TRANSACTIVATION OF THE HUMAN MULTIDRUG-RESISTANCE (MDR1) GENE PROMOTER BY P53 MUTANTS

Multidrug resistance in human cancer is associated with overexpression of the MDR1 gene, which encodes a plasma membrane energy-dependent ef flux pump termed P-glycoprotein (or the multidrug transporter), which confers cross-resistance to multiple hydrophobic natural product cytot oxic drugs. We have previously shown in cotransfection experiments tha t activity of the human MDR1 gene promoter is modulated by Ras and p53 , suggesting that expression of die MDR1 gene may be associated with t he activation of oncogenes and/or functional loss of tumor suppressor genes during oncogenesis. To further characterize the effects of p53 o n the MDR1 promoter, we have shown in the current study that the regio n 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 t ransactivate the MDR1 promoter in several different cell types, includ ing embryo fibroblasts derived from the p53-deficient (p53-/-) mice ge nerated by gene targeting.