Cited by 184Cancer-related Molecular PathwaysCell death mechanisms and regulationHeat shock proteins research

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p53 Upregulates Death Receptor 4 Expression through an Intronic p53 Binding Site

Liu, Xiangguo, Yue, Ping, Khuri, Fadlo R., Sun, Shi-Yong·2004·Cancer Research

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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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Authors: Liu, X., Yue, P., Khuri, F. R., & Sun, S.-Y.
Affiliations: Emory University (US)
ORCID: Liu, Xiangguo
Yue, Ping
Khuri, Fadlo R.
Sun, Shi-Yong
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2004-08-01
Volume: 64
Issue: 15
Pages: 5078-5083
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-04-1195
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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p53 Upregulates Death Receptor 4 Expression through an Intronic p53 Binding Site

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