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First published online 1 September 2005
doi: 10.1242/jcs.02560
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Research Article |
1 Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA
2 Department of Biological Chemistry, Howard Hughes Medical Institute, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Author for correspondence (e-mail: rjavier{at}bcm.tmc.edu)
Accepted 23 June 2005
The development of human cancers is frequently associated with a failure of epithelial cells to form tight junctions and to establish proper apicobasal polarity. Interestingly, the oncogenic potential of the adenovirus E4-ORF1 protein correlates with its binding to the cellular PDZ proteins MUPP1, MAGI-1, ZO-2 and SAP97, the first three of which assemble protein complexes at tight junctions. Given that E4-ORF1 sequesters these three PDZ proteins in the cytoplasm of fibroblasts, we postulated that E4-ORF1 would inhibit tight junction formation in epithelial cells. Providing further support for this idea, we identified MUPP1-related PATJ, a key component of the tight junction-associated CRB3-PALS1-PATJ polarity complex, as a new PDZ-protein target for both the E4-ORF1 and high-risk human papillomavirus type 18 E6 oncoproteins. Moreover, in epithelial cells, E4-ORF1 blocked the tight junction localization of PATJ and ZO-2, as well as their interacting partners, and disrupted both the tight junction barrier and apicobasal polarity. These significant findings expose a direct link between the tumorigenic potential of E4-ORF1 and inactivation of cellular PDZ proteins involved in tight junction assembly and polarity establishment.
Key words: Tight junction, Polarity, PATJ, ZO-2, E4-ORF1, E6
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