ACTIVATION OF DIFFERENT STAT5 ISOFORMS CONTRIBUTES TO CELL-TYPE RESTRICTED SIGNALING IN RESPONSE TO INTERFERONS

Tyrosine phosphorylation and activation of the transcription factor St at5 occur in response to stimuli like granulocyte-macrophage colony-st imulating factor, interleukin-3, or erythropoietin that stimulate both proliferation and differentiation of hematopoietic cells, It is uncle ar whether Stat5 is part of a proliferative response or part of the ev ents leading to cellular differentiation, Here we report that agents p romoting differentiation but not proliferation of hematopoietic cells, like phorbol ester or both types of interferons (IFNs), activate Stat 5 in promonocytic U937 cells, Both IFN types caused tyrosine phosphory lation and DNA binding of predominantly one Stat5 isoform (Stat5a) des pite expression of both Stat5a and Stat5b proteins, Monocytic differen tiation of U937 cells led to a strong decrease in IFN-gamma-mediated a ctivation of Stat5 but not of Stat1. Transactivation of Stat5-target g enes occurred in response to IFN-gamma, which activates both Stat5 and Stat1, but not in response to granulocyte-macrophage colony-stimulati ng factor, which activates only Stat5. Tyrosine phosphorylation of Sta t5 is not generally part of the IFN response, IFN-gamma did not cause Stat5 activation in HeLa cells, despite the expression of both Stat5 i soforms at similar levels. By contrast, IFN-alpha caused tyrosine phos phorylation and DNA binding of exclusively the b isoform of Stat5, and activated Stat5b formed a DNA binding activity previously found in He La cells and designated IFN-alpha activation factor 2. Taken together, our results demonstrate that ligand binding of IFN receptors leads to an isoform-specific activation of Stat5 in a restricted number of cel l lineages, Moreover, they suggest that Stat5 might be part of the dif ferentiation response of myeloid cells.