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.
Mesh Terms:
Animals, Cell Cycle Proteins, Cells, Cultured, Cyclin E, F-Box Proteins, Humans, Ligases, Mice, Mice, Knockout, Peptides, Phosphorylation, Proto-Oncogene Proteins c-myc, RNA Interference, Recombinant Proteins, S-Phase Kinase-Associated Proteins, Serine, Stem Cells, Threonine, Transcriptional Activation, Ubiquitin, Ubiquitin-Protein Ligases
Animals, Cell Cycle Proteins, Cells, Cultured, Cyclin E, F-Box Proteins, Humans, Ligases, Mice, Mice, Knockout, Peptides, Phosphorylation, Proto-Oncogene Proteins c-myc, RNA Interference, Recombinant Proteins, S-Phase Kinase-Associated Proteins, Serine, Stem Cells, Threonine, Transcriptional Activation, Ubiquitin, Ubiquitin-Protein Ligases
EMBO J.
Date: May. 19, 2004
PubMed ID: 15103331
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