Details

Autor(en) / Beteiligte

• Choi, Jason C.
• Wu, Wei
• Muchir, Antoine
• Iwata, Shinichi
• Homma, Shunichi
• Worman, Howard J.

Titel

Dual Specificity Phosphatase 4 Mediates Cardiomyopathy Caused by Lamin A/C (LMNA) Gene Mutation

Ist Teil von

• The Journal of biological chemistry, 2012-11, Vol.287 (48), p.40513-40524

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (LmnaH222P/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 LmnaH222P/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. 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.