STAT-3 activation is required for normal G-CSF-dependent proliferation and granulocytic differentiation.
To investigate the role of signal transducer and activator of transcription (STAT) proteins in granulocyte colony-stimulating factor (G-CSF)-regulated biological responses, we generated transgenic mice with a targeted mutation of their G-CSF receptor (termed d715F) that abolishes G-CSF-dependent STAT-3 activation and attenuates STAT-5 activation. Homozygous mutant mice are severely neutropenic with an accumulation of immature myeloid precursors in their bone marrow. G-CSF-induced proliferation and granulocytic differentiation of hematopoietic progenitors is severely impaired. Expression of a constitutively active form of STAT-3 in d715F progenitors nearly completely rescued these defects. Conversely, expression of a dominant-negative form of STAT-3 in wild-type progenitors results in impaired G-CSF-induced proliferation and differentiation. These data suggest that STAT-3 activation by the G-CSFR is critical for the transduction of normal proliferative signals and contributes to differentiative signals.
McLemore
M L
ML
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Grewal
S
S
Liu
F
F
Archambault
A
A
Poursine-Laurent
J
J
Haug
J
J
Link
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DC
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006410:Hematopoiesis / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
D017931:DNA Primers; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D016179:Granulocyte Colony-Stimulating Factor