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The Fbw7 tumor suppressor regulates glycogen synthase kinase 3 phosphorylation-dependent c-Myc protein degradation.

Myc proteins regulate cell growth and division and are implicated in a wide range of human cancers. We show here that Fbw7, a component of the SCF(Fbw7) ubiquitin ligase and a tumor suppressor, promotes proteasome-dependent c-Myc turnover in vivo and c-Myc ubiquitination in vitro. Phosphorylation of c-Myc on threonine-58 (T58) by glycogen synthase kinase 3 regulates the binding of Fbw7 to c-Myc as well as Fbw7-mediated c-Myc degradation and ubiquitination. T58 is the most frequent site of c-myc mutations in lymphoma cells, and our findings suggest that c-Myc activation is one of the key oncogenic consequences of Fbw7 loss in cancer. Because Fbw7 mediates the degradation of cyclin E, Notch, and c-Jun, as well as c-Myc, the loss of Fbw7 is likely to elicit profound effects on cell proliferation during tumorigenesis.

Pubmed ID: 15150404


  • Welcker M
  • Orian A
  • Jin J
  • Grim JE
  • Grim JA
  • Harper JW
  • Eisenman RN
  • Clurman BE


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

June 15, 2004

Associated Grants

  • Agency: NIA NIH HHS, Id: AG11085
  • Agency: NIA NIH HHS, Id: R01 AG011085
  • Agency: NCI NIH HHS, Id: R01CA102742-01
  • Agency: NCI NIH HHS, Id: R01CA20525
  • Agency: NCI NIH HHS, Id: R01CA84069

Mesh Terms

  • Base Sequence
  • Cell Cycle Proteins
  • Cell Line
  • F-Box Proteins
  • Fibroblasts
  • Glycogen Synthase Kinase 3
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Proto-Oncogene Proteins c-myc
  • Recombinant Proteins
  • Sequence Alignment
  • Transduction, Genetic
  • Transfection
  • Tumor Suppressor Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases