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Systems analysis of MAP kinase signalling to the nucleus; implications for stem cells and cancer


Project Description

The MAP kinase pathways play important roles in normal cellular function and are often disrupted in diseases such as cancer. One major route through which these pathways function is through changing the activities of transcription factors. However, the simplistic model that MAP kinase signaling takes a linear route from the cell membrane to the nucleus and through a limited number of transcription factors to control gene expression programmes, is clearly a vast over-simplification. Recently, in an attempt to expand this regulatory network we performed two genome-wide RNAi screens to identify novel regulators of MAP kinase pathway signalling that impact on gene expression programmes. Several novel regulators were identified. The aim of this project is to discover the role of these novel regulators in controlling the transcriptional output of the MAP kinase signalling pathways by using systems based approaches. Novel methodologies based around Next generation sequencing will be employed and the biological role of the findings will be determined in the context of embryonic stem cell differentiation and under conditions of highly active ERK signalling in cancer such as in oesophageal adenocarcinoma.

Funding Notes

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

References

• Odrowaz, Z.A., O’Donnell, A. and Sharrocks, A.D. (2012) Immediate-early gene activation by the MAP kinase pathways: what do and don’t we know? Biochem Soc Trans. 40, 58-66.

• Odrowaz, Z. and Sharrocks, A.D. (2012) ELK1 uses different DNA binding modes to regulate functionally distinct subclasses of target genes. PLoS Genetics. 8, e1002694.

• Yang, S-H., Kalkan, T., Morissroe, C., Marks, H., Stunnenberg, H., Smith, A., and Sharrocks, A.D. (2014) Otx2 and Oct4 drive early enhancer activation during ES cell transition from naïve pluripotency. Cell Reports. 7:1968-81

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