McLemore M L, Grewal S, Liu F, Archambault A, Poursine-Laurent J, Haug J, Link D C
Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Immunity. 2001 Feb;14(2):193-204. doi: 10.1016/s1074-7613(01)00101-7.
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.
为了研究信号转导及转录激活蛋白（STAT）在粒细胞集落刺激因子（G-CSF）调节的生物学反应中的作用，我们构建了G-CSF受体发生靶向突变（称为d715F）的转基因小鼠，该突变消除了G-CSF依赖的STAT-3激活并减弱了STAT-5激活。纯合突变小鼠严重中性粒细胞减少，骨髓中存在未成熟髓系前体细胞的积累。G-CSF诱导的造血祖细胞增殖和粒细胞分化严重受损。在d715F祖细胞中表达组成型活性形式的STAT-3几乎完全挽救了这些缺陷。相反，在野生型祖细胞中表达显性负性形式的STAT-3会导致G-CSF诱导的增殖和分化受损。这些数据表明，G-CSFR激活STAT-3对于正常增殖信号的转导至关重要，并有助于分化信号的传递。
