title: A novel role for STAT1 in regulating murine erythropoiesis: deletion of STAT1 results in overall reduction of erythroid progenitors and alters their distribution.
abstract: Erythropoietin (EPO) activates many distinct signal transduction cascades on engagement of its receptor. Deletion of the EPO, EPO receptor (EPO-R), or JAK2 genes in mice results in embryonic lethality due to a fatal anemia. EPO activates signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5a/b transcription factors in erythroid cell lines. Studies have focused on STAT5 as the primary target of EPO-dependent JAK2 activation. However, STAT5a/b(-/-) mice are viable, displaying a nonfatal anemia during embryogenesis, and delayed differentiation in adult erythropoiesis. Importantly, EPO-R cytoplasmic tyrosines are dispensable for viability in vivo. Interestingly, no cytoplasmic tyrosines are required for phosphorylation of STAT1. This led us to examine whether STAT1-deficient mice have altered erythropoiesis. A shift in erythropoiesis was observed in STAT1(-/-) mice, with reduced bone marrow-derived erythroid colony-forming units (CFU-Es) and a compensatory increase in splenic burst-forming units (BFU-Es) and CFU-Es. Both types of splenic-derived cells displayed EPO hyperresponsiveness. A 1.6-fold reduction in total CFU-Es was observed in STAT1-deficient mice, whereas total BFU-Es were comparable. Flow cytometry of STAT1-deficient erythroid cells revealed a less differentiated phenotype, associated with increased apoptosis of early erythroblasts. STAT1-deficient erythroblasts from phenylhydrazine-primed mice displayed enhanced phosphorylation of STAT5a/b, Erk1/2, and protein kinase B (PKB)/Akt. These results illustrate that STAT1 plays an important role in the regulation of erythropoiesis.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Adrienne
authors.initials: A
authors.lastname: Halupa
authors.forename: Monica L
authors.initials: ML
authors.lastname: Bailey
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.forename: Norman N
authors.initials: NN
authors.lastname: Iscove
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Dwayne L
authors.initials: DL
authors.lastname: Barber
mesh_terms: D000740:Anemia / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004900:Erythroblasts / Q000201:enzymology; D015672:Erythroid Precursor Cells / Q000166:cytology / Q000502:physiology*; D004920:Erythropoiesis / Q000502:physiology*; D004921:Erythropoietin / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008894:Milk Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013154:Spleen / Q000166:cytology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D050799:STAT5 Transcription Factor; C494080:Stat1 protein, mouse; C494093:Stat5a protein, mouse; D015534:Trans-Activators; D004921:Erythropoietin; D007371:Interferon-gamma; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3