Receptor density dictates the behavior of a subset of steroid ligands in glucocorticoid receptor-mediated transrepression.
By co-expressing glucocorticoid receptor (GR) and transcriptional reporter systems in GR-deficient Cos-7 cells, we profiled potency and efficacy of a panel of GR ligands as a function of GR expression levels (density). Our results show that potency and efficacy for GR full agonists, such as dexamethasone, in these transrepression assays are affected by receptor density. Intriguingly, receptor density dramatically influenced the behavior of the GR antagonist RU486 or the GR agonist medroxyprogesterone acetate (MPA). At high receptor density, both MPA and RU486 behaved as full agonists in transrepression: reducing GR density, however, resulted in conversion of these ligands from full agonist to full antagonists. In contrast, varying GR density could not convert cortisol and budesonide from GR agonists to antagonists. These results have clearly demonstrated, for the first time, an effect of receptor density on the agonist and antagonist properties of RU486 and MPA in GR-mediated transrepression.
Zhao
Qihong
Q
Department of Immunology, Bristol-Myers Squibb, Route 206 and Province Line Road, Princeton, NJ 08540, USA. qihong.zhao@bms.com
Pang
Jian
J
Favata
Margaret F
MF
Trzaskos
James M
JM
D000818:Animals; D019819:Budesonide / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003907:Dexamethasone / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D008024:Ligands; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D017258:Medroxyprogesterone Acetate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D015735:Mifepristone / Q000819:agonists / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000235:genetics; D012097:Repressor Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013256:Steroids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D008024:Ligands; D016328:NF-kappa B; D011965:Receptors, Glucocorticoid; D012097:Repressor Proteins; D013256:Steroids; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D015735:Mifepristone; D019819:Budesonide; D003907:Dexamethasone; D017258:Medroxyprogesterone Acetate; D008156:Luciferases; D006854:Hydrocortisone