Apoptosis in cerebellar granule neurons is associated with reduced interaction between CREB-binding protein and NF-κB

Asligul Yalcin, Elena Koulich, Salah Mohamed, Li Liu, Santosh R. D'Mello

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Cerebellar granule neurons undergo apoptosis when switched from medium containing depolarizing levels of potassium (high K+ medium, HK) to medium containing low K+ (LK). NF-κB, a ubiquitously expressed transcription factor, is involved in the survival-promoting effects of HK. However, neither the expression nor the intracellular localization of the five NF-κB proteins, or of IκB-α and IκB-β, are altered in neurons primed to undergo apoptosis by LK, suggesting that uncommon mechanisms regulate NF-κB activity in granule neurons. In this study, we show that p65 interacts with the transcriptional co-activator, CREB-binding protein (CBP), in healthy neurons. The decrease in NF-κB transcriptional activity caused by LK treatment is accompanied by a reduction in the interaction between p65 and CBP, an alteration that is accompanied by hyperphosporylation of CBP. LK-induced CBP hyperphosphorylation can be mimicked by inhibitors of protein phosphatase (PP) 2A and PP2A-like phosphatases such as okadaic acid and cantharidin, which also causes a reduction in p65-CBP association. In addition, treatment with these inhibitors induces cell death. Treatment with high concentrations of the broad-spectrum kinase inhibitor staurosporine prevents LK-mediated CBP hyperphosphorylation and inhibits cell death. In vitro kinase assays using glutathione-S-transferase (GST)-CBP fusion proteins map the LK-regulated site of phosphorylation to a region spanning residues 1662-1840 of CBP. Our results are consistent with possibility that LK-induced apoptosis is triggered by CBP hyperphosphorylation, an alteration that causes the dissociation of CBP and NF-κB.

Original languageEnglish (US)
Pages (from-to)397-408
Number of pages12
JournalJournal of Neurochemistry
Volume84
Issue number2
DOIs
StatePublished - Jan 2003

Keywords

  • Apoptosis
  • CREB-binding protein
  • Depolarization
  • NF-κB
  • Neuronal survival
  • Phosphatase 2A

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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