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Advances in Brief |
-1 Orphan Receptor1
Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010
Estrogen-related receptor (ERR) 
-1 shares a high amino acid sequence homology with estrogen receptor . Although estrogens are not ligands of ERR-1, our recent results suggest that toxaphene and chlordane, two organochlorine pesticides with estrogen-like activity, behave as antagonists for this orphan nuclear receptor. The two compounds increased ERR-1-mediated expression of the reporter enzyme ß-galactosidase in a yeast-based assay. The screen was developed by expressing the hERR-1-yeast Gal 4 activation domain fusion protein in yeast cells carrying the ß-galactosidase reporter plasmid, which contains an ERR-1-binding element. In transfection experiments using mammalian cell lines, such as the SK-BR-3 breast cancer cell line, the compounds were found to have an antagonist activity against ERR-1-mediated expression of the reporter chloramphenicol acetyltransferase. In contrast to the findings with ERR-1, the two compounds were found to slightly induce the estrogen receptor -mediated expression of chloramphenicol acetyltransferase in SK-BR-3 cells. In a ligand-independent manner, the ERR-1 activity in SK-BR-3 cells was induced 3-fold by cotransfection with the GRIP1 coactivator expression plasmid. Toxaphene was found to be capable of suppressing the GRIP1 coactivator-induced ERR-1 activity in SK-BR-3 cells. In addition, a stable ERR-1 expressing HepG2 hepatoma cell line was generated, and the aromatase activity in the transfected cell line was found to be twice that in the untransfected cell line. The enzyme aromatase converts androgens to estrogens, and aromatase expression in HepG2 cells is regulated in part by an ERR-1-modulating promoter. A 24-h incubation of an ERR-1-transfected HepG2 cell line with 10 µM toxaphene reduced its aromatase activity to the level in the untransfected cell line. Because toxaphene is not an inhibitor of aromatase, it is thought that the decrease of the aromatase activity in ERR-1 transfected HepG2 cells following toxaphene treatment resulted from a suppression of the aromatase expression by toxaphene acting as the antagonist of ERR-1. Toxaphene and chlordane are among the 12 persistent organic pollutants identified by the United Nations Environment Programme as requiring urgent attention. Their antagonistic effects on ERR-1 should not be overlooked.
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