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Activation of human O6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone

Oncogene volume 18, pages 525–532 (1999)Cite this article

Abstract

O6-methylguanine-DNA methyltransferase (MGMT), a ubiquitous DNA repair protein, removes the mutagenic DNA adduct O6-alkylguanine, which is synthesized both endogenously and after exposure to alkylnitrosamines and alkylating antitumor drugs such as 2-chloroethyl-N-nitrosourea (CNU). The MGMT gene is highly regulated in mammalian cells and its overexpression, observed in many types of tumor cells, is often associated with cellular resistance to CNU. Dexamethasone, a synthetic glucocorticoid hormone, was found to increase MGMT expression in HeLa S3 cells, concomitant with their increased resistance to CNU. Two putative glucocorticoid responsive elements (GREs) were identified in the human MGMT (hMGMT) promoter. Transient expression of the luciferase reporter gene driven by an hMGMT promoter fragment containing these GREs was activated by dexamethasone. DNase I footprinting assays demonstrated the binding of glucocorticoid receptor to these sequences. In vitro transcription experiment showed that these DNA sequences are functional in glucocorticoid receptor signal-mediated activation of transcription. These results suggest glucocorticoid-mediated induction of the MGMT gene contributes to high level expression of MGMT.

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Acknowledgements

The authors like to thank Dr E Whorton for helping with the statistical analysis, Dr D Konkel for a careful editing of the manuscript and Ms Wanda Smith for expert secretarial assistance. This research was supported by US Public Health Service grants CA 31721 and ES 07572 (to SM)

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Author notes

  1. Chilakamarti V Ramana

    Present address: The Cleveland Clinic Foundation Research Institute, 9500 Euclid Avenue, Cleveland, OH, 44195

  2. Zhenping Chen

    Present address: Department of Immunology and Microbiology, University of Texas Medical Branch, Galveston, TX, 77555, USA

Authors and Affiliations

  1. Sealy Center for Molecular Science and Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, 77555, Texas, USA

    Tapan Biswas, Chilakamarti V Ramana, Ganesan Srinivasan, Tapas K Hazra, Zhenping Chen, E Brad Thompson & Sankar Mitra

  2. Department of Immunology and Microbiology, University of Texas Medical Branch, Galveston, 77555, Texas, USA

    Istvan Boldogh

  3. Reactor Institute, Kyoto University, 590-04, Osaka, Japan

    Keizo Tano

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Biswas, T., Ramana, C., Srinivasan, G. et al. Activation of human O6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone. Oncogene 18, 525–532 (1999). https://doi.org/10.1038/sj.onc.1202320

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