HUMAN ESTROGEN-RECEPTOR TRANSACTIVATIONAL CAPACITY IS DETERMINED BY BOTH CELLULAR AND PROMOTER CONTEXT AND MEDIATED BY 2 FUNCTIONALLY DISTINCT INTRAMOLECULAR REGIONS

We have used a series of human estrogen receptor (ER) mutants to evalu ate the cell- and promoter-specific transcriptional activities of the TAF1 and TAF2 transactivation regions within the human ER. We show tha t the manifestation of TAF1 or TAF2 function depends strongly upon pro moter context; on certain promoters, both the TAF1 and TAF2 activators are required for wild-type transcriptional activity, whereas on other promoters, the TAF1 and TAF2 activators function independently. Using these constructs, we show that the antagonist activity of the triphen ylethylene-derived antiestrogens, e.g. tamoxifen, arises from their in trinsic inability to activate ER TAF2 function. However, on certain pr omoters, these antiestrogens efficiently activate gene transcription t hrough ER. Consistent with this observation, the TAF2 function of the ER is not required on all promoters. In these TAF2-independent promote r contexts, TAF2 function may be provided by a separate transcription factor bound to the promoter. These data suggest that 1) TAF1 may be t he major transcriptional activator of the ER; and 2) TAF2 functions as a transcriptional facilitator. On promoters where TAF2 function is pr ovided independently of the ER, the TAF1 function of the ER can functi on independently of TAF2 activity, allowing triphenylethylene-derived antiestrogens to demonstrate partial agonist activity. These observati ons provide a possible molecular explanation for the tissue-specific p artial agonist properties of tamoxifen and related triphenylethylene a ntiestrogens observed in vivo.