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.
Mesh Terms:
Adenovirus E1A Proteins, Animals, Binding Sites, COS Cells, Cricetinae, DNA-Binding Proteins, Dexamethasone, Glucocorticoids, HeLa Cells, Histone Acetyltransferases, Humans, Mammary Tumor Virus, Mouse, Mice, Milk Proteins, Nuclear Receptor Coactivator 3, Phosphorylation, Prolactin, Promoter Regions, Genetic, Receptors, Glucocorticoid, STAT5 Transcription Factor, Terminal Repeat Sequences, Trans-Activators, Transcriptional Activation, Tyrosine
Adenovirus E1A Proteins, Animals, Binding Sites, COS Cells, Cricetinae, DNA-Binding Proteins, Dexamethasone, Glucocorticoids, HeLa Cells, Histone Acetyltransferases, Humans, Mammary Tumor Virus, Mouse, Mice, Milk Proteins, Nuclear Receptor Coactivator 3, Phosphorylation, Prolactin, Promoter Regions, Genetic, Receptors, Glucocorticoid, STAT5 Transcription Factor, Terminal Repeat Sequences, Trans-Activators, Transcriptional Activation, Tyrosine
Mol. Endocrinol.
Date: Oct. 01, 1998
PubMed ID: 9773981
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