Abstract

This proposal is structured to test the hypothesis that regulation of the MGMT gene in mammalian cells is affected by multiple hormonal agents. This hypothesis will be tested by characterizing the cis- elements in the human MGMT promotor, the cognate proteins responsible for promotor activation, and the signalling intermediates. A variety of experimental approaches including reporter gene assay, DNA-protein interaction and in vitro transcriptions will be used to address the following specific aims: 1) To characterize steroid-dependent activation of the MGMT promotor; 2) To elucidate the mechanism of AP-1 interaction with the MGMT promotor; 3) To characterize the cAMP response element(s) and its function; 4) To identify and quantitate signalling intermediates during phorbol ester and cAMP activation, and to test whether MGMT overexpression is due to altered signalling; and 5) To clone and characterize the mouse MGMT promoter preparatory to studying MGMT regulation in vivo in wild type and transgenic mice.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007572-03
Application #
2518684
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1995-09-01
Project End
1999-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Texas Medical Br Galveston
Department
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555

  Publications

Bocangel, Dora; Sengupta, Shiladitya; Mitra, Sankar et al. (2009) p53-Mediated down-regulation of the human DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) via interaction with Sp1 transcription factor. Anticancer Res 29:3741-50
Mitra, Sankar (2007) MGMT: a personal perspective. DNA Repair (Amst) 6:1064-70
Bhakat, Kishor K; Mitra, Sankar (2003) CpG methylation-dependent repression of the human O6-methylguanine-DNA methyltransferase gene linked to chromatin structure alteration. Carcinogenesis 24:1337-45
Biswas, Tapan; Clos 2nd, Lawrence J; SantaLucia Jr, John et al. (2002) Binding of specific DNA base-pair mismatches by N-methylpurine-DNA glycosylase and its implication in initial damage recognition. J Mol Biol 320:503-13
Bhakat, K K; Mitra, S (2000) Regulation of the human O(6)-methylguanine-DNA methyltransferase gene by transcriptional coactivators cAMP response element-binding protein-binding protein and p300. J Biol Chem 275:34197-204
Roy, G; Horton, J K; Roy, R et al. (2000) Acquired alkylating drug resistance of a human ovarian carcinoma cell line is unaffected by altered levels of pro- and anti-apoptotic proteins. Oncogene 19:141-50
Horton, J K; Roy, G; Piper, J T et al. (1999) Characterization of a chlorambucil-resistant human ovarian carcinoma cell line overexpressing glutathione S-transferase mu. Biochem Pharmacol 58:693-702
Biswas, T; Ramana, C V; Srinivasan, G et al. (1999) Activation of human O6-methylguanine-DNA methyltransferase gene by glucocorticoid hormone. Oncogene 18:525-32
Boldogh, I; Ramana, C V; Chen, Z et al. (1998) Regulation of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase via protein kinase C-mediated signaling. Cancer Res 58:3950-6
Bhattacharyya, D; Hazra, T K; Behnke, W D et al. (1998) Reversible folding of Ada protein (O6-methylguanine-DNA methyltransferase) of Escherichia coli. Biochemistry 37:1722-30

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