APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death
Open accessAbstract
p53 is a transcriptional activator which has been implicated as a key regulator of neuronal cell death after acute injury. We have shown previously that p53-mediated neuronal cell death involves a Bax-dependent activation of caspase 3; however, the transcriptional targets involved in the regulation of this process have not been identified. In the present study, we demonstrate that p53 directly upregulates Apaf1 transcription as a critical step in the induction of neuronal cell death. Using DNA microarray analysis of total RNA isolated from neurons undergoing p53-induced apoptosis a 5–6-fold upregulation of Apaf1 mRNA was detected. Induction of neuronal cell death by camptothecin, a DNA-damaging agent that functions through a p53-dependent mechanism, resulted in increased Apaf1 mRNA in p53-positive, but not p53-deficient neurons. In both in vitro and in vivo neuronal cell death processes of p53-induced cell death, Apaf1 protein levels were increased. We addressed whether p53 directly regulates Apaf1 transcription via the two p53 consensus binding sites in the Apaf1 promoter. Electrophoretic mobility shift assays demonstrated p53–DNA binding activity at both p53 consensus binding sequences in extracts obtained from neurons undergoing p53-induced cell death, but not in healthy control cultures or when p53 or the p53 binding sites were inactivated by mutation. In transient transfections in a neuronal cell line with p53 and Apaf1 promoter–luciferase constructs, p53 directly activated the Apaf1 promoter via both p53 sites. The importance of Apaf1 as a p53 target gene in neuronal cell death was evaluated by examining p53-induced apoptotic pathways in primary cultures of Apaf1-deficient neurons. Neurons treated with camptothecin were significantly protected in the absence of Apaf1 relative to those derived from wild-type littermates. Together, these results demonstrate that Apaf1 is a key transcriptional target for p53 that plays a pivotal role in the regulation of apoptosis after neuronal injury.
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APAF1 is activated by p53.
“APAF1 is activated by p53 too.183, 184, 185”
From Census and evaluation of p53 target genes (2017) · cites this paper as [184]
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- Authors
- Fortin, A., Cregan, S. P., MacLaurin, J. G., Kushwaha, N., Hickman, E. S., Thompson, C. S., Hakim, A., Albert, P. R., Cecconi, F., Helin, K., Park, D. S., & Slack, R. S.
- Affiliations
- University of Ottawa (CA)
- European Institute of Oncology (IT)
- University of Rome Tor Vergata (IT)
- Corresponding author
- Fortin, Andre
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2001-10-08
- Volume
- 155
- Issue
- 2
- Pages
- 207-216
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC2198828
- OpenAlex
- W2119044841
- Cited by
- 194
- References
- 54
- Citations by year
- 2025: 4 · 2024: 3 · 2023: 6 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 5 · 2012: 3
- FWCI
- 6.65
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- Apaf-1, p53, neuronal cell death, apoptosis, transcriptional regulation, p53 target genes, p53 binding sites, camptothecin, Bax, caspase-3, DNA damage, neuroprotection
- MeSH terms
- Animals, Base Sequence, Camptothecin, Cell Line, Cells, Cultured, Brain Ischemia, Mice, Transgenic, Neurons, Promoter Regions, Genetic, Proteins, RNA, Messenger, Protein Biosynthesis, Transcriptional Activation, Tumor Suppressor Protein p53, Apoptosis, Mice, Apoptotic Protease-Activating Factor 1
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