The Wilms' tumor suppressor, WT1, inhibits 12-O-tetradecanoylphorbol-13-acetate activation of the multidrug resistance-1 promoter

Overexpression of P-glycoprotein, the product of the multidrug resistance-1 (MDR1) gene, is associated with treatment failure in some hematopoietic tu mors. Although expression of P-glycoprotein in normal hematopoietic cells i s tightly regulated during hematopoietic differentiation, its aberrant over expression in hematopoietic malignancies occurs at the transcriptional leve l. We have demonstrated that 12-O-tetradecanoylphorbol-13-acetate (IPA) inc reases transcription of the MDR1 gene and activates the MDR1 promoter, and that promoter activation by TPA requires binding of the zinc finger transcr iption factor EGR1 to specific MDR1 promoter sequences (C, McCoy and M, M, Cornwell, Mel. Cell, Biol,, 15: 6100-6108, 1995). We demonstrate here that the Wilms' tumor (WT) suppressor, WT1, a member of the EGR family, inhibits the response of the MDR1 promoter to TPA in K562 cells. Inhibition is like ly a direct effect of WT1 binding to the MDR1 promoter because: (a) WT1 exp ression does not inhibit the increase in EGR1 after TPA treatment; (b) inhi bition by WT1 requires the zinc finger domain; (c) WT1 binds to MDR1 promot er sequences that bind EGR1 and are responsive to TPA; and (d) there is an inverse correlation between WT1 protein expression and MDR1 expression and promoter activity, These results suggest that the MDR1 gene is a target for regulation by WT1 and suggest mechanisms by which MDR1 may be regulated by WT1 and EGR1 during normal and aberrant hematopoiesis.