PMID- 19141071 OWN - NLM STAT- MEDLINE DCOM- 20090422 LR - 20220317 IS - 1471-4159 (Electronic) IS - 0022-3042 (Print) IS - 0022-3042 (Linking) VI - 108 IP - 5 DP - 2009 Mar TI - The CREB/CRE transcriptional pathway: protection against oxidative stress-mediated neuronal cell death. PG - 1251-65 LID - 10.1111/j.1471-4159.2008.05864.x [doi] 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-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. FAU - Lee, Boyoung AU - Lee B AD - Department of Neuroscience, Ohio State University, Columbus, 43210, USA. FAU - Cao, Ruifeng AU - Cao R FAU - Choi, Yun-Sik AU - Choi YS FAU - Cho, Hee-Yeon AU - Cho HY FAU - Rhee, Alex D AU - Rhee AD FAU - Hah, Cyrus K AU - Hah CK FAU - Hoyt, Kari R AU - Hoyt KR FAU - Obrietan, Karl AU - Obrietan K LA - eng GR - R01 MH062335-05/MH/NIMH NIH HHS/United States GR - NS47176/NS/NINDS NIH HHS/United States GR - MH62335/MH/NIMH NIH HHS/United States GR - R01 NS047176-04/NS/NINDS NIH HHS/United States GR - R01 MH062335-07/MH/NIMH NIH HHS/United States GR - R01 MH062335/MH/NIMH NIH HHS/United States GR - R01 NS047176/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20090128 PL - England TA - J Neurochem JT - Journal of neurochemistry JID - 2985190R RN - 0 (A-CREB protein) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Fluoresceins) RN - 0 (Multienzyme Complexes) RN - 0 (Organic Chemicals) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Trans-Activators) RN - 0 (Transcription Factors) RN - 0 (fluoro jade) RN - 01MI4Q9DI3 (Pilocarpine) RN - 147336-22-9 (Green Fluorescent Proteins) RN - 7C0697DR9I (Atropine) RN - EC 1.14.14.18 (Heme Oxygenase-1) RN - EC 5.2.1.- (Cyclophilins) SB - IM MH - Animals MH - Atropine MH - Brain-Derived Neurotrophic Factor/pharmacology MH - Cells, Cultured MH - Corpus Striatum/cytology MH - Cyclic AMP Response Element-Binding Protein/*metabolism MH - Cyclophilins/genetics/metabolism MH - Disease Models, Animal MH - Electroencephalography MH - Embryo, Mammalian MH - Fluoresceins MH - Green Fluorescent Proteins/genetics MH - Heme Oxygenase-1/genetics/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Multienzyme Complexes/metabolism MH - Neurons/drug effects/*physiology MH - Organic Chemicals/metabolism MH - Oxidative Stress/drug effects/*physiology MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha MH - Pilocarpine MH - Rats MH - Rats, Sprague-Dawley MH - Recombinant Fusion Proteins/genetics/metabolism MH - Signal Transduction/*physiology MH - Status Epilepticus/chemically induced/*pathology MH - Trans-Activators/genetics/metabolism MH - Transcription Factors MH - Transfection/methods PMC - PMC2884273 MID - NIHMS105454 EDAT- 2009/01/15 09:00 MHDA- 2009/04/23 09:00 PMCR- 2010/06/14 CRDT- 2009/01/15 09:00 PHST- 2009/01/15 09:00 [entrez] PHST- 2009/01/15 09:00 [pubmed] PHST- 2009/04/23 09:00 [medline] PHST- 2010/06/14 00:00 [pmc-release] AID - JNC5864 [pii] AID - 10.1111/j.1471-4159.2008.05864.x [doi] PST - ppublish SO - J Neurochem. 2009 Mar;108(5):1251-65. doi: 10.1111/j.1471-4159.2008.05864.x. Epub 2009 Jan 28.