Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy.

Abstract

Muscle wasting is a debilitating consequence of fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissue-specific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.

• Authors: M D Gomes, S H Lecker, R T Jagoe, A Navon, A L Goldberg
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 98 Issue 25 Pg. 14440-5 (Dec 04 2001) ISSN: 0027-8424 [Print] United States
• PMID: 11717410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• DNA, Complementary
• Muscle Proteins
• RNA, Messenger
• FBXO32 protein, human
• Fbxo32 protein, mouse
• SKP Cullin F-Box Protein Ligases
• Ligases

Topics

• Amino Acid Sequence
• Animals
• Base Sequence
• Cloning, Molecular
• DNA, Complementary (genetics)
• Fasting (metabolism)
• Gene Expression
• Ligases (genetics)
• Male
• Mice
• Mice, Inbred C57BL
• Molecular Sequence Data
• Muscle Proteins (genetics)
• Muscular Atrophy (etiology, genetics, metabolism)
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (genetics, metabolism)
• SKP Cullin F-Box Protein Ligases