Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7

Masayoshi Yada, Shigetsugu Hatakeyama, Takumi Kamura, Masaaki Nishiyama, Ryosuke Tsunematsu, Hiroyuki Imaki, Noriko Ishida, Fumihiko Okumura, Keiko Nakayama, Keiichi I. Nakayama

Research output: Contribution to journalArticlepeer-review

545 Citations (Scopus)

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 Fbw7-1- 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.

Original languageEnglish
Pages (from-to)2116-2125
Number of pages10
JournalEMBO Journal
Volume23
Issue number10
DOIs
Publication statusPublished - 2004 May 19

Keywords

  • Fbw7
  • SCF complex
  • Skp2
  • Ubiquitin ligase
  • c-Myc

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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