STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells

Signal transducers and activators of transcription (STATs) play key roles i n growth factor-mediated intracellular signal transduction, In the present study using a constitutively active STAT5 mutant, we show that STAT5 has pl eiotropic functions regulating cell proliferation, differentiation and apop tosis in an IL-3-dependent Ba/F3 cell line, The mutant STAT5 possessed cons titutive tyrosine phosphorylation and DNA binding activity induced expressi on of bcl-xL. and pim-1 in the absence of IL-3 in Ba/F3 cells, and rendered Ba/F3 cells factor-independent. Unexpectedly, IL-3 treatment of the factor -independent Ba/F3 cells expressing the constitutively active STAT5 resulte d in apoptosis within 24 h, or differentiation followed by cell death. In t hese cells, mRNA expression of growth inhibitory genes downstream of STAT5 such as CIS, JAB/SOCS-1/SSI-1, and p21(WAF1/Cip1) was highly induced, corre lating with prolonged hyper-phosphorylation of the mutant STAT5 after IL-3 stimulation. Of the STAT5-regulated genes, we found that constitutive expre ssion of JAB/SOCS-1/SSI-1 was sufficient to induce apoptosis of Ba/F3 cells , while p21(WAF1/Cip1) could induce differentiation of these cells. In cont rast, constitutive expression of pim-1 nas sufficient to induce IL3-indepen dent growth of Ba/F3 cells. These findings suggest that a single transcript ion factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes.