Transactivation of the human multidrug resistance (MDR1) gene promoter by p53 mutants

K T Nguyen1, B Liu, K Ueda

  • 1Cancer Institute of New Jersey, Piscataway.

Oncology Research
|January 1, 1994
PubMed

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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