Format

Send to

Choose Destination
J Biol Chem. 2012 Nov 23;287(48):40513-24. doi: 10.1074/jbc.M112.404541. Epub 2012 Oct 9.

Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation.

Author information

1
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

Abstract

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.

PMID:
23048029
PMCID:
PMC3504766
DOI:
10.1074/jbc.M112.404541
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center