Date of Award


Degree Type


Degree Name

Master of Science




Dr. Sean Cregan


Oxidative stress and ER dysfunction have been implicated as key triggers of neuronal apoptosis in acute and chronic neurodegenerative conditions. In the present study we demonstrate that oxidative- and ER-stressors induce PUMA expression and neuronal cell death through a p53-independent mechanism. Since the p53 family members, p63 and p73, can transactivate certain p53-responsive genes, we examined the possibility that these family members might co-operate with p53 or compensate for its loss in this context. Wildtype and p63-deficient cortical neurons exhibited similar levels of PUMA induction and neuronal apoptosis in response to oxidative and ER-stress. Furthermore, attenuation of p53 family activity via adenoviral transduction of Ad- ANp73a did not confer protection against ER-stress mediated apoptosis. Taken together, these results indicate that the p53-independent pathway regulating PUMA expression during ER-stress is not coordinated by the p53 family members, p63 or p73. Therefore, we have proposed two putative upstream regulators, ATF4 and CHOP, as potential regulators of PUMA induction via ER dysfunction.



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