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

Welcker, Markus and Orian, Amir and Grim, Jonathan E and Grim, Jonathan A and Eisenman, Robert N and Clurman, Bruce E (2004) A nucleolar isoform of the Fbw7 ubiquitin ligase regulates c-Myc and cell size. Current biology : CB, 14 (20). pp. 1852-1857. ISSN 0960-9822

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Article URL: http://dx.doi.org/10.1016/j.cub.2004.09.083

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.

Item Type: Article
DOI: 10.1016/j.cub.2004.09.083
PubMed ID: 15498494
Keywords or MeSH Headings: Cell Cycle Proteins/genetics/metabolism; Cell Nucleolus/metabolism; Cell Size; Cells, Cultured; F-Box Proteins/genetics/metabolism; Gene Expression Regulation; Gene Transfer Techniques; Humans; Immunoblotting; Protein Isoforms/genetics/metabolism; Proto-Oncogene Proteins c-myc/metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Ubiquitin-Protein Ligases/genetics/metabolism;
Depositing User: Library Staff
Date Deposited: 03 Apr 2009 19:30
Last Modified: 13 May 2010 21:26
URI: http://authors.fhcrc.org/id/eprint/201

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