FUNCTIONAL INTERACTIONS BETWEEN STAT5 AND THE GLUCOCORTICOID RECEPTOR

SIGNAL transduction pathways enable extracellular signals to activate latent transcription factors in the cytoplasm of cells. Dimerization, nuclear localization and binding to specific DNA sequences result in t he induction of gene transcription by these proteins. These events are necessary for the functioning of the JAK/STAT pathway and of the gluc ocorticoid-receptor pathway. In the former, the protein Stat5, which i s a member of a family of signal transducers and activators of transcr iption, is activated by cytokines, hormones and growth factors(1-7). T hese polypeptide ligands bind at the outside of the cell to specific t ransmembrane receptors and activate intracellular Janus protein tyrosi ne kinases (JAKs) to tyrosine-phosphorylate STAT proteins; interaction with the SH2 domain of the dimerization partner then confers the abil ity to bind to DNA at the STAT-response element and induce transcripti on(8-10). In the glucocorticoid-receptor pathway, the receptor interac ts with its steroid hormone ligand in the cytoplasm, undergoes an allo steric change that enables the hormone receptor complex to bind to spe cific DNA-response elements (glucocorticoid response elements, or GRE) and modulate transcription(11,12). Although these pathways appear to he unrelated, we show here that the glucocorticoid receptor can act as a transcriptional co-activator for Stat5 and enhance Stat5-dependent transcription. Stat5 forms a complex with the glucocorticoid receptor which binds to DNA independently of the GRE. This complex formation be tween Stat5 and the glucocorticoid receptor diminishes the glucocortic oid response of a GRE-containing promoter.