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New insights into cell cycle-dependent control of transcription: implications for cancer


Project Description

Defects in the cell cycle are the underlying basis to cancer. Work in my lab is aimed at understanding the molecular basis to tumourigenesis through studying pathways which impact on the cell cycle and are deregulated in cancer.

The cell cycle is regulated at several critical positions by distinct transcription factor complexes. These complexes are often conserved between lower eukaryotes and mammals, hence simple eukaryotes like yeast can provide a genetically tractable system to probe the fundamental mechanisms that are applicable to higher eukaryotes. The Forkhead transcription factor Fkh2 plays a key role in regulating the G2-M phase transition in S. cerevisiae. Fkh2 coordinates cell cycle cues by being targeted by Cdk-cyclin and Plk1 enzymes. In mammals, the Forkhead protein FOXM1 plays an analogous role. Recently, we have identified hundreds of target genes for FOXM1, and made the novel discovery that it is recruited to DNA independently of its sequence-specific DNA binding activity. Moreover, it appears to control gene expression in two different ways. We aim to investigate how FOXM1 promotes cell cycle-dependent transcription, and to identify novel regulators that impact on FOXM1 activity in this context. The mechanistic insights we uncover will form the basis to downstream analysis in oesophageal cancer cells and samples from patients with oesophageal adenocarcinoma.

The projects will employ a series of molecular biology techniques, including site-directed mutagenesis, affinity purification of proteins, protein phosphorylation assays and a variety of DNA binding and protein-protein interaction assays. Our work also encompasses a number of key postgenomic approaches including microarray, multiplex gene expression analysis (Nanostring and Fluidigm technologies) ChIP-seq and RNAi screening technologies. The integration of Bioinformatic and computational approaches is also a key area in the lab.

Funding Notes

This project has a Band 3 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Zoulfia Darieva, Richard Bulmer, Aline Pic-Taylor, Kathryn S. Doris, Marco Geymonat, Steven G. Sedgwick, Brian A. Morgan and Sharrocks, A.D. (2006) Polo kinase controls cell cycle-dependent transcription by direct targeting of a coactivator protein. Nature. 444, 494-498

Chen, X., Muller, G.A., Quaas, M., Fischer, M., Han, N., Stutchbury, B., Sharrocks, A.D. and Engeland, K. (2013) The Forkhead Transcription Factor FOXM1 controls cell cycle-dependent gene expression through an atypical chromatin binding mechanism. Mol. Cell Biol. 33, 227-236.

Dibb, M., Han, N., Ang, Y. and Sharrocks, A.D. (2012) The FOXM1-PLK1 axis is commonly upregulated in oeasophageal adenocarcinoma. British Journal of Cancer. 107, 1766-1775.

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