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The MDR1 downstream promoter contains sequence-specific binding sites for wild-type p53
B E Strauss1, C Shivakumar, S P Deb
1Department of Pathology, University of California, San Diego, La Jolla 92093-0063, USA.
Biochemical and Biophysical Research Communications
|December 26, 1995
Summary
Wild-type p53 protein suppresses the human multidrug resistance gene-1 (MDR1) promoter activity. This interaction occurs at the transcriptional level, impacting p-glycoprotein expression.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- The p53 protein is a critical tumor suppressor involved in regulating cellular responses to stress.
- The multidrug resistance gene-1 (MDR1) encodes P-glycoprotein, a transporter protein associated with multidrug resistance in cancer.
Purpose of the Study:
- To investigate the interaction between wild-type p53 and the promoter region of the human MDR1 gene.
- To determine if p53 influences MDR1 gene expression.
Main Methods:
- Reporter gene assays were performed using constructs containing segments of the MDR1 promoter (-189 to +133, -119 to +4, -189 to +4, -2 to +133).
- Cotransfection assays were conducted in BHK and Saos-2 cell lines with varying amounts of wild-type p53 expression vectors.
- DNA binding assays were used to demonstrate sequence-specific binding of p53 to the MDR1 promoter.
Main Results:
- Wild-type p53 demonstrated dose-dependent inhibition of reporter activity driven by the full MDR1 promoter and its isolated segments.
- Specific DNA segments of the MDR1 promoter were identified as being negatively regulated by wild-type p53.
- Sequence-specific binding of wild-type p53 protein to the MDR1 promoter was confirmed in vitro.
Conclusions:
- Wild-type p53 negatively regulates the expression of the MDR1 gene at the transcriptional level.
- The findings suggest a potential role for p53 in modulating the expression of P-glycoprotein, impacting multidrug resistance.