The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death
Article first published online: 22 DEC 2008
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 108, Issue 5, pages 1251–1265, March 2009
How to Cite
Lee, B., Cao, R., Choi, Y.-S., Cho, H.-Y., Rhee, A. D., Hah, C. K., Hoyt, K. R. and Obrietan, K. (2009), The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death. Journal of Neurochemistry, 108: 1251–1265. doi: 10.1111/j.1471-4159.2008.05864.x
- Issue published online: 9 FEB 2009
- Article first published online: 22 DEC 2008
- Received September 22, 2008; revised manuscript received November 28, 2008; accepted December 15, 2008.
- cell death;
- cyclic AMP-response element binding protein;
- oxidative stress;
- peroxisome proliferator-activated receptor gamma coactivator-1α;
- reactive oxygen species;
Formation of reactive oxygen and nitrogen species is a precipitating event in an array of neuropathological conditions. In response to excessive reactive oxygen species (ROS) levels, transcriptionally dependent mechanisms drive the up-regulation of ROS scavenging proteins which, in turn, limit the extent of brain damage. Here, we employed a transgenic approach in which cAMP-response element binding protein (CREB)-mediated transcription is repressed (via A-CREB) to examine the contribution of the CREB/cAMP response element pathway to neuroprotection and its potential role in limiting ROS toxicity. Using the pilocarpine-evoked repetitive seizure model, we detected a marked enhancement of cell death in A-CREB transgenic mice. Paralleling this, there was a dramatic increase in tyrosine nitration (a marker of reactive species formation) in A-CREB transgenic mice. In addition, inducible expression of peroxisome proliferator-activated receptor gamma coactivator-1α was diminished in A-CREB transgenic mice, as was activity of complex I of the mitochondrial electron transport chain. Finally, the neuroprotective effect of brain-derived neurotrophic factor (BDNF) against ROS-mediated cell death was abrogated by disruption of CREB-mediated transcription. Together, these data both extend our understanding of CREB functionality and provide in vivo validation for a model in which CREB functions as a pivotal upstream integrator of neuroprotective signaling against ROS-mediated cell death.