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CCAAT/Enhancer-Binding Protein (Nuclear Factor for Interleukin 6) Transactivates the Human MDR1 Gene by Interaction with an Inverted CCAAT Box in Human Cancer Cells

Program in Cancer Biology (G.K.C., B.I.S.), Division of Oncology, Department of Medicine (G.K.C., S.S., T.T., R.P.E., B.I.S.), Stanford University School of Medicine, Stanford, California

We investigated the mechanisms of MDR1 gene activation by CCAAT/enhancer binding protein (C/EBP, or nuclear factor for interleukin 6) in human cancer cells. Transfection of the breast cancer cell line MCF-7 and its doxorubicin-selected variant MCF-7/ADR by either C/EBP or C/EBP-LIP (a dominant-negative form of C/EBP) confirmed their roles in the activation or repression of the endogenous, chromosomally embedded MDR1 gene. Cotransfection experiments with promoter constructs revealed a C/EBP interaction on the MDR1 promoter via the region within -128 to -75. Deletions within the putative AP-1 box (-123 to -111) increased MDR1 promoter activity when stimulated by C/EBP, suggesting that the AP-1 site negatively regulates MDR1 activation by C/EBP. Mutations within the inverted CCAAT box (Y box) (-82 to -73) abolished the C/EBP-stimulated MDR1 promoter activity, indicating that the Y box is required for MDR1 activation by C/EBP. Chromatin immunoprecipitation (ChIP) revealed that C/EBP precipitates a transcription complex containing C/EBP, the MDR1 promoter sequences (-250 to +54), and the hBrm protein. In conclusion, alteration of expression or function of C/EBP plays an important role in MDR1 gene regulation. C/EBP activates the endogenous MDR1 gene of MCF-7 cells, and this activation was associated with a novel C/EBP interaction region within the proximal MDR1 promoter (-128 to -75). The mechanisms of MDR1 activation by C/EBP include C/EBP binding of the chromatin of the MDR1 gene and interactions of C/EBP with the Y box and Y box-associated proteins.

Received July 30, 2003; accepted December 22, 2003.

Address correspondence to: Dr. B. I. Sikic, 269 Campus Drive, Room CCSR North 1105, Oncology Division, Stanford University Medical Center, Stanford, CA 94305-5151. E-mail: brandy{at}stanford.edu

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