Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells
Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells
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DOI：
10.1101/gad.430207
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发表时间：
2007-08-15
影响因子：
10.5
通讯作者：
Jones, Nic
中科院分区：
文献类型：
--
作者：
Breitwieser, Wolfgang;Lyons, Steve;Jones, Nic
ATF2转录因子被应激激活的丝裂原激活蛋白激酶(MAPKs)JNK和p38磷酸化。我们表明这种磷酸化对于ATF2在体内的功能是必不可少的，因为携带关键磷酸化位点突变的小鼠具有与DNA结合结构域缺失时相同的强烈表型。此外，将该突变与ATF2同源基因ATF7的敲除结合，会导致胚胎死亡，并导致发育中的肝脏和心脏严重异常。突变胎肝的特点是发育中的肝细胞和造血细胞出现高水平的凋亡。此外，我们观察到由于失去了涉及依赖ATF2的MAPK磷酸酶转录激活的负反馈环路，活性p38显著增加。在胚胎肝细胞中，这种增加会导致细胞凋亡，因为它可以被p38的化学抑制所抑制。我们的发现证明了在发育过程中精细调控MAPK活性的重要性。
The ATF2 transcription factor is phosphorylated by the stress-activated mitogen-activated protein kinases (MAPKs) JNK and p38. We show that this phosphorylation is essential for ATF2 function in vivo, since a mouse carrying mutations in the critical phosphorylation sites has a strong phenotype identical to that seen upon deletion of the DNA-binding domain. In addition, combining this mutant with a knockout of the ATF2 homolog, ATF7, results in embryonic lethality with severe abnormalities in the developing liver and heart. The mutant fetal liver is characterized by high levels of apoptosis in developing hepatocytes and haematopoietic cells. Furthermore, we observe a significant increase in active p38 due to loss of a negative feedback loop involving the ATF2-dependent transcriptional activation of MAPK phosphatases. In embryonic liver cells, this increase drives apoptosis, since it can be suppressed by chemical inhibition of p38. Our findings demonstrate the importance of finely regulating the activities of MAPKs during development.