Receptors bound to antiprogestin form abortive complexes with hormone responsive elements

The mechanism of action of antisteroids is not understood and explanations of their antagonistic activity have been sought at all levels of hormone action. It has been proposed that antisteroids after binding to receptor trap it into a nonactivated (non-DNA-binding) form possibly through interaction with a heat-shock protein of relative molecular mass (Mr) 90000 (90 K) or that the antisteroids provoke binding of receptor to nonspecific DNA sites but not to hormone responsive elements (HREs) or that the antisteroid-receptor complexes can bind to HREs but form abortive complexes that fail to regulate transcription. The authors have constructed a deleted cDNA encoding a mutant form of rabbit progesterone receptor which exhibits constitutive activity i.e. binds to HREs in the absence of hormone and thus bypasses the 1st 2 steps discussed above. Cotransfection experiments allowed the expression of both constitutive and wild-type receptors in the same recipient cells. Antiprogestin RU 486 wild-type receptor complexes completely suppressed the activity of the constitutive receptor on a reporter gene showing that the inhibition is at the level of their common responsive elements. (authors)