Essential role of B-Raf in ERK activation during extraembryonic development
Essential role of B-Raf in ERK activation during extraembryonic development
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DOI：
10.1073/pnas.0507399103
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发表时间：
2006-01-31
影响因子：
11.1
通讯作者：
Baccarini, M
中科院分区：
文献类型：
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作者：
Galabova-Kovacs, G;Matzen, D;Baccarini, M
Raf家族的激酶已被广泛研究为丝裂原活化蛋白激酶激酶/细胞外信号调节激酶（ERK）模块在调节和去调节增殖中的激活剂。遗传证据表明，在体内仅表达一种Raf激酶的低等生物中，Raf是ERK激活所必需的，但迄今为止在表达多种Raf激酶的哺乳动物中缺乏。两种被研究得最好的Raf激酶B-Raf和Raf-1的消融在小鼠妊娠中期是致命的，阻碍了对这些蛋白基本功能的详细研究。在这里，我们将常规和条件基因消融结合起来，表明B-Raf对ERK激活和胎盘血管发育至关重要。b - raf缺失的胎盘显示完全没有磷酸化的ERK， HIF-1 α和VEGF水平强烈降低，而所有这些参数在raf -1缺失的胎盘中是正常的。此外，通过外胚限制性基因失活获得的b -raf缺陷胚胎，其ERK磷酸化和发育均不受影响。这些数据表明，B-Raf在胚胎外哺乳动物体内发育过程中对ERK的激活起着非冗余的作用。
The kinases of the Raf family have been intensively studied as activators of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) module in regulated and deregulated proliferation. Genetic evidence that Raf is required for ERK activation in vivo has been obtained in lower organisms, which express only one Raf kinase, but was hitherto lacking in mammals, which express more than one Raf kinase. Ablation of the two best studied Raf kinases, B-Raf and Raf-1, is lethal at midgestation in mice, hampering the detailed study of the essential functions of these proteins. Here, we have combined conventional and conditional gene ablation to show that B-Raf is essential for ERK activation and for vascular development in the placenta. B-Raf-deficient placentae show complete absence of phosphorylated ERK and strongly reduced HIF-1 alpha and VEGF levels, whereas all these parameters are normal in Raf-1-deficient placentae. In addition, neither ERK phosphorylation nor development are affected in B-raf-deficient embryos that are born alive obtained by epiblast-restricted gene inactivation. The data demonstrate that B-Raf plays a nonredundant role in ERK activation during extraembyronic mammalian development in vivo.