期刊
EMBO JOURNAL
卷 25, 期 6, 页码 1406-1417出版社
WILEY
DOI: 10.1038/sj.emboj.7601030
关键词
adenovirus; Dlg1; E4-ORF1; PI 3-kinase; tumor suppressor
资金
- NCI NIH HHS [R01 CA058541, R01 CA58541, T32 CA009197, T32 CA09197] Funding Source: Medline
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.
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