COMPARISON OF THE TRANSACTIVATION DOMAINS OF STAT5 AND STAT6 IN LYMPHOID-CELLS AND MAMMARY EPITHELIAL-CELLS

Stat (signal transducers and activators of transcription) and Jak (Jan us kinases) proteins are central components in the signal transduction events in hematopoietic and epithelial cells. They are rapidly activa ted by various cytokines, hormones, and growth factors. Upon ligand bi nding and cytokine receptor dimerization, Stat proteins are phosphoryl ated on tyrosine residues by Jak kinases. Activated Stat proteins form home- or heterodimers, translocate to the nucleus, and induce transcr iption from responsive genes. Stat5 and Stat6 are transcription factor s active in mammary epithelial cells and immune cells. Prolactin activ ates Stat5, and interleukin-4 (IL-4) activates Stat6. Both cytokines a re able to stimulate cell proliferation, differentiation, and survival . We investigated the transactivation potential of Stat6 and found tha t it is not restricted to lymphocytes. IL-4-dependent activation of St at6 was also observed in HC11 mammary epithelial cells. In these cells , Stat6 activation led to the induction of the beta-casein gene promot er. The induction of this promoter was confirmed in COS7 cells. The gl ucocorticoid receptor was able to further enhance IL-4-induced gene tr anscription through the action of Stat6. Deletion analysis of the carb oxyl-terminal region of Stat6 and recombination of this region with a heterologous DNA binding domain allowed the delimitation and character ization of the transactivation domain of Stat6. The potencies of the t ransactivation domains of Stat5, Stat6, and viral protein VP16 were co mpared. Stat6 had a transactivation domain which was about 10-fold str onger than that of Stat5. In pre-B cells (Ba/F3), the transactivation domain of Stat6 was IL-4 regulated, independently from its DNA binding function.