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Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
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.
Insights
Mutant p53 up-regulates the MDR1 gene, a key drug resistance factor, but not MRP1. This occurs via interaction with Ets-1, offering new insights into cancer drug resistance mechanisms.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Multidrug resistance (MDR) is a significant challenge in cancer therapy.
- The MDR1 and MRP1 genes are frequently overexpressed in human tumors harboring mutant p53.
- The precise transcriptional regulation of MDR1 and MRP1 by mutant p53 remained unclear.
Purpose of the Study:
- To investigate whether mutant p53 transcriptionally regulates the MDR1 and MRP1 genes.
- To elucidate the mechanism by which mutant p53 influences the expression of these drug resistance genes.
Main Methods:
- Analysis of MDR1 and MRP1 promoter activity in the presence of mutant p53.
- Assessment of endogenous MDR1 and MRP1 gene expression.
- Investigation of the role of Ets binding sites in MDR1 regulation.
- Biochemical analysis of protein-protein interactions between mutant p53 and Ets-1.
Main Results:
- Mutant p53 did not activate the MRP1 promoter or endogenous MRP1 gene.
- Mutant p53 strongly induced the MDR1 promoter and endogenous MDR1 gene expression.
- Transcriptional activation of MDR1 by mutant p53 was dependent on an Ets binding site.
- Mutant p53 and Ets-1 synergistically activated MDR1 transcription.
- Ets-1 specifically interacted with mutant p53, but not wild-type p53, in vivo.
Conclusions:
- Mutant p53 directly induces the expression of the MDR1 gene, a critical determinant of drug resistance.
- The interaction between mutant p53 and Ets-1 is crucial for the transcriptional activation of MDR1.
- These findings provide a novel mechanism for MDR1 regulation in cancer and potential therapeutic targets.