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

http://www.ncbi.nlm.nih.gov/pubmed/15150404

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 RIS Download

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

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