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p53 Upregulates Death Receptor 4 Expression through an Intronic p53 Binding Site
Abstract
Death receptor 4 (DR4) is one of the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors and triggers apoptosis on ligation with TRAIL or overexpression. Our previous study demonstrated that DR4 expression could be regulated in a p53-dependent fashion. In the present study, we have demonstrated that DR4 is a p53 target gene and is regulated by p53 through a functional intronic p53 binding site (p53BS) based on the following lines of evidence: (a) the p53BS in the DR4 gene is almost identical to the one found in the first intron of the DR5 gene in terms of their locations and sequences; (b) DR4 p53BS bound to p53 protein in intact cells upon p53 activation as demonstrated by a chromatin immunoprecipitation assay; (c) a luciferase reporter vector carrying the DR4 p53BS upstream of an SV40 promoter exhibited enhanced luciferase activity when transiently cotransfected with a wild-type p53 expression vector in p53-null cell lines or stimulated with DNA-damaging agents in a cell line having wild-type p53; and (d) when the DR4 p53BS, together with its own corresponding promoter region in the same orientation as it sits in its natural genomic locus, was cloned into a basic luciferase vector without a promoter element, its transcriptional activity was strikingly increased by cotransfection of a wild-type p53 expression vector or treatment with DNA-damaging agents. However, wild-type p53 or DNA-damaging agents completely lost their activity to increase transcriptional activity of a reporter construct with deleted DR4 p53BS. Thus, we conclude that p53 directly regulates the expression of the DR4 gene via the novel intronic p53BS.
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“TNF receptors include the p53-induced targets FAS47, 48, 49 and TNFRSF10A–D;38, 39 these can be activated by external stimuli such as binding with FASL or TNF-α, thereby leading to caspase-dependent apoptosis.178”
From Census and evaluation of p53 target genes (2017) · cites this paper as [39]
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KILLER/DR5 is a DNA damage–inducible p53–regulated death receptor gene
Wu, G. S., Burns, T. F., McDonald, E. R., Jiang, W., Meng, R., Krantz, I. D., Kao, G., Gan, D.-D., Zhou, J.-Y., Muschel, R. J., et al. (1997) · Nature Genetics · doi:10.1038/ng1097-141 · Cited by 1,081
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Identification of Modulators of TRAIL-Induced Apoptosis via RNAi-Based Phenotypic Screening
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Transcriptional control of human p53-regulated genes
Riley, T., Sontag, E., Chen, P., & Levine, A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2395 · Cited by 1,921
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Jin, Z., & El‐Deiry, W. S. (2005) · Cancer Biology & Therapy · doi:10.4161/cbt.4.2.1508 · Cited by 1,345
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Metadata
- Authors
- Liu, X., Yue, P., Khuri, F. R., & Sun, S.-Y.
- Affiliations
- Emory University (US)
- Venue
- Cancer Research
- Published
- 2004-08-01
- Volume
- 64
- Issue
- 15
- Pages
- 5078-5083
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2127891491
- Cited by
- 184
- References
- 29
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 8 · 2022: 2 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 7 · 2017: 7 · 2016: 7 · 2015: 5 · 2014: 11 · 2013: 5 · 2012: 17
- FWCI
- 5.12
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- 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, death receptor 4, DR4, TRAIL receptors, DR5, transcriptional activation, DNA-damaging agents, apoptosis
- MeSH terms
- Binding Sites, Breast Neoplasms, Chromatin, DNA, DNA Damage, Female, Humans, Introns, Luciferases, Precipitin Tests, Promoter Regions, Genetic, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Transcriptional Activation, Up-Regulation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Receptors, Tumor Necrosis Factor, Receptors, TNF-Related Apoptosis-Inducing Ligand
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