Constitutively active calcineurin mediates delayed neuronal death through Fas-ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia

Norifumi Shioda, Feng Han, Shigeki Moriguchi, Kohji Fukunaga

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

We recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain-mediated limited proteolysis following brain ischemia. The calpain-induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T-cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase-B (Akt), mediated ischemia-induced neuronal death through Fas-ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser-256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas-ligand by binding to its promoter region. Consistent with activation of the Fas-ligand promoter by FKHR dephosphorylation, Fas-ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas-ligand expression via up-regulation of both NFAT and FKHR transcriptional activity in brain ischemia.

Original languageEnglish
Pages (from-to)1506-1517
Number of pages12
JournalJournal of Neurochemistry
Volume102
Issue number5
DOIs
Publication statusPublished - 2007 Sep 1

Keywords

  • Brain ischemia
  • Calcineurin
  • Calpain
  • Fas-ligand
  • Forkhead transcription factor
  • Neuronal death

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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