Date of Award


Degree Type


Degree Name

Master of Science




Dr. Sean Cregan

Second Advisor

Dr. Susan Meakin

Third Advisor

Dr. Robert Gros


Apoptosis plays an important role in both neurodevelopment and neurodegeneration. The Bcl-2 protein family consists of multiple pro-apoptotic and anti- apoptotic family members that play a key role in regulating apoptotic cell death. The pro-apoptotic member Bax has been shown to be a key mediator of neuronal apoptosis, however the mechanisms regulating Bax activation remain poorly defined. In the present study we have investigated the signaling pathways regulating Bax activation using an in vitro model of activity-dependent neuronal survival. We demonstrate that the Bcl-2 family member Puma is upregulated and that this is essential for Bax-mediated cell death. We therefore investigated two known pro-apoptotic signaling pathways: the cJun N-terminal kinase (JNK) and glycogen synthase kinase-3 (GSK3) pathways. We found that inhibition of JNK and/or GSK3 attenuates Puma induction and neuronal cell death. Furthermore, we demonstrate that activation of the PI3K/AKT pathway inhibits Puma induction and promotes neuronal survival at least in part through inhibition of JNK and GSK3 activation. Taken together these results indicate that the JNK, GSK3, and AKT pathways converge to modulate Bax activation and neuronal apoptosis by regulating the transcriptional induction of the Bcl-2 family protein Puma.



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