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A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size.

Current biology : CB (2004-10-23)
Markus Welcker, Amir Orian, Jonathan E Grim, Jonathan A Grim, Robert N Eisenman, Bruce E Clurman
ABSTRACT

The human tumor suppressor Fbw7/hCdc4 functions as a phosphoepitope-specific substrate recognition component of SCF ubiquitin ligases that catalyzes the ubiquitination of cyclin E , Notch , c-Jun and c-Myc . Fbw7 loss in cancer may thus have profound effects on the pathways that govern cell division, differentiation, apoptosis, and cell growth. Fbw7-inactivating mutations occur in human tumor cell lines and primary cancers , and Fbw7 loss in cultured cells causes genetic instability . In mice, deletion of Fbw7 leads to embryonic lethality associated with defective Notch and cyclin E regulation . The human Fbw7 locus encodes three protein isoforms (Fbw7alpha, Fbw7beta, and Fbw7gamma) . We find that these isoforms occupy discrete subcellular compartments and have identified cis-acting localization signals within each isoform. Surprisingly, the Fbw7gamma isoform is nucleolar, colocalizes with c-Myc when the proteasome is inhibited, and regulates nucleolar c-Myc accumulation. Moreover, we find that knockdown of Fbw7 increases cell size consistent with its ability to control c-Myc levels in the nucleolus. We suggest that interactions between c-Myc and Fbw7gamma within the nucleolus regulate c-Myc's growth-promoting function and that c-Myc activation is likely to be an important oncogenic consequence of Fbw7 loss in cancers.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-hFBXW7 antibody , Mouse monoclonal, clone FB407, purified from hybridoma cell culture
Sigma-Aldrich
Monoclonal Anti-hFBXW7γ antibody produced in mouse, ~2 mg/mL, clone FB343, purified immunoglobulin, buffered aqueous solution

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