The CREB/CRE transcriptional pathway: Protection against oxidative stress-mediated neuronal cell death

Boyoung Lee, Ruifeng Cao, Yun Sik Choi, Hee Yeon Cho, Alex D. Rhee, Cyrus K. Hah, Kari R. Hoyt, Karl Obrietan

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1251-1265
Number of pages15
JournalJournal of Neurochemistry
Volume108
Issue number5
DOIs
StatePublished - Mar 2009

Keywords

  • Cell death
  • Cyclic AMP-response element binding protein
  • Oxidative stress
  • Peroxisome proliferator-activated receptor gamma coactivator-1α
  • Reactive oxygen species
  • Striatum

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