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Title: Investigation of the role of cyclin dependent kinases in neuronal apoptosis
Author: Barkley, Laura Rose
ISNI:       0000 0001 3445 4295
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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Apoptosis and cell proliferation are fundamental processes that occur in all mammalian cells and there is evidence that there may be cross-talk between the two processes. Previous work has shown that activation of Cdk2 kinase is essential for apoptosis in resting thymocytes. The aim of this thesis was to determine whether cyclin dependent kinases (Cdks) can also regulate cell death in neuronal PC12 cells and sympathetic neurons. In the presence of nerve growth factor (NGF) PC12 cells stop dividing and acquire a neuronal phenotype. The removal of NGF causes these differentiated cells to undergo apoptosis. An increase in Cdk2 kinase activity and cyclin E-associated kinase activity was observed following NGF withdrawal in PC12 cells. However, the early activation of Cdk2 can not be attributed to cyclin E. In contrast, Cdk5, Cdc2, Cdk4 or cyclin A-associated kinase activity did not change. Roscovitine, a pharmacological Cdk inhibitor that specifically inhibits Cdk2, Cdk5 and Cdc2, was able to block this increase in Cdk2 kinase activity and protected PC12 cells from NGF withdrawal-induced apoptosis. Therefore, the activation of Cdk2 by an unknown regulator and cyclin E appears to be required for apoptosis in PC12 cells. Developing sympathetic neurons also die by apoptosis when deprived of NGF. An increase in Cdk2, Cdk5 and Cdc2 kinase activity was observed following NGF withdrawal. Cyclin A and cyclin E-associated kinase activity, and Cdk4 and cyclin D1-associated kinase activity did not change. Roscovitine was able to protect sympathetic neurons from NGF withdrawal-induced apoptosis. HD and NG-75, which are more potent pharmacological Cdk inhibitors, were also able to protect sympathetic neurons from apoptosis. Thus, Cdk2, Cdc2 and Cdk5 are activated during apoptosis in sympathetic neurons, and Cdk activation is upstream of mitochondrial cytochrome c release.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available