Award details

D-type cyclins and the phosphorylation-dependent regulation of the function of p21Cip1

Reference	BB/C508134/1
Principal Investigator / Supervisor	Dr David Mann
Co-Investigators / Co-Supervisors
Institution	Imperial College London
Department	Biological Sciences
Funding type	Research
Value (£)	217,384
Status	Completed
Type	Research Grant
Start date	01/10/2004
End date	30/09/2008
Duration	48 months

Abstract

Commitment to execute the mammalian cell cycle is primarily regulated during the G1 phase by the D-type cyclins complexed with either cyclin-dependent kinase (cdk) 4 or 6 and by cyclin E/cdk2. These holoenzymes are believed to phosphorylate key substrates to enforce S phase entry. The action of these G1-specific cyclin/cdk holoenzymes is opposed by the inhibitory proteins p21 and p27. These proteins stoichiometrically bind to the cyclin and the cdk components and inhibit the enzyme activity. Paradoxically, these cdk inhibitors can promote activation of D-type cyclin/cdk holoenzymes by facilitating complex formation and promotion of nuclear localisation. It is evident therefore that p21 and p27 exhibit functions that are diametrically opposed: they favour cell cycle arrest through inhibition of cyclin/cdk complexes whilst they are also essential activators of the proliferation-promoting D cyclin/cdk complexes. The nature of the switch controlling conversion between these states is unknown. We have recently identified a novel phosphorylation site in p21 that may regulate these opposing functions of p21. This proposal is designed to investigate the role of this phosphorylation event in the functional modulation of the p21 protein. We will employ quantitative and qualitative determination of protein:protein interactions and a range of cell based studies combined with molecular biological techniques to generate recombinant proteins (both wild type or site-specific mutants). Through the experiments described we hope to uncover a novel mode of cell cycle regulation that may offer a novel route to therapeutic intervention through the promotion of the anti-proliferative function of the cdk inhibitor p21.

Summary

unavailable

Committee	Closed Committee - Biochemistry & Cell Biology (BCB)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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