It is becoming increasingly clear that post-translational modifications of DNA and proteins play an important role in human health and many disease states. Within FY2000 we have extended our studies on the impact of DNA methylation on human cancers. Using a combination of human tumor samples and in vitro biochemistry and molecular biology we have ascertained the methylation status on the promoter for the human hereditary breast and ovarian cancer susceptibility gene, BRCA-1. These studies revealed a critical requirement for the cyclic- AMP response element binding (CREB) protein in the transcription of this gene. This is particularly interesting given the intense interest in a protein that binds CREB known as CREB binding protein or CBP and its ability to acetylate histones and the tumor suppressor gene p53. We are currently exploring the mechanisms by which p53 may influence glucocorticoid receptor activation of transcription. As models we are using recently developed human osteosacoma cells that lack p53 in comparison to cells that retain wild type p53.Additional experiments have described the transcriptional mechanisms that underlie the estrogen receptor dependent activation of the Cathepsin D gene in human breast cancer cells. In addition we have begun to explore the specific contributions made by the two distinct isoforms of the estrogen receptor in collaboration with the Korach group. The continued evaluation of these and additional novel human genetic systems will provide the underpinning of our efforts to define a molecular map of the hormone dependent changes that occur in human cells. This will be critical for an enhanced understanding the impact of environmental endocrine disruptors on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES071007-02
Application #
6432406
Study Section
(LRDT)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Deroo, Bonnie J; Archer, Trevor K (2002) Differential activation of the IkappaBalpha and mouse mammary tumor virus promoters by progesterone and glucocorticoid receptors. J Steroid Biochem Mol Biol 81:309-17
Deroo, Bonnie J; Rentsch, Claudia; Sampath, Sowmini et al. (2002) Proteasomal inhibition enhances glucocorticoid receptor transactivation and alters its subnuclear trafficking. Mol Cell Biol 22:4113-23
Deroo, B J; Archer, T K (2001) Glucocorticoid receptor-mediated chromatin remodeling in vivo. Oncogene 20:3039-46
Deroo, B J; Archer, T K (2001) Glucocorticoid receptor activation of the I kappa B alpha promoter within chromatin. Mol Biol Cell 12:3365-74
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Kinyamu, H K; Fryer, C J; Horwitz, K B et al. (2000) The mouse mammary tumor virus promoter adopts distinct chromatin structures in human breast cancer cells with and without glucocorticoid receptor. J Biol Chem 275:20061-8
Mancini, D N; Singh, S M; Archer, T K et al. (1999) Site-specific DNA methylation in the neurofibromatosis (NF1) promoter interferes with binding of CREB and SP1 transcription factors. Oncogene 18:4108-19