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Trevor Littlewood

Oncogenic signalling in cancer

 

Understanding the molecular activities of oncogenes and how they interact functionally to drive and maintain tumours is central to the identification of plausible therapeutic interventions. Despite the fact that the myc oncogene was discovered over thirty years ago, its nature as a pleiotropic transcription factor has complicated analysis of its precise functions. We are currently investigating the mechanism of cooperation between Myc and oncogenic Ras proteins both in cultured cells and in genetically modified animals using reversible systemic or tissue-specific switching of oncogene expression or oncoprotein activity.

We are also investigating the commonalities of functions between oncogenes. For example, recent evidence indicates that the Adenovirus E1A protein functionally compensates for Myc in cultured cells – it is able to drive cell proliferation and apoptosis in the absence of Myc activity. However, whether E1A is isofunctional with Myc in the genesis and maintenance of tumours (for example, by recruiting and supporting the tumour microenvironment) has yet to be determined.

Lab members

Molly Craxton, Dan Lu, Alessandra Perfetto

Key publications

1. Wilson, CH., Gamper,I., Perfetto,A., Auw, J., Littlewood,TD. and Evan, GI. (2014).The kinetics of ER fusion protein activation in vivo. Oncogene 33, 4877-4880.

2. Littlewood TD, Kreuzaler, P and Evan, GI. (2012). All things to all people. Cell, 151, 11-13.

3. Yu, H., Clarke, M.C., Figg, N., Littlewood, T.D. and Bennett, M.R. (2011). Smooth muscle cells apoptosis promotes vessel remodeling and repair via activation of cell migration, proliferation and collagen synthesis. Arterioscler. Thromb. Vasc. Biol. 31, 2402-2409.

4. Allard D., Figg N., Bennett M and Littlewood T.(2008). Akt regulates the survival of vascular smooth muscle cells via inhibition of Foxo3a and GSK3. J. Biol. Chem., 19739-19747.

5. Tucka J., Yu H., Gray K., Figg N., Maguire J., Lam B., Bennett M. and Littlewood T. (2014). Akt1 regulates vascular smooth muscle cell apoptosis through Foxo3a and Apaf1 and protects against arterial remodeling and atherosclerosis. Aretrioscler. Thromb. Vasc. Biol.34, 2421-2428.

The microarray data generated with FoxO3aA3ER-expressing vascular smooth muscle cells is available here. Please note that these data are averaged from 6 biological replicates per sample and statistical analysis is included.  The full paper can be accessed at http://atvb.ahajournals.org/content/34/11/2421.full.html?ijkey=33Oroy7Uu4ztdKN&keytype=ref