Modulation of expression of the MDR1 promoter by AP-1

The mechanisms underlying P-glycoprotein (Pgp-170) transcriptional regulation in multiple drug resistant (MDR) human tumors are not fully understood. We have previously shown that binding activity of the transcription factor AP-1 to a synthetic MDR1 promoter element was increased in nuclear extracts from drug resistant MCF-7 human breast cancer cells when compared to drug sensitive wild type cells. Transient transfection assays were employed to assess whether the AP-1 binding element contributes to increased gene expression in heterologous reporter constructs. Luciferase reporter constructs containing triplicates of either the actual MDR1 promoter sequence (-108 to -123) or a consensus AP-1 binding sequence were transfected into a series of increasingly adriamycin-resistant subclones of the MCF-7 cell line. Our results showed that the highly resistant MCF-7 cells expressed luciferase at a 4 to 6-fold higher level than the wild type cells, indicating the AP-1 binding element present in the promoter region of the MDR1 gene may play a functional role in the transcriptional regulation of MDR1. This is the first report demonstrating differential regulation of the MDR1 promoter region by AP-1 in drug resistant human tumor cells.

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