THE TRANSACTIVATION DOMAIN AF-2 BUT NOT THE DNA-BINDING DOMAIN OF THEESTROGEN-RECEPTOR IS REQUIRED TO INHIBIT DIFFERENTIATION OF AVIAN ERYTHROID PROGENITORS

Earlier work demonstrated that an activated estrogen receptor (ER) is required for long-term self-renewal of c-ErbB-expressing avian erythro id progenitors. Here, we demonstrate that activation of the ER does no t only arrest or retard differentiation of early progenitors but that it affects erythroid differentiation at all stages of erythroid matura tion. A search for genes whose expression is affected by the ER showed that the 17 beta-estradiol-activated receptor suppressed the differen tiation-associated up-regulation of Gata-1, SCL-1, and globin genes in partially mature cells. In the same cells, the expression of carbonic anhydrase II (CAII) and histone H5 was enhanced. This led to prematur e expression of CAII, a possible explanation for the toxic effects of overexpressed ER. Repression specifically required the transactivation domain AF-2, but neither an intact DNA-binding domain (DBD) nor the A F-1 domain. The transcriptional activation of CAII, however, required both an intact AF-2 and a functional DBD. The requirement for the AF-2 , but not the DBD, suggested that the ER may compete with other nuclea r hormone receptors for transcriptional coactivators that bind AF-2, a domain well conserved within this family of transcription factors. We show, however, that this model does not apply for the most likely can didate, the avian thyroid hormone receptor.