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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.

Pubmed ID: 15489953

Authors

  • Li HH
  • Kedar V
  • Zhang C
  • McDonough H
  • Arya R
  • Wang DZ
  • Patterson C

Journal

The Journal of clinical investigation

Publication Data

October 18, 2004

Associated Grants

  • Agency: NHLBI NIH HHS, Id: HL072347
  • Agency: NHLBI NIH HHS, Id: HL65619

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