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Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):9085-90. Epub 2004 May 18.

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

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  • 1Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Erratum in

  • Proc Natl Acad Sci U S A. 2006 Jan 10;103(2):504. Grim, Jonathan A [corrected to Grim, Jonathan E].

Abstract

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.

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PMID:
15150404
[PubMed - indexed for MEDLINE]
PMCID:
PMC428477
Free PMC Article
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