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Stable Transfection of the P-Glycoprotein Promoter Reproduces the Endogenous Overexpression Phenotype: The Role of MED-1¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021

Cellular resistance to multiple chemotherapeutic agents is most often due to the overexpression of P-glycoprotein (Pgp). The mechanism(s) underlying Pgp overexpression had not been determined, due, in part, to a failure to reproduce the overexpression in transient transfection assays. We now report that stable transfection of a Pgp (pgp1) promoter/luciferase construct in the drug-sensitive Chinese hamster cell line DC-3F and its drug-resistant sublines reproduced the overexpression phenotype, with up to 18-fold higher activity observed in the resistant cell lines compared with DC-3F. Moreover, mutation of a pgp1 promoter element, multiple start site element downstream (MED-1), decreased transcription in drug-resistant cells without affecting activity in drug-sensitive cells. This is the first report of a Pgp promoter element differentially regulated in drug-resistant cells. Moreover, these data suggest that the regulation of Pgp transcription is modulated by chromatin structure, and that stable transfections may be more suitable for identifying promoter elements important for overexpression in drug-resistant cells.

¹ This work was supported by National Cancer Institute Grants P30-CA-08748 (Memorial Sloan-Kettering Cancer Center) and RO1-CA-57307, the Samuel and May Rudin Foundation, the Wendy Will Case Cancer Fund, and the Frank L. Horsfall, Jr., Fellowship (T. A. I.). The authors are members of the Cornell Graduate School of Medical Sciences.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: (212) 639-8972; Fax: (212) 639-2767; E-mail: k-scotto@mskcc.org.

Received 2/14/96. Accepted 3/15/96.

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