P300 CREB-BINDING PROTEIN ENHANCES THE PROLACTIN-MEDIATED TRANSCRIPTIONAL INDUCTION THROUGH DIRECT INTERACTION WITH THE TRANSACTIVATION DOMAIN OF STAT5, BUT DOES NOT PARTICIPATE IN THE STAT5-MEDIATED SUPPRESSION OF THE GLUCOCORTICOID RESPONSE/

Stat5 was discovered as a PRL-induced member of the Stat (signal trans ducer and activator of transcription) family. Its induction by many ot her cytokines and interleukins suggests that Stat5 plays a crucial rol e not only in mammary epithelial, but also in hematopoietic cells. Cel l type- and promoter-specific functions of Stat5 are most likely modul ated by the interaction with other transcription factors. We recently showed cross-talk between Stat5 and the glucocorticoid receptor. The a ctivated glucocorticoid receptor forms a complex with Stat5 and enhanc es Stat5-mediated transcriptional induction. Conversely, Stat5 diminis hes the induction of glucocorticoid-responsive genes. Here, we investi gated the role of p300/CBP(CREB-binding protein), a transcriptional co activator of several groups of transcription factors, in Stat5-mediate d transactivation and in the cross-talk between Stat5 and the glucocor ticoid receptor. p300/CBP acts as a coactivator of Stat5. Its ectopic expression enhances PRL-induced Stat5-mediated transcriptional activat ion. Consistent with this observation, we find that the adenovirus E1A protein, which binds to p300/CBP, suppresses Stat5-induced transcript ional activation. This inhibition requires the Stat5 transactivation d omain and the p300/CBP binding site of E1A. Coimmunoprecipitation and mammalian two-hybrid assays demonstrate a direct interaction between t he carboxyl-terminal transactivation domain of Stat5 and p300/CBP, p30 0/CBP also positively interacts with the glucocorticoid receptor and e nhances glucocorticoid receptor-dependent transcriptional activation o f the mouse mammary tumor virus-long terminal repeat promoter. Overexp ression of p300/CBP does not counteract the Stat5-mediated inhibition of glucocorticoid receptor-dependent transactivation, i.e. the repress ion of the glucocorticoid response by Stat5 is not a consequence of co mpetition for limiting amounts of p300/CBP.