Abstract

We created fusion chimeras between GR and other nuclear receptors that manifest ligand dependent cytoplasmic/nuclear translocation for the chimeric receptor in response to the heterologous ligand. The approach has been successfuly developed for the retinoic acid receptor (RAR), the estrogen receptor (ER), and the progesterone receptor (PR), and the thyroid hormone receptor (ThR). We developed cell lines which express fluorescently tagged versions of the receptor chimeras. We have utilized this fluorescent protein fusion technology to show that U.S. water supplies are heavily contaminated with chemicals that have glucocorticoid and androgen activity. We have filed US patent application No. 61/656,473 to cover licensing of this technology We have also utilized this fluorescent protein fusion technology to develop high through-put automated screens to identify small molecule modulators of nuclear receptor responses.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010308-16
Application #
8937705
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Lynch, Caitlin; Sakamuru, Srilatha; Huang, Ruili et al. (2017) Identifying environmental chemicals as agonists of the androgen receptor by using a quantitative high-throughput screening platform. Toxicology 385:48-58
Presman, Diego M; Hager, Gordon L (2017) More than meets the dimer: What is the quaternary structure of the glucocorticoid receptor? Transcription 8:32-39
Stavreva, Diana A; Varticovski, Lyuba; Levkova, Ludmila et al. (2016) Novel cell-based assay for detection of thyroid receptor beta-interacting environmental contaminants. Toxicology 368-369:69-79
Grøntved, Lars; Waterfall, Joshua J; Kim, Dong Wook et al. (2015) Transcriptional activation by the thyroid hormone receptor through ligand-dependent receptor recruitment and chromatin remodelling. Nat Commun 6:7048
Voss, Ty C; Hager, Gordon L (2014) Dynamic regulation of transcriptional states by chromatin and transcription factors. Nat Rev Genet 15:69-81
Dull, Angie B; George, Anuja A; Goncharova, Ekaterina I et al. (2014) Identification of compounds by high-content screening that induce cytoplasmic to nuclear localization of a fluorescent estrogen receptor ? chimera and exhibit agonist or antagonist activity in vitro. J Biomol Screen 19:242-52
Miranda, Tina B; Voss, Ty C; Hager, Gordon L (2013) High-throughput fluorescence-based screen to identify factors involved in nuclear receptor recruitment to response elements. Methods Mol Biol 1042:3-12
Stavreva, Diana A; George, Anuja A; Klausmeyer, Paul et al. (2012) Prevalent glucocorticoid and androgen activity in US water sources. Sci Rep 2:937
Biddie, Simon C; John, Sam; Sabo, Pete J et al. (2011) Transcription factor AP1 potentiates chromatin accessibility and glucocorticoid receptor binding. Mol Cell 43:145-55
Sung, Myong-Hee; McNally, James G (2011) Live cell imaging and systems biology. Wiley Interdiscip Rev Syst Biol Med 3:167-82

Showing the most recent 10 out of 14 publications