Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival

Barbara Bedogni, Giovambattista Pani, Renata Colavitti, Antonella Riccio, Silvia Borrello, Mike Murphy, Robin Smith, Maria Luisa Eboli, Tommaso Galeotti

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

Reactive oxygen species (ROS) act as both signaling molecules and mediators of cell damage in the nervous system and are implicated in the pathogenesis of neurodegenerative diseases. Neurotrophic factors such as the nerve-derived growth factor (NGF) support neuronal survival during development and promote regeneration after neuronal injury through the activation of intracellular signals whose molecular effectors and downstream targets are still largely unknown. Here we present evidence that early oxidative signals initiated by NGF in PC12 cells, an NGF-responsive cell line, play a critical role in preventing apoptosis induced by serum deprivation. This redox-signaling cascade involves phosphatidylinositol 3-kinase, the small GTPase Rac-1, and the transcription factor cAMP-responsive element-binding protein (CREB), a molecule essential to promote NGF-dependent survival. We found that ROS are necessary for NGF-dependent phosphorylation of CREB, an event directly correlated with CREB activity, whereas hydrogen peroxide induces a robust CREB phosphorylation. Cells exposed to NGF show a late decrease in the intracellular content of ROS when compared with untreated cells and increased expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase, a general inhibitor of cell death. Accordingly, serum deprivation-induced apoptosis was selectively inhibited by low concentrations of the mitochondrially targeted antioxidant Mito Q (mitoquinol/mitoquinone). Taken together, these data demonstrate that the oxidant-dependent activation of CREB is a component of NGF survival signaling in PC12 cells and outline an intriguing circuitry by which a cytosolic redox cascade promotes cell survival at least in part by increasing mitochondrial resistance to oxidative stress.

Original languageEnglish (US)
Pages (from-to)16510-16519
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number19
DOIs
StatePublished - May 9 2003
Externally publishedYes

Fingerprint

Nerve Growth Factor
Superoxide Dismutase
Oxidation-Reduction
Cell Survival
Intercellular Signaling Peptides and Proteins
Carrier Proteins
Cells
Reactive Oxygen Species
Phosphorylation
PC12 Cells
Antioxidants
Chemical activation
Phosphatidylinositol 3-Kinase
Neurodegenerative diseases
Apoptosis
Molecules
Oxidative stress
Monomeric GTP-Binding Proteins
Nerve Growth Factors
Neurology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival. / Bedogni, Barbara; Pani, Giovambattista; Colavitti, Renata; Riccio, Antonella; Borrello, Silvia; Murphy, Mike; Smith, Robin; Eboli, Maria Luisa; Galeotti, Tommaso.

In: Journal of Biological Chemistry, Vol. 278, No. 19, 09.05.2003, p. 16510-16519.

Research output: Contribution to journalArticle

Bedogni, Barbara ; Pani, Giovambattista ; Colavitti, Renata ; Riccio, Antonella ; Borrello, Silvia ; Murphy, Mike ; Smith, Robin ; Eboli, Maria Luisa ; Galeotti, Tommaso. / Redox regulation of cAMP-responsive element-binding protein and induction of manganous superoxide dismutase in nerve growth factor-dependent cell survival. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 19. pp. 16510-16519.
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