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Title: Induction of apoptosis by cytosine arabinoside in sympathetic neurons
Author: Anderson, C. N. G.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 1999
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To test whether araC interfered with NGF signalling, I examined the effect of araC treatment on signalling pathways both before and during apoptosis. Using a solid-phase kinase assay and antibodies to active forms of signalling proteins, I found that treatment of neurons with araC induced apoptosis without affecting NGF-maintained signalling. AraC caused no reduction in the activity of either mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) or protein kinase B/Akt, a kinase implicated in NGF-mediated survival. AraC also did not activate c-Jun N-terminal kinase (JNK) or cause c-Jun N-terminal phosphorylation, processes that are implicated in apoptosis induced by NGF withdrawal. In investigating a role for p53 in araC-induced apoptosis, I established that p53 protein levels were elevated before and during apoptosis by treatment with araC. There was, however, no increase in the levels of p53 protein after NGF withdrawal. Furthermore, neurons from p53 null mice were resistant to treatment with araC, although in response to NGF withdrawal, these neurons and neurons from wild type animals died at a similar rate. It was found previously that MAPK/ERK activity was not necessary for NGF-induced survival. I found, by contrast, that MAPK/ERK activity protected against araC-induced toxicity as inhibition of the MAPK pathway by PD98059 resulted in a significant increase in the rate of apoptosis induced by araC in the presence of NGF. Consistent with this finding, ciliary neurotrophic factor, which induces survival but not sustained activation of MAPK/ERK, failed to protect against araC toxicity. The data presented here suggests that araC does not inhibit NGF-mediated signalling, but instead causes apoptosis by a p53-dependent mechanism which can be inhibited by MAPK/ERK activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available