Article
- The EMBO Journal (2004) 23, 2116 - 2125
- doi:10.1038/sj.emboj.7600217
Published online: 22 April 2004
Subject Categories:
Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7
Masayoshi Yada1,2, Shigetsugu Hatakeyama1,2, Takumi Kamura1,2, Masaaki Nishiyama1,2, Ryosuke Tsunematsu1,2, Hiroyuki Imaki1,2, Noriko Ishida2,3, Fumihiko Okumura1,2, Keiko Nakayama2,3 and Keiichi I Nakayama1,2
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Fukuoka, Japan
- CREST, Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama, Japan
- Division of Developmental Biology, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University School of Medicine, Sendai, Miyagi, Japan
Correspondence to:
Keiichi I Nakayama, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan. Tel.: +81 92 642 6815; Fax: +81 92 642 6819; E-mail: nakayak1@bioreg.kyushu-u.ac.jp
Received 16 October 2003; Accepted 31 March 2004
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.
Keywords:
- c-Myc,
- Fbw7,
- SCF complex,
- Skp2,
- ubiquitin ligase
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