Mutant p53 cooperates with ETS and selectively up-regulates human MDR1 not MRP1

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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

J Sampath1, D Sun, V J Kidd

  • 1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.

The Journal of Biological Chemistry
|August 3, 2001
PubMed

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.

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