Redox Regulation of cAMP-responsive Element-binding Protein and Induction of Manganous Superoxide Dismutase in Nerve Growth Factor-dependent Cell Survival
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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.
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Dose/response studies demonstrated effects of mitoquinone extending an order of magnitude or more downward from the 1 μM (or higher) dose used in other reported studies.
“Also, dose/response studies demonstrated effects of mitoquinone extending an order of magnitude or more downward from the 1 μM (or higher) dose used in other reported studies of the cellular actions of this compound (25, 81, 283), some of which reported a mitoQ-induced resistance to apoptosis (25, 81).”
From Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities (2010) · cites this paper as [25]
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- Authors
- Bedogni, B., Pani, G., Colavitti, R., Riccio, A., Borrello, S., Murphy, M., Smith, R., Eboli, M. L., & Galeotti, T.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Johns Hopkins University (US)
- University of Otago (NZ)
- Corresponding author
- Galeotti, Tommaso
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 278
- Issue
- 19
- Pages
- 16510-16519
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2046601184
- Cited by
- 124
- References
- 54
- Citations by year
- 2026: 1 · 2024: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 6 · 2016: 9 · 2015: 6 · 2014: 1 · 2013: 6 · 2012: 6
- FWCI
- 4.61
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Consiglio Nazionale delle Ricerche
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- nerve growth factor, CREB phosphorylation, reactive oxygen species, redox signaling, apoptosis, serum deprivation, PC12 cells, phosphatidylinositol 3-kinase, Rac1, manganese superoxide dismutase, hydrogen peroxide, MitoQ, mitochondrial oxidative stress, neurotrophic signaling, neuronal survival
- MeSH terms
- Animals, Cell Survival, Mitochondria, Oxidation-Reduction, Phosphorylation, Superoxide Dismutase, Signal Transduction, PC12 Cells, Cyclic AMP Response Element-Binding Protein, Oxidative Stress, Nerve Growth Factor, Rats
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