PROLACTIN, GROWTH-HORMONE, ERYTHROPOIETIN AND GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTOR INDUCE MGF-STAT5 DNA-BINDING ACTIVITY

The molecular components which mediate cytokine signaling from the cel l membrane to the nucleus were studied. Upon the interaction of cytoki nes with their receptors, members of the janus kinase (Jak) family of cytoplasmic protein tyrosine kinases and of the signal transducers and activators of transcription (Stat) family of transcription factors ar e activated through tyrosine phosphorylation. It has been suggested th at the Stat proteins are substrates of the Jak protein tyrosine kinase s, MGF-Stat5 is a member of the Stat family which has been found to co nfer the prolactin response. MGF-Stat5 can be phosphorylated and activ ated in its DNA binding activity by Jak2. The activation of MGF-Stat5 is not restricted to prolactin. Erythropoietin (EPO) and growth hormon e (GH) stimulate the DNA binding activity of MGF-Stat5 in COS cells tr ansfected with vectors encoding EPO receptor and MGF-Stat5 or vectors encoding GH receptor and MGF-Stat5. The activation of DNA binding by p rolactin, EPO and GH requires the phosphorylation of tyrosine residue 694 of MGF-Stat5. The transcriptional induction of a beta-casein promo ter luciferase construct in transiently transfected COS cells is speci fic for the prolactin activation of MGF-Stat5; it is not observed in E PO- and GH-treated cells. In the UT7 human hematopoietic cell line, EP O and granulocyte-macrophage colony stimulating factor activate the DN A binding activity of a factor closely related to MGF-Stat5 with respe ct to its immunological reactivity, DNA binding specificity and molecu lar weight. These results suggest that MGF-Stat5 regulates physiologic al processes in mammary epithelial cells, as well as in hematopoietic cells. Its DNA binding activity and transactivation potential are diff erentially regulated in a cytokine- and promoter-specific manner.