Nishina H, Vaz C, Billia P, Nghiem M, Sasaki T, De la Pompa J L, Furlonger K, Paige C, Hui C, Fischer K D, Kishimoto H, Iwatsubo T, Katada T, Woodgett J R, Penninger J M
The Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Suite 706, Toronto, Ontario M5G 2C1, Canada.
Development. 1999 Feb;126(3):505-16. doi: 10.1242/dev.126.3.505.
The stress signaling kinase SEK1/MKK4 is a direct activator of stress-activated protein kinases (SAPKs; also called Jun-N-terminal kinases, JNKs) in response to a variety of cellular stresses, such as changes in osmolarity, metabolic poisons, DNA damage, heat shock or inflammatory cytokines. We have disrupted the sek1 gene in mice using homologous recombination. Sek1(-/- )embryos display severe anemia and die between embryonic day 10.5 (E10.5) and E12.5. Haematopoiesis from yolk sac precursors and vasculogenesis are normal in sek1(-/- )embryos. However, hepatogenesis and liver formation were severely impaired in the mutant embryos and E11.5 and E12.5 sek1(-/- )embryos had greatly reduced numbers of parenchymal hepatocytes. Whereas formation of the primordial liver from the visceral endoderm appeared normal, sek1(-/-) liver cells underwent massive apoptosis. These results provide the first genetic link between stress-responsive kinases and organogenesis in mammals and indicate that SEK1 provides a crucial and specific survival signal for hepatocytes.
应激信号激酶SEK1/MKK4是应激激活蛋白激酶（SAPKs，也称为Jun氨基末端激酶，JNKs）的直接激活剂，可响应多种细胞应激，如渗透压变化、代谢毒物、DNA损伤、热休克或炎性细胞因子。我们利用同源重组在小鼠中破坏了sek1基因。Sek1(-/-)胚胎表现出严重贫血，并在胚胎第10.5天（E10.5）至E12.5天之间死亡。Sek1(-/-)胚胎中来自卵黄囊前体的造血和血管生成是正常的。然而，突变胚胎中的肝发生和肝脏形成严重受损，E11.5和E12.5的sek1(-/-)胚胎实质肝细胞数量大幅减少。虽然来自脏内胚层的原始肝脏形成似乎正常，但sek1(-/-)肝细胞发生了大量凋亡。这些结果提供了哺乳动物中应激反应激酶与器官发生之间的首个遗传联系，并表明SEK1为肝细胞提供了关键且特定的存活信号。
