@article{fe9eaa24124240bdae48669d972233bd,
title = "Activation of human O6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone",
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.",
keywords = "CNU, DNA damage, DNA repair, Gene regulation, Glucocorticoid",
author = "Tapan Biswas and Ramana, {Chilakamarti V.} and Ganesan Srinivasan and Istvan Boldogh and Hazra, {Tapas K.} and Zhenping Chen and Keizo Tano and Thompson, {E. Brad} and Sankar Mitra",
note = "Funding Information: 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) Izumi T, Henner WD and Mitra S. (1996). Biochemistry, 35, 14679 – 14683. Klein-Hitpass L, Tsai SY, Weigel NL, Allan GF, Riley D, Rodriguez R, Schrader WT, Tsai MJ and O{\textquoteright}Malley BW. (1990). Cell, 60, 247 – 257. Kokkinakis DM, Ahmed MM, Delgado R, Fruitwala MM, Mohiuddin M and Albores-Saavedra J. (1997). Cancer Res., 57, 5360 – 5368. Leblanc B and Moss T. (1994). DNA-Protein Interactions: Principles and Protocols. Kneale GG (ed). Humana Press Inc: Totowa, NJ. pp. 1 – 10. Levin VA, Leibel SA and Gutin PH. (1997). Cancer: Principles and Practice of Oncology. DeVita Jr VT et al. (ed). Lippincott-Raven, Philadelphia, PA., pp. 2022 – 2082. Liu L, Lee K, Wasan E and Gerson SL. (1996). Cancer Res., 56, 1880 – 1885. Ludlum DB. (1990). Mutation Res., 233, 117 – 126. McEwan IJ, Dahlman-Wright K, Amlot T, Ford J, Wright APH and Gustafsson J-A. (1995). Mutat. Res., 333, 15 – 22. Mitra S and Kaina B. (1993). Prog. Nucl. Acids Res. Mol. Biol., 44, 109 – 141. Myrnes B, Nordstrand K, Giercksky K, Sjunneskog C and Krokan H. (1984). Carcinogenesis, 5, 1061 – 1064. Nakatsu Y, Hattori K, Hayakawa H, Shimizu K and Sekiguchi M. (1993). Mutat. Res., 293, 119 – 132. Patel SA, Graunke DM and Pieper RO. (1997). Mol. Cell. Biol., 17, 5813 – 5822. Pegg AE. (1990). Cancer Res., 50, 6119 – 6129. Pegg AE, Swenn K, Chae MY, Dolan ME and Moschel RC. (1995). Biochem. Pharmacol., 50, 1141 – 1148.",
year = "1999",
month = jan,
day = "14",
doi = "10.1038/sj.onc.1202320",
language = "English (US)",
volume = "18",
pages = "525--532",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Springer Nature",
number = "2",
}