TY - JOUR
T1 - The CREB/CRE transcriptional pathway
T2 - Protection against oxidative stress-mediated neuronal cell death
AU - Lee, Boyoung
AU - Cao, Ruifeng
AU - Choi, Yun Sik
AU - Cho, Hee Yeon
AU - Rhee, Alex D.
AU - Hah, Cyrus K.
AU - Hoyt, Kari R.
AU - Obrietan, Karl
PY - 2009/3
Y1 - 2009/3
N2 - 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.
AB - 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.
KW - Cell death
KW - Cyclic AMP-response element binding protein
KW - Oxidative stress
KW - Peroxisome proliferator-activated receptor gamma coactivator-1α
KW - Reactive oxygen species
KW - Striatum
UR - http://www.scopus.com/inward/record.url?scp=59449090590&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=59449090590&partnerID=8YFLogxK
U2 - 10.1111/j.1471-4159.2008.05864.x
DO - 10.1111/j.1471-4159.2008.05864.x
M3 - Article
C2 - 19141071
AN - SCOPUS:59449090590
SN - 0022-3042
VL - 108
SP - 1251
EP - 1265
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
IS - 5
ER -