glucan inhibits lipopolysaccharide-induced nonalcoholic steatohepatitis in mice.
24307739 - Mpys/sting-mediated tnf-α, not type i ifn, is essential for the mucosal adjuvant activ...
23460269 - Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury i...
24358869 - Cocaine self-administration in mice with forebrain knock-down of trpc5 ion channels.
23672639 - Neurogenic factor-induced langerhans cell activation in diabetic mice with mechanical a...
21972099 - App transgenic mice and their application to drug discovery.
10491409 - Pathogenesis of septic shock in pseudomonas aeruginosa pneumonia.
23962989 - Methallothionein-3 contributes to vascular endothelial growth factor induction in a mou...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-27     Completed Date:  2013-02-28     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  40513-24     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Autophagy
Cardiomyopathies / enzymology*,  genetics,  metabolism,  physiopathology
Dual-Specificity Phosphatases / genetics,  metabolism*
Female
Heart / physiopathology
Humans
Lamin Type A / genetics*,  metabolism
MAP Kinase Signaling System
Male
Mice
Mice, Inbred CBA
Mice, Transgenic
Mitogen-Activated Protein Kinase Phosphatases / genetics,  metabolism*
Mutation, Missense*
Myocardium / enzymology,  metabolism
Grant Support
ID/Acronym/Agency:
F32-HL094037/HL/NHLBI NIH HHS; R01 AR048997/AR/NIAMS NIH HHS; R01AR048997/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/LMNA protein, human; 0/Lamin Type A; EC 3.1.3.-/Mitogen-Activated Protein Kinase Phosphatases; EC 3.1.3.48/DUSP4 protein, human; EC 3.1.3.48/Dual-Specificity Phosphatases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  A novel histone H4 arginine 3 methylation-sensitive histone H4 binding activity and transcriptional ...
Next Document:  Effect of envelope proteins on the mechanical properties of influenza virus.