PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: Involvement of c-Fos in PACAP-induced Bcl-2 expression

Nicolas Aubert, Anthony Falluel-Morel, David Vaudry, Xavier Xifro, José Rodriguez-Alvarez, Cécile Fisch, Stéphane De Jouffrey, Jean François Lebigot, Alain Fournier, Hubert Vaudry, Bruno J. Gonzalez

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

Abstract

The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) inhibits C2-ceramide-induced cell death through blockade of the mitochondrial apoptotic pathway in rat cerebellar granule neurones. However, the gene induction processes and transcription factors involved in the anti-apoptotic effect of PACAP remain unknown. Here, we show that PACAP and C2-ceramide activate activator protein-1 (AP-1) DNA binding in a dose- and time-dependent manner, but generate different AP-1 dimers. Thus, PACAP increased the proportion of c-Fos and Jun D while C2-ceramide increased c-Jun and reduced c-Fos in AP-1 complexes. In addition, PACAP strongly activated c-Fos gene expression while C2-ceramide markedly increased c-Jun phosphorylation. The effect of PACAP on c-Fos expression was blocked by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) inhibitor, U0126, while phosphorylation of c-Jun induced by C2-ceramide was abrogated by the protein phosphatase 2A (PP2A) inhibitor, okadaic acid. Transfection of immature granule cells with c-Fos siRNA, which strongly reduced basal and PACAP-stimulated levels of the protein, totally prevented the stimulatory effect of PACAP on Bcl-2 expression. The present study demonstrates that AP-1 complexes containing c-Fos mediate the effect of PACAP on Bcl-2 gene expression in cerebellar granule neurones. Our data also indicate that different AP-1 dimers are associated with the pro-apoptotic effect of C2-ceramide and the anti-apoptotic effect of PACAP. © 2006 The Authors.
Original languageEnglish
Pages (from-to)1237-1250
JournalJournal of Neurochemistry
Volume99
DOIs
Publication statusPublished - 1 Nov 2006

Keywords

  • Activator protein-1
  • Apoptosis
  • Ceramide
  • Cerebellar granule cells
  • Pituitary adenylate cyclase-activating polypeptide

Fingerprint Dive into the research topics of 'PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: Involvement of c-Fos in PACAP-induced Bcl-2 expression'. Together they form a unique fingerprint.

Cite this