Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex.
Calcineurin, which binds to the Z-disc in cardiomyocytes via alpha-actinin, promotes cardiac hypertrophy in response to numerous pathologic stimuli. However, the endogenous mechanisms regulating calcineurin activity in cardiac muscle are not well understood. We demonstrate that a muscle-specific F-box protein called atrogin-1, or muscle atrophy F-box, directly interacts with calcineurin ... A and alpha-actinin-2 at the Z-disc of cardiomyocytes. Atrogin-1 associates with Skp1, Cul1, and Roc1 to assemble an SCF(atrogin-1) complex with ubiquitin ligase activity. Expression of atrogin-1 decreases levels of calcineurin A and promotes its ubiquitination. Moreover, atrogin-1 attenuates agonist-induced calcineurin activity and represses calcineurin-dependent transactivation and NFATc4 translocation. Conversely, downregulation of atrogin-1 using adenoviral small interfering RNA (siRNA) expression enhances agonist-induced calcineurin activity and cardiomyocyte hypertrophy. Consistent with these cellular observations, overexpression of atrogin-1 in hearts of transgenic mice reduces calcineurin protein levels and blunts cardiac hypertrophy after banding of the thoracic aorta. These studies indicate that the SCF(atrogin-1) ubiquitin ligase complex interacts with and represses calcineurin by targeting calcineurin for ubiquitin-mediated proteolysis, leading to inhibition of cardiac hypertrophy in response to pathologic stimuli.
Mesh Terms:
Actinin, Animals, COS Cells, Calcineurin, Cardiomegaly, Cell Cycle Proteins, Cercopithecus aethiops, Cullin Proteins, Echocardiography, F-Box Proteins, Gene Expression Regulation, Developmental, Humans, Macromolecular Substances, Mice, Mice, Transgenic, Muscle Proteins, Myocytes, Cardiac, Organ Size, Rats, Recombinant Fusion Proteins, SKP Cullin F-Box Protein Ligases, Transcription, Genetic, Two-Hybrid System Techniques, Ubiquitin, Ubiquitin-Protein Ligases
Actinin, Animals, COS Cells, Calcineurin, Cardiomegaly, Cell Cycle Proteins, Cercopithecus aethiops, Cullin Proteins, Echocardiography, F-Box Proteins, Gene Expression Regulation, Developmental, Humans, Macromolecular Substances, Mice, Mice, Transgenic, Muscle Proteins, Myocytes, Cardiac, Organ Size, Rats, Recombinant Fusion Proteins, SKP Cullin F-Box Protein Ligases, Transcription, Genetic, Two-Hybrid System Techniques, Ubiquitin, Ubiquitin-Protein Ligases
J. Clin. Invest.
Date: Oct. 01, 2004
PubMed ID: 15489953
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