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EMBO J. 2004 May 19;23(10):2116-25. Epub 2004 Apr 22.

Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7.

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  • 1Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Fukuoka, Japan.

Abstract

The F-box protein Skp2 mediates c-Myc ubiquitylation by binding to the MB2 domain. However, the turnover of c-Myc is largely dependent on phosphorylation of threonine-58 and serine-62 in MB1, residues that are often mutated in cancer. We now show that the F-box protein Fbw7 interacts with and thereby destabilizes c-Myc in a manner dependent on phosphorylation of MB1. Whereas wild-type Fbw7 promoted c-Myc turnover in cells, an Fbw7 mutant lacking the F-box domain delayed it. Furthermore, depletion of Fbw7 by RNA interference increased both the abundance and transactivation activity of c-Myc. Accumulation of c-Myc was also apparent in mouse Fbw7-/- embryonic stem cells. These observations suggest that two F-box proteins, Fbw7 and Skp2, differentially regulate c-Myc stability by targeting MB1 and MB2, respectively.

PMID:
15103331
[PubMed - indexed for MEDLINE]
PMCID:
PMC424394
Free PMC Article
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