| Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation. | |
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MedLine Citation:
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PMID: 23048029 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Jason C Choi; Wei Wu; Antoine Muchir; Shinichi Iwata; Shunichi Homma; Howard J Worman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-10-09 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 287 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-11-27 Completed Date: 2013-02-28 Revised Date: 2013-05-09 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 40513-24 Citation Subset: IM |
Affiliation:
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Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. |
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| MeSH Terms | |
Descriptor/Qualifier:
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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:
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F32-HL094037/HL/NHLBI NIH HHS; R01 AR048997/AR/NIAMS NIH HHS; R01AR048997/AR/NIAMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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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 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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