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

Tapan Biswas, Chilakamarti V. Ramana, Ganesan Srinivasan, Istvan Boldogh, Tapas K. Hazra, Zhenping Chen, Keizo Tano, E. Brad Thompson, Sankar Mitra

Research output: Contribution to journalArticle

61 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)525-532
Number of pages8
JournalOncogene
Volume18
Issue number2
DOIs
StatePublished - Jan 14 1999

Keywords

  • CNU
  • DNA damage
  • DNA repair
  • Gene regulation
  • Glucocorticoid

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Biswas, T., Ramana, C. V., Srinivasan, G., Boldogh, I., Hazra, T. K., Chen, Z., Tano, K., Thompson, E. B., & Mitra, S. (1999). Activation of human O6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone. Oncogene, 18(2), 525-532. https://doi.org/10.1038/sj.onc.1202320