Raf-1 antagonizes erythroid differentiation by restraining caspase activation
Raf-1 antagonizes erythroid differentiation by restraining caspase activation
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DOI：
10.1084/jem.20020562
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发表时间：
2002-11-18
影响因子：
15.3
通讯作者：
Baccarini, M
中科院分区：
文献类型：
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作者：
Kolbus, A;Pilat, S;Baccarini, M
Raf激酶是由有丝分裂原或癌基因激活的关键信号转导子。最好的研究Raf亚型，Raf-1，被确定为细胞凋亡的抑制剂，在小鼠中的常规和条件基因消融。c-raf-1（-/-）胚胎生长迟缓和贫血，并在妊娠中期死亡，胎盘和胎儿肝脏异常。在这里，我们表明，Raf-1缺陷的初级成红细胞不能扩大培养，由于其加速分化成成熟红细胞。此外，Raf-1的表达在分化的野生型细胞中下调，而激活的Raf-1的过表达延迟分化。正如最近所描述的人类红系前体细胞，我们发现，半胱天冬酶的激活是必要的分化小鼠胎肝成红细胞。在缺乏Raf-1的红系祖细胞中，分化相关的半胱天冬酶激活被加速，并因活化激酶的过表达而被延迟。这些结果揭示了Raf-1在红细胞生成中的基本功能，并证明Raf-1限制半胱天冬酶活化的能力在不同于细胞凋亡的背景下具有生物学相关性。
The Raf kinases are key signal transducers activated by mitogens or oncogenes. The best studied Raf isoform, Raf-1, was identified as an inhibitor of apoptosis by conventional and conditional gene ablation in mice. c-raf-1(-/-) embryos are growth retarded and anemic, and die at midgestation with anomalies in the placenta and fetal liver. Here, we show that Raf-1-deficient primary erythroblasts cannot be expanded in culture due to their accelerated differentiation into mature erythrocytes. In addition, Raf-1 expression is down-regulated in differentiating wild-type cells, whereas overexpression of activated Raf-1 delays differentiation. As recently described for human erythroid precursors, we find that caspase activation is necessary for the differentiation of murine fetal liver erythroblasts. Differentiation-associated caspase activation is accelerated in erythroid progenitors lacking Raf-1 and delayed by overexpression of the activated kinase. These results reveal an essential function of Raf-1 in erythropoiesis and demonstrate that the ability of Raf-1 to restrict caspase activation is biologically relevant in a context distinct from apoptosis.