STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells.
Signal transducers and activators of transcription (STATs) play key roles in growth factor-mediated intracellular signal transduction. In the present study using a constitutively active STAT5 mutant, we show that STAT5 has pleiotropic functions regulating cell proliferation, differentiation and apoptosis in an IL-3-dependent Ba/F3 cell line. The mutant STAT5 possessed constitutive tyrosine phosphorylation and DNA binding activity, induced expression 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 resulted in apoptosis within 24 h, or differentiation followed by cell death. In these 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, correlating with prolonged hyper-phosphorylation of the mutant STAT5 after IL-3 stimulation. Of the STAT5-regulated genes, we found that constitutive expression 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 contrast, constitutive expression of pim-1 was sufficient to induce IL-3-independent growth of Ba/F3 cells. These findings suggest that a single transcription factor regulates cell fate by varying the intensity and duration of the expression of a set of target genes.
Nosaka
T
T
Department of Hematopoietic Factors, The Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Kawashima
T
T
Misawa
K
K
Ikuta
K
K
Mui
A L
AL
Kitamura
T
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000032:analysis; D004268:DNA-Binding Proteins / Q000502:physiology*; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D007377:Interleukin-3 / Q000378:metabolism; D053614:Janus Kinase 2; D051379:Mice; D008894:Milk Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000502:physiology*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D007377:Interleukin-3; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D004247:DNA; D011505:Protein-Tyrosine Kinases; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; C496636:Pim1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1