dc.contributor.advisor | Campbell, Veronica | |
dc.contributor.author | Gowran, Aoife | |
dc.date.accessioned | 2016-12-15T10:15:35Z | |
dc.date.available | 2016-12-15T10:15:35Z | |
dc.date.issued | 2008 | |
dc.identifier.citation | Aoife Gowran, 'An investigation of the molecular signalling events which occur in cannabiniod-mediated neuronal apoptosis', [thesis], Trinity College (Dublin, Ireland). Department of Physiology, 2008, pp 402 | |
dc.identifier.other | THESIS 8519 | |
dc.description.abstract | The plant-derived cannabinoid Δ9-Tetrahydrocannabinol, is the predominant psychoactive moiety of cannabis and exerts a variety of psychological and physiological effects in humans. Previous investigations in this laboratory have shown that Δ9-Tetrahydrocannabinol (5 μM) induces apoptosis in cortical neurones via signalling through the cannabinoid receptor type 1. The phosphorylation of the tumour suppressor protein, p53 at serine residue 15 is a critical step in stabilising p53 and promoting p53-induced apoptosis. I report that Δ9-Tetrahydrocannabinol activates p53 by inducing the phosphorylation of serine residue 15, which was mediated by the stress activated protein kinase, c-jun N terminal kinase 1. Furthermore, Δ9-Tetrahydrocannabinol induced the translocation of phosphorylated-p53 ser15 to the lysosomal membrane; an event that coincided with Δ9-Tetrahydrocannabinol-induced lysosomal membrane destabilisation. Δ9-Tetrahydrocannabinol also induced the selective translocation of cathepsin-D, a lysosomal protease which was required for Δ9- Tetrahydrocannabinol-induced caspase-3 activation and DNA fragmentation. Depleting neurones of p53 using small interfering RNA inhibited Δ9-Tetrahydrocannabinol- induced lysosomal membrane destabilisation and DNA fragmentation, indicating that p53 signalling is pivotal in Δ9-Tetrahydrocannabinol-induced lysosomal branch of neuronal apoptosis. Additional evidence for the proclivity of Δ9-Tetrahydrocannabinol to regulate p53 signalling was demonstrated by the alterations observed in the p53 post translational modifying proteins, murine double minute 2 and small ubiquitin modifier 1. The observed changes in these p53 regulatory proteins could potentially increase the activity of p53, thus promoting Δ9-Tetrahydrocannabinol-induced p53-dependent neuronal apoptosis. | |
dc.format | 1 volume | |
dc.language.iso | en | |
dc.publisher | Trinity College (Dublin, Ireland). Department of Physiology | |
dc.relation.isversionof | http://stella.catalogue.tcd.ie/iii/encore/record/C__Rb13383275 | |
dc.subject | Physiology, Ph.D. | |
dc.subject | Ph.D. Trinity College Dublin | |
dc.title | An investigation of the molecular signalling events which occur in cannabiniod-mediated neuronal apoptosis | |
dc.type | thesis | |
dc.type.supercollection | thesis_dissertations | |
dc.type.supercollection | refereed_publications | |
dc.type.qualificationlevel | Doctoral | |
dc.type.qualificationname | Doctor of Philosophy (Ph.D.) | |
dc.rights.ecaccessrights | openAccess | |
dc.format.extentpagination | pp 402 | |
dc.description.note | TARA (Trinity’s Access to Research Archive) has a robust takedown policy. Please contact us if you have any concerns: rssadmin@tcd.ie | |
dc.identifier.uri | http://hdl.handle.net/2262/78399 | |