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MYCN-mediated regulation of the MRP1 promoter in human neuroblastoma

Oncogene volume 23, pages 753–762 (2004)Cite this article

Abstract

In the childhood cancer neuroblastoma (NB), the level of expression of the multidrug resistance-associated protein (MRP1) gene is strongly correlated with expression of the MYCN oncogene in primary NB tumors, suggesting that MRP1 may be a target for MYCN-mediated gene regulation. In this study, we show that MYCN induction in human NB cells results in increased MRP1 mRNA and protein levels, which in turn is accompanied by increased drug resistance and enhanced MRP1-mediated drug efflux. Furthermore, luciferase activity from MRP1 promoter/luciferase gene reporter constructs was significantly increased in NB cells with exogenous overexpression of MYCN, whereas activity was decreased in NB cells stably transfected with MYCN-antisense vectors. Decreased luciferase activity was observed with promoter constructs that lacked one or two E-box sequences or had E-box double point mutations, while a truncated MRP1 promoter lacking all three E-boxes exhibited only basal levels of activity. Specific electrophoretic mobility shifts of MRP1 E-box sequences were detected with nuclear extracts from NB cells with MYCN overexpression, and complex formation was inhibited with the addition of antibodies directed against MYCN or MYC. These findings indicate that by interacting with E-box elements within the promoter, MYCN can upregulate MRP1 expression and modulate drug resistance in NB.

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Acknowledgements

This work was supported in part by the Neuroblastoma Children's Cancer Society, Friends for Steven Pediatric Cancer Research Fund, the Elise Anderson Neuroblastoma Research Fund, the North Suburban Medical Research Junior Board, and the Robert H Lurie Comprehensive Cancer Center, NIH, NCI Core Grant 5P30CA60553, as well as Children's Cancer Institute Australia for Medical Research and grants from the National Health and Medical Research Council (Australia) and New South Wales Cancer Council (Australia). Children's Cancer Institute Australia for Medical Research is affiliated with Sydney Children's Hospital and the University of New South Wales (Sydney, Australia).

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  1. Chitra F Manohar

    Present address: Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, CA, 94550, USA

Authors and Affiliations

  1. The Robert H Lurie Comprehensive Cancer Center, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA

    Chitra F Manohar, James A Bray & Helen R Salwen

  2. Children's Cancer Institute Australia for Medical Research, Sydney, Australia

    Janice Madafiglio, Andy Cheng, Claudia Flemming, Glenn M Marshall, Murray D Norris & Michelle Haber

  3. Department of Pediatrics, Northwestern University's Feinberg School of Medicine, Chicago, IL, USA

    Susan L Cohn

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  1. Chitra F Manohar
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Correspondence to Susan L Cohn.

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Manohar, C., Bray, J., Salwen, H. et al. MYCN-mediated regulation of the MRP1 promoter in human neuroblastoma. Oncogene 23, 753–762 (2004). https://doi.org/10.1038/sj.onc.1207151

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