In vivo Imaging Analysis of Steroid-Nuclear Receptor Function

Hager, Gordon L.

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 successfully developed for the glucocorticoid receptor (GR), the retinoic acid receptor (RAR), the estrogen receptor (ER), the aryl hydrocarbon receptor (AhR), 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. US patent No. 20150168416 was granted covering licensing of this technology. We have collaborated with multiple intramural and extramural investigators to track hormone contamination in U.S. waterways, and explore the implication of these findings for human health.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Cancer Institute (NCI)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIABC010308-21
• Application #: 10014345
• Support Year: 21
• Fiscal Year: 2019

Institution

• Name: National Cancer Institute Division of Basic Sciences

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