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Phosphorylation‐dependent degradation of c‐Myc is mediated by the F‐box protein Fbw7
Author(s) -
Yada Masayoshi,
Hatakeyama Shigetsugu,
Kamura Takumi,
Nishiyama Masaaki,
Tsunematsu Ryosuke,
Imaki Hiroyuki,
Ishida Noriko,
Okumura Fumihiko,
Nakayama Keiko,
Nakayama Keiichi I
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600217
Subject(s) - biology , phosphorylation , f box protein , transactivation , ubiquitin , microbiology and biotechnology , ubiquitin ligase , mutant , immunoprecipitation , pin1 , biochemistry , transcription factor , gene , isomerase
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.