The Fbw7 Tumor Suppressor Regulates Glycogen Synthase Kinase 3 Phosphorylation-dependent C-Myc Protein Degradation

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2004 May 20

PMID 15150404

Citations 524

Authors

Markus Welcker

Amir Orian

Jianping Jin

Jonathan E Grim

Jonathan A Grim

J Wade Harper

Robert N Eisenman

Bruce E Clurman

Affiliations

Soon will be listed here.

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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