Atrogin-1/muscle atrophy F-box inhibits calcineurin-dependent cardiac hypertrophy by participating in an SCF ubiquitin ligase complex.

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.
Authors	Hui-Hua Li, Vishram Kedar, Chunlian Zhang, Holly McDonough, Ranjana Arya, Da-Zhi Wang, Cam Patterson
Journal	The Journal of clinical investigation (J Clin Invest) Vol. 114 Issue 8 Pg. 1058-71 (Oct 2004) ISSN: 0021-9738 [Print] United States
PMID	15489953 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
Chemical References	ACTN2 protein, human Actn2 protein, mouse Actn2 protein, rat Cell Cycle Proteins Cullin 1 Cullin Proteins F-Box Proteins Macromolecular Substances Muscle Proteins Recombinant Fusion Proteins Ubiquitin Actinin Fbxo32 protein, rat SKP Cullin F-Box Protein Ligases Ubiquitin-Protein Ligases Calcineurin
Topics	Actinin (genetics, metabolism) Animals COS Cells Calcineurin (genetics, metabolism) Cardiomegaly (genetics, metabolism, pathology) Cell Cycle Proteins (genetics, metabolism) Chlorocebus aethiops Cullin Proteins (genetics, metabolism) Echocardiography F-Box Proteins (genetics, metabolism) Gene Expression Regulation, Developmental Humans Macromolecular Substances Mice Mice, Transgenic Muscle Proteins Myocytes, Cardiac (cytology, pathology, physiology) Organ Size Rats Recombinant Fusion Proteins (genetics, metabolism) SKP Cullin F-Box Protein Ligases (genetics, metabolism) Transcription, Genetic Two-Hybrid System Techniques Ubiquitin (metabolism) Ubiquitin-Protein Ligases (genetics, metabolism)

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