A positive feedback mechanism in the transcriptional activation of Apaf-1 by p53 and the coactivator Zac-1
Abstract
p53 exerts its tumor suppressor effects by activating genes involved in cell growth arrest and programmed cell death. The p53 target genes inducing growth arrest are well defined whereas those inducing apoptosis are not fully characterized. Proapoptotic activity of p53 was shown to involve several genes like Bax, Noxa and Puma, which may function in the release of cytochrome c from the mitochondria. Cytochrome c associates with Apaf-1 and caspase 9 to form the apoptosome. Genetic and cellular data indicate that Apaf-1 deficiency abrogates the apoptotic effect of p53 and substitutes for p53 loss in promoting tumor formation. Here we show that Apaf-1, the mammalian homologue of C. elegans CED4, is a direct target of p53 as demonstrated by gel shift analysis of the target site sequence in the presence of p53 and by Apaf-1 promoter-luciferase assays. We also show that the p53 activation of the Apaf-1 luciferase construct can be enhanced by the putative tumor suppressor gene product, Zac-1, a transcription factor that has previously been shown to inhibit cell proliferation. Furthermore, we demonstrate that Zac-1 is a possible direct target of p53 since the sequence upstream to the first coding exon of Zac-1 contains a p53 recognition site and the luciferase construct containing this region is activated by p53. These results suggests the existence of a tightly controlled self amplifying mechanism of transcriptional activation leading to apoptosis by p53.
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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 [185]
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- Authors
- Rozenfeld-Granot, G., Krishnamurthy, J., Kannan, K., Toren, A., Amariglio, N., Givol, D., & Rechavi, G.
- Affiliations
- Tel Aviv University (IL)
- Weizmann Institute of Science (IL)
- Corresponding author
- Givol, David
- Venue
- Oncogene
- Published
- 2002-02-27
- Volume
- 21
- Issue
- 10
- Pages
- 1469-1476
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2046481261
- Cited by
- 72
- References
- 35
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 5 · 2017: 5 · 2016: 2 · 2015: 2 · 2014: 2 · 2013: 1 · 2012: 2
- FWCI
- 2.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation
- Tel Aviv University
- Sackler Faculty of Medicine, Tel-Aviv University
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, Apaf-1, transcriptional activation, positive feedback loop, apoptosis, p53 target genes, transcriptional coactivator, CED-4, apoptosome, cytochrome c release, caspase-9, tumor suppressor
- MeSH terms
- Animals, Base Sequence, Binding Sites, Cell Line, Humans, Luciferases, Molecular Sequence Data, Promoter Regions, Genetic, Proteins, RNA, Messenger, Transcription Factors, Protein Biosynthesis, Transcriptional Activation, Trans-Activators, Up-Regulation, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Genes, Reporter, Cell Cycle Proteins, Electrophoretic Mobility Shift Assay, Tumor Suppressor Proteins, Mice, Apoptotic Protease-Activating Factor 1
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