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RU486 is a recently described antiprogesterone. In order to be able to understand its mechanism of action it is necessary to analyze its effect on a discrete gene product. We show here that the induction of uteroglobin mRNA by progesterone in the rabbit endometrium may be a suitable model for such studies since RU486 totally inhibits this effect without itself exerting any agonistic activity. Moreover, RU486, which does not bind to the estrogen receptor and is devoid of general antiestrogenic activity, partially inhibits the induction by estradiol of uteroglobin mRNA. Studies of the interaction between [3H]RU486 and the progesterone receptor have been undertaken with the aim of understanding the antagonistic effect of this compound. The binding to DNA-cellulose of heat-activated [3H]RU486-receptor complexes was slightly decreased (37%) when compared with that of the agonist [3H]R5020-receptor complexes (47%). Detailed analysis of this difference showed that it was due to both a decreased activation of complexes and to a diminished affinity of activated complexes towards DNA. The change in activation was shown by the fact that at high concentrations of DNA, where all activated complexes are bound, agonist-receptor complexes were bound to DNA in higher proportion than antagonist-receptor complexes. Moreover a difference was also observed when studying the binding of agonist-receptor and antagonist-receptor complexes to charged resins (phosphocellulose, DEAE-cellulose) which are known to discriminate between activated and non-activated complexes. Decreased affinity to DNA of antagonist-receptor complexes was shown by studying their binding at various concentrations of DNA, either in crude cytosol or after isolating a homogenous population of activated-receptor complexes by DNA-cellulose chromatography and by comparing the salt extraction from DNA-cellulose of agonist-receptor and antagonist-receptor complexes. Both effects (decreased activation and diminished affinity towards DNA) were relatively moderate and could account only for a small decrease in the agonistic activity of RU486. Thus, the fact that this compound is a complete antagonist without any agonistic activity can only be explained by a defect in some further step of hormone action as, for instance in the specific interaction with the regulatory regions of the uteroglobin gene. No immunological difference could be detected between [3H]R5020-receptor and [3H]RU486-receptor complexes, both interacted with the five monoclonal antibodies raised against purified R5020-receptor complexes.(ABSTRACT TRUNCATED AT 400 WORDS)
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H Loosfelt, and
D Philibert, and
E Milgrom
January 1987,
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M Rauch, and
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