Professor Steve Winder
Professor of Molecular Cell Biology
Room: B2 06 Florey building
Brief career history
My group is using molecular and cellular approaches to understand the biology of the adhesion receptor dystroglycan. We are focussed on modulating dystroglycan signalling as a therapeutic route to treat Duchenne muscular dystrophy. We are also investigating the functions of dystroglycan in organising and stabilising the nuclear lamina, in cancer and in muscular dystrophies.
Regulation of dystroglycan function in muscular dystrophy and cancer
The laminin binding protein dystroglycan plays multiple roles in cell adhesion, signalling and membrane cytoskeleton stability. Perturbation of dystroglycan function underlies several muscular dystrophies and is also a secondary consequence of adenocarcinoma progression. Changes to the post-translational modification of dystroglycan are crucial in directing the associations, cellular localisation and ultimately degradation of dystroglycan. Our aim is to elucidate the mechanisms and consequences of these post-translational modifications in order to better understand dystroglycan function and to identify potential therapeutic targets for the treatment of muscular dystrophy or cancer.
We employ in vitro, in/ex vivo fish and mouse genetic models with clinically relevant archival tissue samples or immortalised cell lines. Dystroglycan function is dissected through the use of molecular cell biology approaches, and potential therapeutic targets are assessed in vitro and in vivo. Recently we have developed a novel therapeutic approach for the treatment of Duchenne muscular dystrophy using inhibitors of tyrosine phosphorylation and proteasomal degradation. Through the use of zebrafish screening and phenotypic analysis in mdx mice and human DMD myoblasts we are in the process of validating the potential for repurposed drugs as a precursor to initiating clinical trials. Physiological analysis is carried out I collaboration with Nic Wells at the RVC London.
In vitro models of prostate cancer have revealed a role for the post-translational proteolytic processing and nuclear targeting of dystroglycan. Current efforts are centred around characterising a role as part of the LINC complex in the inner nuclear membrane. These studies form part of an ongoing collaboration with Bulmaro Cisneros, CINVESTAV Mexico City.
Undergraduate and postgraduate taught modules
Level 4/Maters (MSc)
Targeting dystroglycan to the nucleus in muscular dystrophy and cancer
This project is eligible for a department scholarship. These scholarships are awarded on a competitive basis – find out more on our funding webpage.
Open to self funded students as well as possible BMS funded.
Dystroglycan is an essential cell adhesion receptor required for early embryonic development. Genetic loss of function gives rise to severe muscular dystrophies with neuronal involvement. Post-translational loss of function also occurs in Duchenne muscular dystrophy and in some cancers. This includes phosphorylation, proteolysis and ubiquitination. Moreover some proteolytic fragments of dystroglycan are targeted to the nucleus where they have effects on transcription. As part of our analysis of dystroglycan post-translational modifications, we identified a lipid modification - palmitoylation of a conserved cysteine residue that could act to anchor bioactive dystroglycan fragments to the membrane, both at the cell surface and in the nucleus.
To examine the function of dystroglycan palmitoylation in cellular targeting and in cellular phenotypes associated with muscular dystrophy and cancer.
PCR-based site-directed mutagenesis, and cloning of dystroglycan mutants. Overexpression of dystroglycan mutants in tissue culture cells. Analysis of subcellular distribution of dystroglycan by quantitative immunofluorescence microscopy and cell fractionation. In vitro assays of cell invasion and metastatic growth.
Informal enquiries about this project welcome.
For further information about these projects and how to apply, please see our PhD Opportunities page.
- Lipscomb L, Piggott RW, Emmerson T & Winder SJ (2016) Dasatinib as a treatment for Duchenne muscular dystrophy. Human Molecular Genetics, 25(2), 266-274. View this article in WRRO
- Martínez-Vieyra IA, Vásquez-Limeta A, González-Ramírez R, Morales-Lázaro SL, Mondragón M, Mondragón R, Ortega A, Winder SJ & Cisneros B (2013) A role for β-dystroglycan in the organization and structure of the nucleus in myoblasts. Biochimica et Biophysica Acta - Molecular Cell Research, 1833(3), 698-711.
- Mathew G, Mitchell A, Down JM, Jacobs LA, Hamdy FC, Eaton C, Rosario DJ, Cross SS & Winder SJ (2013) Nuclear targeting of dystroglycan promotes the expression of androgen regulated transcription factors in prostate cancer.. Sci Rep, 3, 2792. View this article in WRRO
- Miller G, Moore CJ, Terry R, La riviere T, Mitchell A, Piggott R, Dear TN, Wells DJ & Winder SJ (2012) Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse. Human Molecular Genetics, 21(20), 4508-4520.