|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
First published online November 18, 2003
doi: 10.1242/10.1242/jcs.00809
Research Article |
1 Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham B15 2TA, United Kingdom
2 International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy
* Author for correspondence (e-mail: s.roberts{at}bham.ac.uk)
Accepted 29 July 2003
Human papillomavirus E6 oncoproteins induce the proteasomal degradation of several multi-PDZ (PSD95/Dlg/ZO-1) domain-containing proteins such as the human homologue of Drosophila discs large. Binding to PDZ domain-containing proteins is mediated by a PDZ-binding motif contained within the C-terminus of E6. The ability of E6 proteins to induce degradation of PDZ domain-containing proteins correlates with their oncogenic potential. Here we examined the biological effect of this region of the human papillomavirus type 18 E6 oncoprotein on keratinocyte morphology. Our results show that in simian virus 40-immortalized human keratinocytes, stable expression of E6 correlated with the induction of an exaggerated mesenchymal-like morphology and actin cytoskeleton disorganization compared with parental cells. The altered phenotype was accentuated in cells expressing an E6 protein containing a mutation (Arg153Leu) within a protein kinase A recognition motif that abrogates protein kinase A's negative regulation of the activity of the PDZ-binding domain. The E6-induced changes indicated an epithelial-mesenchymal transition and were supported by the finding that E6-expressing cells contained vimentin. Changes to the epithelial phenotype of cells expressing a mutant E6 protein (Thr156Glu) that is unable to degrade discs large was significantly less marked, although they did show evidence of epithelial-mesenchymal transition. These observations imply that the activity of the E6 PDZ-binding motif contributes only to a part of the transition. Further analysis of the E6 cell lines showed a decrease in adherens junction and desmosome formation. Cells expressing a functional PDZ-binding motif showed the greatest disruption of intercellular junction formation, but this did not correlate with a decrease in total cellular levels of the individual components of adhesion junctions. This suggests that the activity of the PDZ-binding motif may have influenced either the assembly or integrity of functional adhesion complexes. An E6-mediated decrease in peripheral membrane levels of PDZ proteins like discs large could be the basis for the enhanced morphological transformation of immortalized keratinocytes.
Key words: Human papillomavirus, E6, Discs large, Cell shape, Intercellular adhesion, Epithelial-mesenchymal transition
This article has been cited by other articles:
|
|
 |
|
  R. Garcia-Mata, A. D. Dubash, L. Sharek, H. S. Carr, J. A. Frost, and K. Burridge The Nuclear RhoA Exchange Factor Net1 Interacts with Proteins of the Dlg Family, Affects Their Localization, and Influences Their Tumor Suppressor Activity Mol. Cell. Biol., December 15, 2007; 27(24): 8683 - 8697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Topffer, A. Muller-Schiffmann, K. Matentzoglu, M. Scheffner, and G. Steger Protein tyrosine phosphatase H1 is a target of the E6 oncoprotein of high-risk genital human papillomaviruses J. Gen. Virol., November 1, 2007; 88(11): 2956 - 2965. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-H. Chung, K. K. Frese, R. S. Weiss, B. V. V. Prasad, and R. T. Javier A New Crucial Protein Interaction Element That Targets the Adenovirus E4-ORF1 Oncoprotein to Membrane Vesicles J. Virol., May 1, 2007; 81(9): 4787 - 4797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Storrs and S. J. Silverstein PATJ, a Tight Junction-Associated PDZ Protein, Is a Novel Degradation Target of High-Risk Human Papillomavirus E6 and the Alternatively Spliced Isoform 18 E6 J. Virol., April 15, 2007; 81(8): 4080 - 4090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Handa, T. Yugawa, M. Narisawa-Saito, S.-i. Ohno, M. Fujita, and T. Kiyono E6AP-Dependent Degradation of DLG4/PSD95 by High-Risk Human Papillomavirus Type 18 E6 Protein J. Virol., February 1, 2007; 81(3): 1379 - 1389. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Kuballa, K. Matentzoglu, and M. Scheffner The Role of the Ubiquitin Ligase E6-AP in Human Papillomavirus E6-mediated Degradation of PDZ Domain-containing Proteins J. Biol. Chem., January 5, 2007; 282(1): 65 - 71. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. James, J. H. Lee, and A. J. Klingelhutz Human Papillomavirus Type 16 E6 Activates NF-{kappa}B, Induces cIAP-2 Expression, and Protects against Apoptosis in a PDZ Binding Motif-Dependent Manner. J. Virol., June 1, 2006; 80(11): 5301 - 5307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xie, B. Yamamoto, A. Haoudi, O. J. Semmes, and P. L. Green PDZ binding motif of HTLV-1 Tax promotes virus-mediated T-cell proliferation in vitro and persistence in vivo Blood, March 1, 2006; 107(5): 1980 - 1988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Latorre, M. H. Roh, K. K. Frese, R. S. Weiss, B. Margolis, and R. T. Javier Viral oncoprotein-induced mislocalization of select PDZ proteins disrupts tight junctions and causes polarity defects in epithelial cells J. Cell Sci., September 15, 2005; 118(18): 4283 - 4293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Favre-Bonvin, C. Reynaud, C. Kretz-Remy, and P. Jalinot Human Papillomavirus Type 18 E6 Protein Binds the Cellular PDZ Protein TIP-2/GIPC, Which Is Involved in Transforming Growth Factor {beta} Signaling and Triggers Its Degradation by the Proteasome J. Virol., April 1, 2005; 79(7): 4229 - 4237. [Abstract] [Full Text] [PDF]
|
|
