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Structure, stability, folding and function of the tumour suppressor p16

Objective



Research objectives and content
Regulation of the cell cycle is critical for the development of multicellular organisms and loss of control can lead to cancer. The molecular processes unravelled so far have been shown to be essentially the same in all eukaryotic cells. For a deeper understanding of the cell cycle machinery the structure, function, stability and folding of its component proteins need to be characterised. p16INK4 is a specific cyclin D-dependant kinase inhibitor and a multiple tumor suppressor involved in cancers of the skin, pancreas, oesophagus and bladder. Inactivation of p 16 is frequent in both primary tumors and tumour-derived cell lines. Preliminary studies have shown that the common mechanism of inactivation of pl6 may well be defective folding. Experiments are proposed here to investigate the folding pathway and the mechanism of inactivation using protein engineering combined with equilibrium stability measurements and fast kinetic measurements. Also a detailed structural analysis of peptide fragments of pl6 (in collaboration with Prof. D. Lane, University of Dundee) and of the molecular recognition of p 16 and cyclin-CDKs will be performed using Nuclear Magnetic Resonance (NMR).
Training content (objective, benefit and expected impact)
The training objective of this research project is to obtain a PhD degree from the university of Cambridge and acquire skills in a wide range of biophysical techniques as well as in protein engineering and protein expression and purification. The laboratory of Professor A.R. Fersht, F.R.S. is a stimulating environment for this purpose. It provides first class facilities and technical expertise for training in the multi-disciplinary aspects of the project. I expect to benefit also from the scientific environment of Cambridge, and the laboratories in the area, in particular the Laboratory of Molecular Biology and the EMBL outstation. Links with industry / industrial relevance (22)

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

MRC Centre for Protein Engineering
Address
Hills Road
CB2 2QH Cambridge
United Kingdom