CREB-mediated Bcl-2 protein expression after ischemic preconditioning

Robert Meller, Manabu Minami, Jennifer A. Cameron, Soren Impey, Dexi Chen, Jing Quan Lan, David C. Henshall, Roger P. Simon

Research output: Contribution to journalArticlepeer-review

182 Scopus citations


Bcl-2 plays a pivotal role in the control of cell death and is upregulated by ischemic tolerance. Because Bcl-2 expression is regulated by the transcription factor cyclic AMP response element-binding protein (CREB), we investigated the role of CREB activation in two models of ischemic preconditioning: focal ischemic tolerance after middle cerebral artery occlusion (MCAO) and in vitro ischemic tolerance modeled by oxygen-glucose deprivation (OGD). After preconditioning ischemia (30 minutes MCAO or 30 minutes OGD), phosphorylation of CREB was increased, and there was an increased interaction between the bcl-2 cyclic AMP-responsive element (CRE) promoter and nuclear proteins after preconditioning ischemia in vivo and in vitro. Chromatin immunoprecipitation revealed an increased interaction between CREB-binding protein and the bcl-2 CRE rather than CREB, after preconditioning ischemia. Ischemic tolerance was blocked by a CRE decoy oligonucleotide, which also blocked Bcl-2 expression. The protein kinase A inhibitor H89, the calcium/calmodulin kinase inhibitor KN62, and the MEK inhibitor U0126 blocked ischemic tolerance, but not the phosphatidylinositol 3-kinase inhibitor LY294002. H89, KN62, and U0126 reduced CREB activation and Bcl-2 expression. Taken together, these data suggest that after ischemic preconditioning CREB activation regulates the expression of the prosurvival protein Bcl-2.

Original languageEnglish (US)
Pages (from-to)234-246
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number2
StatePublished - Feb 2005
Externally publishedYes


  • Akt
  • Calcium/calmodulin-dependent protein kinase
  • Ischemic tolerance
  • P42/p44 mitogen activated protein kinase
  • Protein kinase A

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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