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 transcription (STAT) factors constitute two distinct families of transcription factors activated by different signaling pathways. In previous reports, cross-talk between STAT5 and several steroid receptors has been demonstrated. We investigated putative cross-talk between ER alpha and ER beta and STAT5. ER alpha and ER beta were found to potently repress PRL-incluced STAT5 transcriptional activity on a beta -casein promoter construct in a ligand-dependent manner. This down-regulation was found to rely on direct physical interaction 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 interaction is abolished if the ERa DBD is replaced with the DBD of a closely related steroid receptor. The physical interaction, however, is insufficient to confer the repression of STAT5 activity, which in addition requires the ligand-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 findings may enhance the understanding of mechanisms of regulation of the different hormonal signaling pathways occurring during different functional events in tissues coexpressing ERs and STAT5.