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Identification of the signalling networks that regulate Ciz1 levels, cellular proliferation and tumorigenesis


Project Description

This multidisciplinary PhD project, will develop the successful candidate through training in Lancaster University and Northwest Cancer Centre, at The University of Liverpool. This PhD offers extensive training to develop the necessary personal and technical skills required for a successful research career in genome stability and cancer biology.

Project Background
The DNA replication factor Ciz1, coordinates the activity of cyclin A-CDK2 to ensure efficient initiation of DNA replication(1,2). Ciz1 promotes cellular proliferation in vivo and in vitro(1,2) and can induce tumour formation in mouse xenograft models(3). Ciz1 overexpression induces oestrogen hypersensitivity in breast cancer cell lines and is associated with increased mortality in colorectal cancer6. This suggests that strategies that can reduce Ciz1 protein levels may be of clinical benefit. Importantly, reduction of Ciz1 levels using siRNA/shRNA reduces tumour size in breast, lung, prostate, and hepatocellular xenograft models (3). Significantly, although Ciz1 is required for tumour growth and metastasis in xenograft models(3), Ciz1 is a non-essential gene for development, suggesting that Ciz1 may represent a selective, cancer specific therapeutic target.

Our preliminary data suggest that inhibition of CDK2 activity reduces Ciz1 levels via the ubiquitin proteasome system (UPS), a clinically significant observation as CDK inhibition is the first-line treatment in advanced HR+/Her2- breast cancer. Importantly, we have identified three putative E3 ligases that regulate Ciz1 levels. The activity of each E3 ligase will be assessed in cell based and in vitro biochemical assays. The full functional characterisation of this pathway will identify potential biomarkers for patient stratification and establish the mechanistic model for the targeting of Ciz1 in the clinic.

Project Aims
This successful candidate will:

(i) Identify the regulatory ubiquitin E2 conjugating enzymes and E3 ligase that regulate Ciz1 levels.
(ii) Evaluate the use of E3 overexpression to reduce Ciz1 levels and determine the effect on cell cycle progression and cellular proliferation.
(iii) Determine the efficacy of CDK2 inhibition to reduce Ciz1 levels and proliferation in 2D and 3D cancer spheroid models.

This strategy will enable the identification of the signalling networks that regulate Ciz1 accumulation and degradation in vivo and facilitate development of strategies that reduce Ciz1 levels in common cancers.

The successful candidate will be highly motivated students with an interest in cancer biology, the ubiquitin proteasome system and CDK activity. This project will use a wide range of techniques including protein biochemistry, cell biology, siRNA, imaging and in vitro cancer models. In addition, this project is supervised by an experienced team in Lancaster and Liverpool and will provide world class training to develop the successful candidate to reach their full potential.

Funding Notes

Applications should be made directly to Dr Nikki Copeland and should include:

CV (max 2 A4 sides), including details of two academic references
A cover letter outlining their qualifications and interest in the studentship (max 2 A4 sides)

References

Copeland, N. A., Sercombe, H. E., Ainscough, J. F. & Coverley, D. Ciz1 cooperates with cyclin-A-CDK2 to activate mammalian DNA replication in vitro. J Cell Sci 123, 1108-1115 (2010).
2 Copeland, N. A., Sercombe, H. E., Wilson, R. H. & Coverley, D. Cyclin-A-CDK2-mediated phosphorylation of CIZ1 blocks replisome formation and initiation of mammalian DNA replication. J Cell Sci 128, 1518-1527, doi:10.1242/jcs.161919 (2015).
3 Pauzaite, T., Thacker, U., Tollitt, J. & Copeland, N. A. Emerging Roles for Ciz1 in Cell Cycle Regulation and as a Driver of Tumorigenesis. Biomolecules 7, doi:10.3390/biom7010001 (2016).1 Copeland, N. A., Sercombe, H. E., Ainscough, J. F. & Coverley, D. Ciz1 cooperates with cyclin-A-CDK2 to activate mammalian DNA replication in vitro. J Cell Sci 123, 1108-1115 (2010).

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