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The CREB/CRE transcriptional pathway: protection against oxidative stress‐mediated neuronal cell death
Author(s) -
Lee Boyoung,
Cao Ruifeng,
Choi YunSik,
Cho HeeYeon,
Rhee Alex D.,
Hah Cyrus K.,
Hoyt Kari R.,
Obrietan Karl
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05864.x
Subject(s) - creb , neuroprotection , microbiology and biotechnology , reactive oxygen species , biology , programmed cell death , coactivator , transcription factor , neurotrophic factors , transgene , genetically modified mouse , receptor , pharmacology , apoptosis , biochemistry , gene
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.