缺乏转录因子干扰素共有序列结合蛋白(ICSBP)的小鼠是免疫缺陷的并且发展成粒细胞白血病。进一步的分析表明，ICSBP是一种分子开关因子，可指导双电位髓样前体分化为单核细胞谱系。为了揭示骨髓生成失调的分子机制，我们检测了ICSBP(-/-)小鼠骨髓源性巨噬细胞(BMMs)中集落刺激因子1受体(CSF-1R)的信号传导.我们发现在没有ICSBP的情况下,从Erk磷酸化的加速终止和细胞生长的减少可以看出,CSF-1R信号传导减弱。这一发现与增加的CSF-1R泛素化和c-Cbl的增加的积累相一致。c-Cbl是一种泛素连接酶,其已知通过将活化的CSF-1R靶向内吞途径来下调活化的CSF-1R。我们的结果表明，在CSF-1R激活后，c-Cbl本身在ICSBP(+/+)中被部分蛋白水解降解，但在ICSBP(-/-)BMM中没有。主要内体/溶酶体蛋白酶的表达，组织蛋白酶B,在ICSBP(-/-)BMM中大大降低。
Mice deficient for the transcription factor interferon
consensus sequence binding protein (ICSBP) are immunodeficient and develop granulocytic leukemia. Further analyses indicated that ICSBP is a molecular switch factor directing the differentiation of bipotential myeloid precursors to the monocytic lineage. To reveal the molecular mechanisms responsible for the deregulation of myelopoiesis, we examined the signaling of the colony-stimulating factor 1 receptor (CSF-1R) in bone marrow-derived macrophages (BMMs) from ICSBP(-/-) mice. We found that in the absence of ICSBP, CSF-1R signaling is attenuated as seen from an accelerated termination of Erk phosphorylation and reduced cell growth. This finding coincides with an increased CSF-1R ubiquitination and an enhanced accumulation of c-Cbl. c-Cbl is an ubiquitin-ligase known to down-regulate activated CSF-1R by targeting it to the endocytic pathway. Our results indicate that upon CSF-1R activation, c-Cbl itself is partly proteolytically degraded in ICSBP(+/+) but not in ICSBP(-/-) BMMs. Congruently, the expression of a major endosomal/lysosomal protease, cathepsin B, is strongly reduced in ICSBP(-/-) BMMs.
