Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy
- Marcelo D. Gomes*,†,
- Stewart H. Lecker*,†,‡,
- R. Thomas Jagoe*,
- Ami Navon*, and
- Alfred L. Goldberg*,§
- *Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115; and ‡Beth Israel Deaconess Medical Center, Renal Unit DA517, 330 Brookline Avenue, Boston, MA 02215
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Communicated by Joan V. Ruderman, Harvard Medical School, Boston, MA (received for review July 8, 2001)
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.
