RT Journal Article
SR Electronic
T1 Puma Is a Dominant Regulator of Oxidative Stress Induced Bax Activation and Neuronal Apoptosis
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12989
OP 12999
DO 10.1523/JNEUROSCI.3400-07.2007
VO 27
IS 47
A1 Diana Steckley
A1 Meera Karajgikar
A1 Lianne B. Dale
A1 Ben Fuerth
A1 Patrick Swan
A1 Chris Drummond-Main
A1 Michael O. Poulter
A1 Stephen S. G. Ferguson
A1 Andreas Strasser
A1 Sean P. Cregan
YR 2007
UL http://www.jneurosci.org/content/27/47/12989.abstract
AB Oxidative stress has been implicated as a key trigger of neuronal apoptosis in stroke and neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. The Bcl-2 homology 3 (BH3)-only subfamily of Bcl-2 genes consists of multiple members that can be activated in a cell-type- and stimulus-specific manner to promote cell death. In the present study, we demonstrate that, in cortical neurons, oxidative stress induces the expression of the BH3-only members Bim, Noxa, and Puma. Importantly, we have determined that Puma−/− neurons, but not Bim−/− or Noxa−/− neurons, are remarkably resistant to the induction of apoptosis by multiple oxidative stressors. Furthermore, we have determined that Bcl-2-associated X protein (Bax) is also required for oxidative stress induced cell death and that Puma plays a dominant role in regulating Bax activation. Specifically, we have established that the induction of Puma, but not Bim or Noxa, is necessary and sufficient to induce a conformational change in Bax to its active state, its translocation to the mitochondria and mitochondrial membrane permeabilization. Finally, we demonstrate that whereas both Puma and BimEL can bind to the antiapoptotic family member Bcl-XL, only Puma was found to associate with Bax. This suggests that in addition to neutralizing antiapoptotic members, Puma may play a dominant role by complexing with Bax and directly promoting its activation. Overall, we have identified Puma as a dominant regulator of oxidative stress induced Bax activation and neuronal apoptosis, and suggest that Puma may be an effective therapeutic target for the treatment of a number of neurodegenerative conditions.