Influence of hormone antagonists on chromatin remodeling and transcription factor binding to the mouse mammary tumor virus promoter in vivo.
Steroid hormones act via a group of high affinity receptors that regulate transcription by binding to hormone response elements located in the promoters of hormone-inducible genes. Our understanding of these processes has been greatly enhanced by the use of steroid hormone antagonists in both clinical and experimental procedures. However, despite their usefulness in these applications, much about their mechanisms of action remains to be elucidated. Using in vivo analysis techniques, we investigated the influence of type I (ZK98299) and type II (RU486 and ZK112993) steroid hormone antagonists on glucocorticoid-regulated transcription from the mouse mammary tumor virus promoter. Both type I and type II antagonists substantially reduced glucocorticoid-induced expression from the mouse mammary tumor virus promoter stably maintained as chromatin. Concurrent treatment with glucocorticoid and type I or type II antagonists reduced the receptor-dependent chromatin remodeling and loading of transcription factor NF1 that are signature responses of this promoter in the context of chromatin. Treatment with either type I or type II antagonists alone did not induce chromatin remodeling or transcription factor loading. Although type II antagonist-occupied receptor can bind DNA, our results show that this binding is not functionally equivalent to that of agonist-occupied receptor, as it can not interact productively with the cellular apparatus required to open a repressive chromatin structure.
Mymryk
J S
JS
Department of Obstetrics and Gynecology, University of Western Ontario, London, Canada.
Archer
T K
TK
D000818:Animals; D001667:Binding, Competitive; D002843:Chromatin / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology; D006067:Gonanes / Q000494:pharmacology; D006727:Hormone Antagonists / Q000378:metabolism / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics*; D051379:Mice; D015735:Mifepristone / Q000031:analogs & derivatives / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D002843:Chromatin; D005938:Glucocorticoids; D006067:Gonanes; D006727:Hormone Antagonists; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; C064879:ZK 112993; D015735:Mifepristone; D003907:Dexamethasone; C053238:onapristone