Cross-talk between ERs and signal transducer and activator of transcription 5 is E2 dependent and involves two functionally separate mechanisms

Steroid hormone receptors and signal transducers and activators of transcri ption (STAT) factors constitute two distinct families of transcription fact ors activated by different signaling pathways. In previous reports, cross-t alk between STAT5 and several steroid receptors has been demonstrated. We i nvestigated putative cross-talk between ER alpha and ER beta and STAT5. ER alpha and ER beta were found to potently repress PRL-incluced STAT5 transcr iptional activity on a beta -casein promoter construct in a ligand-dependen t manner. This down-regulation was found to rely on direct physical interac tion between the ERs and STAT5, mediated via the ER DNA-binding domain (DBD ). The contact between the ER DBD and STAT5 is highly specific; the interac tion is abolished if the ERa DBD is replaced with the DBD of a closely rela ted steroid receptor. The physical interaction, however, is insufficient to confer the repression of STAT5 activity, which in addition requires the li gand-activated C-terminal part of the Ells, although these domains are not in direct contact with STAT5. Negative cross-talk between ERs and STAT5 is thus mediated via several functionally separated domains of the ERs. Our fi ndings may enhance the understanding of mechanisms of regulation of the dif ferent hormonal signaling pathways occurring during different functional ev ents in tissues coexpressing ERs and STAT5.