In many ways cancer is a disease of cellular signalling disequilibrium. When the equilibrium of key signalling pathways is upset, critical biological functions such as cell growth, survival, motility, proliferation, metabolism and apoptosis are affected, and can lead to the initiation of cancer. Reversible protein phosphorylation is an extremely important mechanism by which the activity of enzymes and proteins in signalling cascades can be regulated. Dual specificity phosphatases (DUSPs) are a unique subgroup of the protein tyrosine phosphatases (PTPs) in that they can dephosphorylate both phospho-tyrosine and phospho-serine/threonine residues within the one substrate. Many DUSPs have been implicated in cancer as critical regulators of key cancer- associated signalling cascades including the mitogen activated protein kinase (MAPK) pathway. Transcript profiling of 51 primary ovarian tumours and four normal ovaries as controls identified an uncharacterised atypical DUSP, DUSP26 as being potentially down-regulated in all histological subtypes of ovarian cancer compared with normal ovaries. DUSP26 is located at 8p12, a chromosomal region previously shown to exhibit allelic imbalance in ovarian cancer. DUSP26 is predominantly expressed in neuro-endocrine tissue, with high expression also in skeletal muscle, prostate and ovary. DUSP26 mRNA expression is reduced in brain cancer, neuroblastoma, and ovarian cancer cell lines compared to normal, consistent with a role for DUSP26 as a tumour suppressor gene. Furthermore, DUSP26 can negatively affect the proliferation of epithelial cells, also consistent with a role as a tumour suppressor gene. Expression of DUSP26 in primary ovarian cancer samples is variable however, and analysis of DUSP26 protein expression is required to reconcile these results. Preliminary results suggest that DUSP26 is epigenetically regulated and that hypermethylation may contribute to its silencing in cancer. In the literature, there is great controversy in regards to the substrate specificity of DUSP26. Results presented in this thesis conclusively demonstrate that DUSP26 is not a MAPK phosphatase, despite reports to the contrary. Instead, using a substrate trapping approach, two novel potential DUSP26 substrates were identified: DNA-dependent protein kinase (DNA-PK) and nuclear mitotic apparatus protein (NuMA), which are often dysregulated in cancer. Consequently, DUSP26 may affect the pathogenesis of cancer via DNA-PK and or NuMA.
| Identifer | oai:union.ndltd.org:ADTP/243025 |
| Date | January 2009 |
| Creators | Patterson, Kate Isabel, Garvan Institute of Medical Research, Faculty of Medicine, UNSW |
| Publisher | Publisher:University of New South Wales. Garvan Institute of Medical Research |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | http://unsworks.unsw.edu.au/copyright, http://unsworks.unsw.edu.au/copyright |
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