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- Title
Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex.
- Authors
Li, Hui-Hua; Kedar, Vishram; Zhang, Chunlian; McDonough, Holly; Arya, Ranjana; Wang, Da-Zhi; Patterson, Cam
- Abstract
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.
- Subjects
PROTEIN metabolism; MUSCLE protein metabolism; ENZYME metabolism; ANIMAL experimentation; ANTHROPOMETRY; CARRIER proteins; CELLS; COMPARATIVE studies; ECHOCARDIOGRAPHY; ENZYMES; GENES; CARDIAC hypertrophy; HYDROLASES; RESEARCH methodology; MEDICAL cooperation; MICE; MOLECULAR structure; MUSCLE proteins; PRIMATES; RATS; RECOMBINANT proteins; RESEARCH; RESEARCH funding; RNA; EVALUATION research; CELL cycle proteins
- Publication
Journal of Clinical Investigation, 2004, Vol 114, Issue 7, p1058
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI200422220