The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death.
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-1alpha 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.
Lee
Boyoung
B
Department of Neuroscience, Ohio State University, Columbus, 43210, USA.
Cao
Ruifeng
R
Choi
Yun-Sik
YS
Cho
Hee-Yeon
HY
Rhee
Alex D
AD
Hah
Cyrus K
CK
Hoyt
Kari R
KR
Obrietan
Karl
K
D000818:Animals; D001285:Atropine; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D021983:Cyclophilins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004569:Electroencephalography; D004622:Embryo, Mammalian; D005452:Fluoresceins; D049452:Green Fluorescent Proteins / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009930:Organic Chemicals / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014162:Transfection / Q000379:methods
C508138:A-CREB protein; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D005452:Fluoresceins; D009097:Multienzyme Complexes; D009930:Organic Chemicals; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C435731:fluoro jade; D010862:Pilocarpine; D049452:Green Fluorescent Proteins; D001285:Atropine; D051547:Heme Oxygenase-1; D021983:Cyclophilins