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dc.contributor.authorHallett, Stephen Timothy-
dc.descriptionPhD thesisen_US
dc.description.abstractThe cyclin-dependent kinases (CDKs) are a well-conserved family of serine/threonine protein kinases that drive mammalian cell cycle progression. The transition of cells through the early G1 stage of the cell cycle is co-ordinated by CDK4 and CDK6 following mitogen-dependent expression of D-type cyclins. Irregular CDK activity results in abnormal cell cycle control and is a significant indicator of poor cancer prognosis. The chaperone Hsp90, with the adaptor co-chaperone Cdc37, plays a key role in regulating the stability and function of a substantial proportion of the kinome including CDK4 and CDK6. However, the mechanism of CDK4(6)-cyclin D complex formation and regulation via the Hsp90 chaperone system remains poorly understood. A range of biophysical and biochemical techniques have been used to investigate the mechanism of CDK4(6)-cyclin D complex formation and regulation by the D-type cyclins and cyclin-dependent kinase inhibitors (CKIs) via the Hsp90 chaperone system. These have revealed that Cdc37 complexes can distinguish D-type cyclins, with CDK6 being more readily relinquished to cyclin D3 than cyclin D1, while the presence of p27KIP1 can stabilise the CDK-cyclin complexes against re-distribution into complexes with Cdc37, potentially providing an assembly role for CDK-cyclin complexes. In contrast to the D-type cyclins the CDKs were found to be readily relinquished by Cdc37 to members of the INK family, potent inhibitors of CDK4 and CDK6. However, this potency can be greatly reduced by the introduction of clinically significant INK point mutations, one of which differs greatly in its ability to bind and displace CDK4 and CDK6. In addition, co-crystal structures of selected CDK4/6 inhibitors bound to CDK2-cyclin A have been determined to gain a greater understanding of inhibitor selectivity and binding modes. Taken together these results suggest the Cdc37-Hsp90 chaperone system provides an opportunity to fine tune the regulation of CDK4 and CDK6 activities during G1.en_US
dc.description.sponsorshipMedical Research Councilen_US
dc.publisherNewcastle Universityen_US
dc.titleStructural and functional characterisation of cyclin-dependent kinase 6-cyclin D complexesen_US
Appears in Collections:Northern Institute for Cancer Research

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