A conserved intronic response element mediates direct p53-dependent transcriptional activation of both the human and murine bax genes
Abstract
Both the human and the mouse bax promoters contain p53 binding sites which are sufficient to confer p53-dependent transcriptional activation in a heterologous setting. Nevertheless in the context of the bax promoter, these sites do not mediate a p53-dependent response, suggesting that bax may not be a direct transcriptional target of p53. Here, data are presented identifying a conserved p53 response element in the first intron of both the human and the murine bax genes. This element both in isolation and in the context of the first intron conferred p53-dependent transcriptional activation upon a minimal promoter. Electrophoretic mobility shift assays demonstrated that this sequence also is capable of mediating sequence specific binding to p53. p53 effectively activated transcription through both human and murine bax gene reporter constructs, whereas deletion of the intronic response element abrogated the p53-responsiveness of both reporters. Interestingly, tumor-derived mutants of p53 which are defective in inducing an apoptotic response retain the ability to activate transcription via the bax intronic p53 site. Since these mutants are transcriptionally inactive on the p53 site in the bax promoter, the ability of these mutants to up-regulating endogenous bax mRNA levels supports a role for the intronic element in p53-dependent up-regulation of bax expression. Taken together, these results show the requirement for a novel intronic element in the p53-dependent transcriptional activation of bax, and demonstrate that bax is indeed a direct and evolutionarily conserved transcriptional target of p53.
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Several proapoptotic BCL-2 family members, including BAX, BBC3 (PUMA) and PMAIP1 (NOXA), are activated by p53.
“Several proapoptotic BCL-2 family members, including BAX,41, 42, 43 BBC3 (PUMA)181 and PMAIP1 (NOXA),182 are activated by p53.”
From Census and evaluation of p53 target genes (2017) · cites this paper as [43]
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- Authors
- Thornborrow, E. C., Patel, S., Mastropietro, A. E., Schwartzfarb, E. M., & Manfredi, J. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Corresponding author
- Manfredi, James J
- ORCID
- Manfredi, James J
- Venue
- Oncogene
- Published
- 2002-02-07
- Volume
- 21
- Issue
- 7
- Pages
- 990-999
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W1976118513
- Cited by
- 132
- References
- 28
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 5 · 2014: 4 · 2013: 9 · 2012: 9
- FWCI
- 4.29
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r29ca069161-05)
- National Cancer Institute (CA-69161)
- Medical Research and Materiel Command
- 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 › Genomics and Chromatin Dynamics
- Keywords
- p53, Bax gene, transcriptional activation, p53 binding sites, apoptosis
- MeSH terms
- Animals, Base Sequence, Cloning, Molecular, Genes, Humans, Introns, Proto-Oncogene Proteins, RNA, Messenger, Tumor Cells, Cultured, Transcriptional Activation, Tumor Suppressor Protein p53, Sequence Alignment, Conserved Sequence, Genes, Reporter, Proto-Oncogene Proteins c-bcl-2, Response Elements, Electrophoretic Mobility Shift Assay, bcl-2-Associated X Protein, Mice
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