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Mutant p53 Cooperates with ETS and Selectively Up-regulates Human MDR1 Not MRP1
Open accessAbstract
The most frequently expressed drug resistance genes, MDR1 and MRP1, occur in human tumors with mutant p53. However, it was unknown if mutant p53 transcriptionally regulated both MDR1 and MRP1. We demonstrated that mutant p53 did not activate either the MRP1 promoter or the endogenous gene. In contrast, mutant p53 strongly up-regulated the MDR1 promoter and expression of the endogenous MDR1 gene. Notably, cells that expressed either a transcriptionally inactive mutant p53 or the empty vector showed no endogenous MDR1 up-regulation. Transcriptional activation of the MDR1 promoter by mutant p53 required an Ets binding site, and mutant p53 and Ets-1 synergistically activated MDR1 transcription. Biochemical analysis revealed that Ets-1 interacted exclusively with mutant p53s in vivo but not with wild-type p53. These findings are the first to demonstrate the induction of endogenous MDR1 by mutant p53 and provide insight into the mechanism.
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“In contrast to wt-p53, GOF mut-p53 exhibits interactions with distinct transcription factors (e.g., NF-ɣ, SREBP, VDR, Sp1, ETS2, NFR2, p73, p63) that promote tumor initiation and progression [13,72,73,74,75,76,77].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [76]
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Metadata
- Authors
- Sampath, J., Sun, D., Kidd, V. J., Grenet, J., Gandhi, A., Shapiro, L. H., Wang, Q., Zambetti, G. P., & Schuetz, J. D.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Schuetz, John D.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2001-10
- Volume
- 276
- Issue
- 42
- Pages
- 39359-39367
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2050569275
- Cited by
- 244
- References
- 42
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 14 · 2023: 8 · 2022: 8 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 13 · 2017: 13 · 2016: 8 · 2015: 14 · 2014: 19 · 2013: 5 · 2012: 16
- FWCI
- 4.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL070694)
- National Cancer Institute (CA-23099, CA63203, P01CA023099, P 30CA 21765, P30CA021765)
- National Institute of Environmental Health Sciences (ES05851)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- mutant p53, ETS1, MDR1, MRP1, multidrug resistance, transcriptional activation, Ets binding site, protein-protein interaction, drug resistance genes, transcriptional cooperation
- MeSH terms
- Base Sequence, Binding Sites, Cell Line, DNA, Flow Cytometry, Genetic Vectors, Glutathione Transferase, Humans, Luciferases, Molecular Sequence Data, Mutation, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Ribonucleases, Transcription Factors, Transcription, Genetic, Protein Biosynthesis, Tumor Cells, Cultured, Blotting, Western, Transcriptional Activation, Up-Regulation, Genes, p53, Tumor Suppressor Protein p53, Genes, MDR, ATP Binding Cassette Transporter, Subfamily B, Member 1, Caspases, ATP-Binding Cassette, Sub-Family C Proteins, Multidrug Resistance-Associated Proteins, Proto-Oncogene Proteins c-ets, Proto-Oncogene Protein c-ets-1
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