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 transducer and activator of transcription) family. Its induction by many other cytokines and interleukins suggests that Stat5 plays a crucial role not only in mammary epithelial, but also in hematopoietic cells. Cell type- and promoter-specific functions of Stat5 are most likely modulated by the interaction with other transcription factors. We recently showed cross-talk between Stat5 and the glucocorticoid receptor. The activated glucocorticoid receptor forms a complex with Stat5 and enhances Stat5-mediated transcriptional induction. Conversely, Stat5 diminishes the induction of glucocorticoid-responsive genes. Here, we investigated the role of p300/CBP(CREB-binding protein), a transcriptional coactivator of several groups of transcription factors, in Stat5-mediated transactivation and in the cross-talk between Stat5 and the glucocorticoid receptor. p300/ CBP acts as a coactivator of Stat5. Its ectopic expression enhances PRL-induced Stat5-mediated transcriptional activation. Consistent with this observation, we find that the adenovirus E1A protein, which binds to p300/CBP, suppresses Stat5-induced transcriptional activation. This inhibition requires the Stat5 transactivation domain and the p300/CBP binding site of E1A. Coimmunoprecipitation and mammalian two-hybrid assays demonstrate a direct interaction between the carboxyl-terminal transactivation domain of Stat5 and p300/CBP. p300/CBP also positively interacts with the glucocorticoid receptor and enhances glucocorticoid receptor-dependent transcriptional activation of the mouse mammary tumor virus-long terminal repeat promoter. Overexpression of p300/CBP does not counteract the Stat5-mediated inhibition of glucocorticoid receptor-dependent transactivation, i.e. the repression of the glucocorticoid response by Stat5 is not a consequence of competition for limiting amounts of p300/CBP.
Pfitzner
E
E
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Jähne
R
R
Wissler
M
M
Stoecklin
E
E
Groner
B
B
D017500:Adenovirus E1A Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D019556:COS Cells / Q000187:drug effects; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D051548:Histone Acetyltransferases; D006801:Humans; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008894:Milk Proteins; D056921:Nuclear Receptor Coactivator 3; D010766:Phosphorylation; D011388:Prolactin / Q000378:metabolism* / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D050799:STAT5 Transcription Factor; D020079:Terminal Repeat Sequences; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014443:Tyrosine / Q000378:metabolism
D017500:Adenovirus E1A Proteins; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D008894:Milk Proteins; D011965:Receptors, Glucocorticoid; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014443:Tyrosine; D003907:Dexamethasone; D011388:Prolactin; D051548:Histone Acetyltransferases; C538866:NCOA3 protein, human; C538867:Ncoa3 protein, mouse; D056921:Nuclear Receptor Coactivator 3