Involvement of Ras in extraembryonic endoderm differentiation of embryonic stem cells.
Involvement of Ras in extraembryonic endoderm differentiation of embryonic stem cells.
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DOI：
10.1016/j.bbrc.2003.11.138
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发表时间：
2004-01
影响因子：
3.1
通讯作者：
Urara Yoshida-Koide;T. Matsuda;Kunikazu Saikawa;Y. Nakanuma;T. Yokota;M. Asashima;H. Koide
中科院分区：
文献类型：
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作者：
Urara Yoshida-Koide;T. Matsuda;Kunikazu Saikawa;Y. Nakanuma;T. Yokota;M. Asashima;H. Koide
胚胎干细胞(ES细胞)来源于胚泡内细胞团，可分化为多种细胞系。在本研究中，我们研究了RAS在ES细胞分化中的可能作用。我们发现，RAS在类胚体(EBS)形成时被激活，这是ES细胞分化的第一步。当在EB分化过程中表达时，RAS的显性-负性突变体抑制了胚胎外内胚层分化的标志基因的诱导，包括GATA-4、GATA-6、α-胎儿蛋白和肝细胞核因子3β，而激活的突变体促进了它们的诱导。选择性地激活Raf/MEK/Erk通路的RAS突变体的表达也促进了胚胎外内胚层标志物的诱导，而MEK抑制剂处理导致了它们的表达下降。此外，RAS还刺激ES细胞内胚层分化抑制因子Nanog的下调。这些结果表明，胚胎分化过程中RAS的激活在胚胎外内胚层分化的启动中起着至关重要的作用。
Embryonic stem (ES) cells, derived from the inner cell mass of blastocyst can differentiate into multiple cell lineages. In this study, we examined the possible involvement of Ras in ES cell differentiation. We found that Ras was activated upon formation of embryoid bodies (EBs), an initial step in ES cell differentiation. When expressed during EB differentiation, a dominant-negative mutant of Ras suppressed induction of marker genes for extraembryonic endoderm differentiation, including GATA-4, GATA-6, α-fetoprotein, and hepatocyte nuclear factor 3β, while an activated mutant promoted their induction. Expression of a Ras mutant that selectively activates the Raf/MEK/Erk pathway also enhanced induction of extraembryonic endoderm markers, and treatment with a MEK inhibitor resulted in their decreased expression. In addition, Ras stimulated downregulation of Nanog, a suppressor of endoderm differentiation in ES cells. These data suggest that Ras activation during EB differentiation plays a crucial role in initiation of extraembryonic endoderm differentiation.