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.
Molly Craxton, Dan Lu, Alessandra Perfetto
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, in the press.
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. Akt1 regulates vascular smooth muscle cell apoptosis through Foxo3a and Apaf1 and protects against arterial remodeling and atherosclerosis (submitted).
This manuscript reports experiments on the identification of FoxO3a transcriptional targets in vascular smooth muscle cells. 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. Prior to publication experimental information can be requested from Trevor Littlewood (firstname.lastname@example.org).