title: Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation.
abstract: Stat5 is activated by multiple receptors of hematopoietic cytokines. To study its role during hematopoiesis, we have generated primary chicken myeloblasts expressing different dominant-negative (dn) alleles of Stat5. This caused a striking inability to generate mature cells, due to massive apoptosis during differentiation. Bcl-2 was able to rescue differentiating cells expressing dnStat5 from apoptosis, suggesting that during cytokine-dependent differentiation the main function of the protein is to ensure cell survival. Our findings with dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic cells from Stat5a/Stat5b-deficient mice. Bone marrow cells from these animals displayed a strong increase in apoptotic cell death during GM-CSF-dependent functional maturation in vitro. The antiapoptotic protein Bcl-x was induced by GM-CSF and IL-3 in a Stat5-dependent fashion. Ectopic expression of Bcl-x rescued Stat5-deficient bone marrow cells from apoptosis, indicating that Stat5 promotes the survival of myeloid progenitor cells through its ability to induce transcription of the bcl-x gene. Finally, the recruitment of myeloid cells to inflammatory sites was found strongly impeded in Stat5-deficient mice. Taken together, our findings suggest that Stat5 may promote cytokine-dependent survival and proliferation of differentiating myeloid progenitor cells in stress or pathological situations, such as inflammation.
authors.affiliation: Institute of Molecular Pathology, Vienna Biocenter, A-1030 Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Kieslinger
authors.forename: I
authors.initials: I
authors.lastname: Woldman
authors.forename: R
authors.initials: R
authors.lastname: Moriggl
authors.forename: J
authors.initials: J
authors.lastname: Hofmann
authors.forename: J C
authors.initials: JC
authors.lastname: Marine
authors.forename: J N
authors.initials: JN
authors.lastname: Ihle
authors.forename: H
authors.initials: H
authors.lastname: Beug
authors.forename: T
authors.initials: T
authors.lastname: Decker
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D001854:Bone Marrow Cells / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D002461:Cell Line, Transformed; D002470:Cell Survival; D002478:Cells, Cultured; D002645:Chickens; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D007249:Inflammation / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D051020:bcl-X Protein