COORDINATION OF TRANSCRIPTION FACTORS, NF-Y AND C/EBP-BETA, IN THE REGULATION OF THE MDR1B PROMOTER

The expression of mdr genes that encode P-glycoprotein, an integral membrane drug transporter, has been associated with the emergence of the multidrug resistance phenotype during treatment with cancer chemotherapeutic drugs. To understand the regulation of the mdr genes, the murine mdr1b promoter has been isolated and characterized in our laboratory. Three nuclear protein binding sites that interact with nuclear proteins present in both drug-sensitive and -resistant murine macrophage-like J774.2 cells have been localized to the promoter. In this report, transcription factor NF-Y has been identified as binding to the Y-box sequence in site 1 and as a major factor in the regulation of the murine mdr1b promoter in the mouse adrenal cell line, Y-1, that endogenously expresses the mdr1b gene. The expression of CCAAT/enhancer binding protein beta (C/EBP beta) in Y-1 cells augmented mdr1b promoter activity and resulted in an increased level of mdr1b mRNA. The effect of C/EBP beta expression on mdr1b promoter activity was sensitive to mutations in the Y-box, suggesting that coordination of NF-Y with C/EBP beta is required for further activation of the mdr1b promoter. Our studies have indicated that NF-Y is a critical factor for the mdr1b promoter, and its coordination with other factors, such as C/EBP beta, could be an important mechanism involved in mdr1b gene expression.