STAT-3 Activation Is Required for Normal G-CSF-dependent Proliferation and Granulocytic Differentiation

Immunity. 2001 Feb;14(2):193-204. doi: 10.1016/s1074-7613(01)00101-7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Cell Differentiation / drug effects
  • Cell Division / drug effects
  • DNA Primers / genetics
  • DNA-Binding Proteins / metabolism*
  • Granulocyte Colony-Stimulating Factor / metabolism
  • Granulocyte Colony-Stimulating Factor / pharmacology*
  • Granulocytes / cytology
  • Granulocytes / drug effects*
  • Granulocytes / metabolism*
  • Hematopoiesis / genetics
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Milk Proteins*
  • Receptors, Granulocyte Colony-Stimulating Factor / genetics
  • Receptors, Granulocyte Colony-Stimulating Factor / metabolism
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Signal Transduction
  • Trans-Activators / metabolism*

Substances

  • DNA Primers
  • DNA-Binding Proteins
  • Milk Proteins
  • Receptors, Granulocyte Colony-Stimulating Factor
  • STAT3 Transcription Factor
  • STAT5 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Granulocyte Colony-Stimulating Factor