Creb activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation

Thierry Arnould, Sebastien Vankoningsloo, Patricia Renard, Andrée Houbion, Noëlle Ninane, Catherine Demazy, José Remacle, Martine Raes

Research output: Contribution to journalArticlepeer-review


We characterized a new signaling pathway leading to the activation of cAMP-responsive element-binding protein (CREB) in several cell lines affected by mitochondrial dysfunction. In vitro kinase assays, inhibitors of several kinase pathways and overexpression of a dominant-negative mutant for calcium/calmodulin kinase IV (CaMKIV), which blocks the activation of CREB, showed that CaMKIV is activated by a mitochondrial activity impairment. A high calcium concentration leading to the disruption of the protein interaction with protein phosphatase 2A explains CaMKIV activation in these conditions. Transcriptionally active phosphorylated CREB was also found in a ρ0 143B human osteosarcoma cell line and in a MERRF cybrid cell line mutated for tRNALys (A8344G). We also showed that phosphorylated CREB is involved in the proliferation defect induced by a mitochondrial dysfunction. Indeed, cell proliferation inhibition can be prevented by CaMKIV inhibition and CREB dominant-negative mutants. Finally, our data suggest that phosphorylated CREB recruits p53 tumor suppressor protein, modifies its transcriptional activity and increases the expression of p21Waf1/Cip1, a p53-regulated cyclin-dependent kinase inhibitor.

Original languageEnglish
Pages (from-to)53-63
Number of pages11
JournalThe EMBO journal
Issue number1-2
Publication statusPublished - 15 Jan 2002


  • Calcium-calmodulin kinase IV
  • Cell proliferation
  • CyclicAMP response element-binding protein
  • Mitochondrial dysfunction
  • Retrograde communication


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