SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis
SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis
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DOI：
10.1073/pnas.95.12.6881
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发表时间：
1998-06-09
影响因子：
11.1
通讯作者：
Zon, LI
中科院分区：
文献类型：
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作者：
Ganiatsas, S;Kwee, L;Zon, LI
SEK1(MKK4/JNKK)是一种丝裂原激活的蛋白激酶激活剂，已被证明在体外参与了两个以SAPK和p38激酶终止的应激激活级联反应。为了确定SEK1在体内的作用，我们研究了SEK1(-/-)胚胎干细胞和成纤维细胞中的应激诱导信号，并评估了SEK1(-/-)小鼠胚胎发育过程中的表型。对SEK1(-/-)胚胎干细胞的研究发现，在刺激的SAPK磷酸化方面存在缺陷，但在p38激酶的磷酸化方面没有缺陷。相反，SEK1(-/-)成纤维细胞在SAPK和p38磷酸化方面都表现出缺陷，这表明压力激活的级联之间存在串扰。在SEK1(-/-)成纤维细胞中，肿瘤坏死因子LY和白介素1刺激这两个应激激活级联反应都受到严重影响。SEK1缺乏可导致胚胎在胚胎发育12.5天后死亡，并与肝脏发育异常有关，这种表型与c-jun缺失的小鼠胚胎相似，提示在肝脏器官发生过程中，SEK1是c-jun磷酸化和激活所必需的。
SEK1 (MKK4/JNKK) is a mitogen-activated protein kinase activator that has been shown to participate in vitro in two stress-activated cascades terminating with the SAPK and p38 kinases. To define the role of SEK1 in vivo, we studied stress-induced signaling in SEK1(-/-) embryonic stem and fibroblast cells and evaluated the phenotype of SEK1(-/-) mouse embryos during development. Studies of SEK1(-/-) embryonic stem cells demonstrated defects in stimulated SAPK phosphorylation but not in the phosphorylation of p38 kinase. In contrast, SEK1(-/-) fibroblasts exhibited defects in both SAPK and p38 phosphorylation, demonstrating that crosstalk exists between the stress-activated cascades. Tumor necrosis factor LY and interleukin 1 stimulation of both stress-activated cascades are severely affected in the SEK1(-/-) fibroblast cells. SEK1 deficiency leads to embryonic lethality after embryonic day 12.5 and is associated with abnormal liver development, This phenotype is similar to c-jun null mouse embryos and suggests that SEK1 is required for phosphorylation and activation of c-jun during the organo-genesis of the liver.