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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Soond, Surinder M. Smith, Paul G. Swingler, Tracey E. Hemmings, Andrew M. Chantry, Andrew Clark, Ian M. Wahl, Lloyd |
| Description | Author Affiliation: Soond SM ( School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, UK.) |
| Abstract | The WWP2 E3 ubiquitin ligase has previously been shown to regulate TGFβ/Smad signalling activity linked to epithelial–mesenchymal transition (EMT). Whilst inhibitory I-Smad7 was found to be the preferred substrate for full-length WWP2-FL and a WWP2-C isoform, WWP2-FL also formed a stable complex with an N-terminal WWP2 isoform (WWP2-N) in the absence of TGFβ, and rapidly stimulated activating Smad2/3 turnover. Here, using stable knockdown experiments we show that specific depletion of individual WWP2 isoforms impacts differentially on Smad protein levels, and in WWP2-N knockdown cells we unexpectedly find spontaneous expression of the EMT marker vimentin. Re-introduction of WWP2-N into WWP2-N knockout cells also repressed TGFβ-induced vimentin expression. In support of the unique role for WWP2-N in regulating TGFβ/Smad functional activity, we then show that a novel V717M-WWP2 mutant in the MZ7-mel melanoma cell line forms a stable complex with the WWP2-N isoform and promotes EMT by stabilizing Smad3 protein levels. Finally, we report the first analysis of WWP2 expression in cancer cDNA panel arrays using WWP2 isoform-specific probes and identify unique patterns of WWP2 isoform abundance associated with early/advanced disease stages. WWP2-N is significantly downregulated in stage IIIC melanoma and up-regulated in stage II/III prostate cancer, and we also find isolated examples of WWP2-FL and WWP2-C overexpression in early-stage breast cancer. Together, these data suggest that individual WWP2 isoforms, and particularly WWP2-N, could play central roles in tumourigenesis linked to aberrant TGFβ-dependent signalling function, and also have potential as both prognostic markers and molecular therapeutic targets. |
| ISSN | 00063002 |
| Journal | Biochimica et Biophysica Acta (BBA) - Reviews on Cancer |
| Issue Number | 12 |
| Volume Number | 1832 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2013-12-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Tumor Markers, Biological Metabolism Breast Neoplasms Epithelial-Mesenchymal Transition Melanoma Prostatic Neoplasms Ubiquitin-Protein Ligases Apoptosis Blotting, Western Pathology Case-Control Studies Cell Proliferation Gene Expression Profiling Immunoprecipitation Luciferases Neoplasm Staging Oligonucleotide Array Sequence Analysis Prognosis Protein Isoforms RNA, Small Interfering Genetics Smad3 Protein Transforming Growth Factor Beta Tumor Cells, Cultured Antagonists & Inhibitors Comparative Study Research Support, Non-U.S. Gov't Biochemistry |
| Content Type | Text |
| Resource Type | Article |
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