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EMBO J. 2006 Mar 22;25(6):1406-17. Epub 2006 Mar 2.

Oncogenic function for the Dlg1 mammalian homolog of the Drosophila discs-large tumor suppressor.

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  • 1Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.

Abstract

The fact that several different human virus oncoproteins, including adenovirus type 9 E4-ORF1, evolved to target the Dlg1 mammalian homolog of the membrane-associated Drosophila discs-large tumor suppressor has implicated this cellular factor in human cancer. Despite a general belief that such interactions function solely to inactivate this suspected human tumor suppressor protein, we demonstrate here that E4-ORF1 specifically requires endogenous Dlg1 to provoke oncogenic activation of phosphatidylinositol 3-kinase (PI3K) in cells. Based on our results, we propose a model wherein E4-ORF1 binding to Dlg1 triggers the resulting complex to translocate to the plasma membrane and, at this site, to promote Ras-mediated PI3K activation. These findings establish the first known function for Dlg1 in virus-mediated cellular transformation and also surprisingly expose a previously unrecognized oncogenic activity encoded by this suspected cellular tumor suppressor gene.

PMID:
16511562
[PubMed - indexed for MEDLINE]
PMCID:
PMC1422156
Free PMC Article

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