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

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 12; no. 10; pp. 1582 - 1593
• Main Authors: Pfitzner, Edith, Jähne, Ruth, Wissler, Manuela, Stoecklin, Elisabeth, Groner, Bernd
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.10.1998; Oxford University Press
• Subjects: Adenovirus E1A Proteins - drug effects; Adenovirus E1A Proteins - genetics; Adenovirus E1A Proteins - metabolism; Animals; Binding Sites; COS Cells - drug effects; Cricetinae; Dexamethasone - pharmacology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Glucocorticoids - metabolism; Glucocorticoids - pharmacology; HeLa Cells - drug effects; HeLa Cells - metabolism; Histone Acetyltransferases; Humans; Mammary Tumor Virus, Mouse - genetics; Mice; Milk Proteins; Mouse mammary tumor virus; Nuclear Receptor Coactivator 3; Phosphorylation; Prolactin - metabolism; Prolactin - pharmacology; Promoter Regions, Genetic; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; STAT5 Transcription Factor; Terminal Repeat Sequences; Trans-Activators - genetics; Trans-Activators - metabolism; Transcriptional Activation; Tyrosine - metabolism
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/mend.12.10.0180

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.