| First Author | Choi JC | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 48 | Pages | 40513-24 |
| PubMed ID | 23048029 | Mgi Jnum | J:192633 |
| Mgi Id | MGI:5465513 | Doi | 10.1074/jbc.M112.404541 |
| Citation | Choi JC, et al. (2012) Dual specificity phosphatase 4 mediates cardiomyopathy caused by lamin A/C (LMNA) gene mutation. J Biol Chem 287(48):40513-24 |
| abstractText | 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. |
