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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Transactivation of the human multidrug resistance (MDR1) gene promoter by p53 mutants
1Cancer Institute of New Jersey, Piscataway.
Abstract:
Multidrug resistance in human cancer is associated with overexpression of the MDR1 gene, which encodes a plasma membrane energy-dependent efflux pump termed P-glycoprotein (or the multidrug transporter), which confers cross-resistance to multiple hydrophobic natural product cytotoxic drugs. We have previously shown in cotransfection experiments that activity of the human MDR1 gene promoter is modulated by Ras and p53, suggesting that expression of the MDR1 gene may be associated with the activation of oncogenes and/or functional loss of tumor suppressor genes during oncogenesis. To further characterize the effects of p53 on the MDR1 promoter, we have shown in the current study that the region of the promoter that is required for transactivation by p53 mutants overlaps with the region that is essential for basal promoter activity. In addition, we also have shown that several different p53 mutants transactivate the MDR1 promoter in several different cell types, including embryo fibroblasts derived from the p53-deficient (p53-l-) mice generated by gene targeting.
Insights
The p53 tumor suppressor influences multidrug resistance (MDR) by affecting the MDR1 gene promoter. This suggests a link between cancer-driving gene mutations and drug resistance mechanisms.
Area of Science:
- Molecular Biology
- Cancer Genetics
Background:
- Multidrug resistance (MDR) in human cancers is often linked to the MDR1 gene, which encodes P-glycoprotein, an efflux pump conferring resistance to chemotherapy drugs.
- Previous studies indicated that the MDR1 gene promoter's activity is modulated by Ras and p53, suggesting a role in oncogenesis.
Purpose of the Study:
- To further investigate the specific effects of the p53 tumor suppressor protein on the human MDR1 gene promoter.
- To characterize the interaction between p53 mutants and the MDR1 promoter region essential for its activity.
Main Methods:
- Utilized cotransfection experiments to study gene promoter activity.
- Employed gene targeting to generate p53-deficient mice.
- Analyzed p53 mutant transactivation of the MDR1 promoter in various cell types, including mouse embryo fibroblasts.
Main Results:
- The promoter region critical for basal MDR1 activity is also required for transactivation by p53 mutants.
- Multiple distinct p53 mutants were shown to activate the MDR1 promoter.
- This activation was observed across several different cell types.
Conclusions:
- p53, a key tumor suppressor, directly impacts the MDR1 gene promoter, influencing multidrug resistance.
- The findings suggest a mechanistic link between tumor suppressor gene function/dysfunction and the development of chemotherapy resistance in cancer.
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