INTERPLAY BETWEEN ESTROGENS, PROGESTINS, RETINOIC ACID AND AP-1 ON A SINGLE REGULATORY SITE IN THE PROGESTERONE-RECEPTOR GENE

Transcriptional regulation of the progesterone receptor gene involves induction by estrogens and down-regulation by progestins, retinoic aci d, and AP-1 proteins. We have previously identified an intragenic (+69 8/+723) estrogen-responsive element present in the progesterone recept or gene, which binds the estradiol receptor and mediates estrogen and 4-OH tamoxifen induction. Progesterone receptor gene expression was eq ually stimulated by estradiol and 4-OH tamoxifen in the presence of a NH2 terminally deleted estrogen receptor mutant lacking activation fun ction 1, suggesting that activation function 2 was the predominant act ivation domain. This was confirmed by the lack of activity of an estro gen receptor mutant deleted of activation function 2. Repression by pr ogestins, retinoic acid, and AP-1 was mediated by the same estrogen re sponsive element although retinoic and progesterone receptors as well as AP-1 proteins did not bind to this element. Repression by these pro teins appears to involve different transactivating regions of the estr ogen receptor. Repression by retinoic receptors involved only activati on function 2 whereas repression by progesterone receptor and AP-1 nec essitated both functional domains. Since these proteins act without di rectly contacting the DNA, it seems likely that repression may be achi eved by protein-protein interactions among different domains of the es trogen receptor and/or the transcriptional machinery.