Akt Activation Protects Hippocampal Neurons from Apoptosis by Inhibiting Transcriptional Activity of p53
Open accessAbstract
Survival factors suppress apoptosis by activating the serine/threonine kinase Akt. To investigate the molecular mechanism underlying activated Akt's ability to protect neurons from hypoxia or nitric oxide (NO) toxicity, we focused on the apoptosis-related functions of p53 and caspases. We eliminated p53 by employing p53-deficient neurons and increased p53 by infection with recombinant adenovirus capable of transducing p53 expression, and we now show that p53 is implicated in the apoptosis induced by hypoxia or NO treatments of primary cultured hippocampal neurons. Although hypoxia and NO induced p53, treatment with insulin-like growth factor-1 significantly inhibited caspase-3-like activation, neuronal death and transcriptional activity of p53. These insulin-like growth factor-1 effects are prevented by wortmannin, a phosphatidylinositol 3-kinase inhibitor. Adenovirus-mediated expression of activated-Akt kinase suppressed p53-dependent transcriptional activation of responsive genes such as Bax, suppressed caspase-3-like protease activity and suppressed neuronal cell death with no effect on the cellular accumulation and nuclear translocation of p53. In contrast, overexpression of kinase-defective Akt failed to suppress these same activities. These results suggest a mechanism where Akt kinase activation reduces p53's transcriptional activity that ultimately rescues neurons from hypoxia- or NO-mediated cell death.
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Expression of active or kinase-defective PKB has little or no effect on the phosphorylation status of p53.
“Expression of active or kinase-defective PKB has little or no effect on the phosphorylation status of p53 (8)”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [8]
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- Authors
- Yamaguchi, A., Tamatani, M., Matsuzaki, H., Namikawa, K., Kiyama, H., Vitek, M. P., Mitsuda, N., & Tohyama, M.
- Affiliations
- Japan Science and Technology Agency (JP)
- Asahikawa Medical University (JP)
- Duke Medical Center (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 276
- Issue
- 7
- Pages
- 5256-5264
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1983587113
- Cited by
- 242
- References
- 43
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 10 · 2022: 7 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 8 · 2017: 2 · 2016: 5 · 2015: 8 · 2014: 4 · 2013: 10 · 2012: 12
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- Akt kinase, p53, hippocampal neurons, neuronal apoptosis, hypoxia, nitric oxide toxicity, caspase-3, insulin-like growth factor I, wortmannin, phosphatidylinositol 3-kinase, Bax, neuroprotection
- MeSH terms
- Animals, Cell Nucleus, Cells, Cultured, DNA, Enzyme Activation, Hippocampus, Insulin-Like Growth Factor I, Mice, Inbred CBA, Mice, Inbred C57BL, Neurons, Nitric Oxide, Proto-Oncogene Proteins, Transcription Factors, Transcriptional Activation, Cell Hypoxia, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Caspases, Active Transport, Cell Nucleus, Proto-Oncogene Proteins c-akt, Mice, Caspase 3
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