Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7.
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.
Yada
Masayoshi
M
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Maidashi, Higashi-ku, Fukuoka, Fukuoka, Japan.
Hatakeyama
Shigetsugu
S
Kamura
Takumi
T
Nishiyama
Masaaki
M
Tsunematsu
Ryosuke
R
Imaki
Hiroyuki
H
Ishida
Noriko
N
Okumura
Fumihiko
F
Nakayama
Keiko
K
Nakayama
Keiichi I
KI
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D013912:Threonine / Q000378:metabolism; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D010455:Peptides; D016271:Proto-Oncogene Proteins c-myc; D011994:Recombinant Proteins; D044786:S-Phase Kinase-Associated Proteins; D025801:Ubiquitin; D013912:Threonine; D012694:Serine; D044767:Ubiquitin-Protein Ligases; D008025:Ligases