TY - JOUR
T1 - Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7
AU - Yada, Masayoshi
AU - Hatakeyama, Shigetsugu
AU - Kamura, Takumi
AU - Nishiyama, Masaaki
AU - Tsunematsu, Ryosuke
AU - Imaki, Hiroyuki
AU - Ishida, Noriko
AU - Okumura, Fumihiko
AU - Nakayama, Keiko
AU - Nakayama, Keiichi I.
PY - 2004/5/19
Y1 - 2004/5/19
N2 - 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 Fbw7-1- 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.
AB - 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 Fbw7-1- 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.
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U2 - 10.1038/sj.emboj.7600217
DO - 10.1038/sj.emboj.7600217
M3 - Article
C2 - 15103331
AN - SCOPUS:2942614705
VL - 23
SP - 2116
EP - 2125
JO - EMBO Journal
JF - EMBO Journal
SN - 0261-4189
IS - 10
ER -