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首页> 外文期刊>Molecular and Cellular Biology >The Grb2/Mek Pathway Represses Nanog in Murine Embryonic Stem Cells
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The Grb2/Mek Pathway Represses Nanog in Murine Embryonic Stem Cells

机译：Grb2 / Mek通路抑制小鼠胚胎干细胞中的Nanog。

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The homeobox gene Nanog is a key intrinsic determinant of self renewal in embryonic stem (ES) cells, and its repression leads ES cells to selectively differentiate into primitive endoderm. Although Nanog repression occurs at the outermost layer of ES cell aggregates independent of the leukemia inhibitory factor (LIF)/STAT3 pathway, it is largely undetermined what external cues and intracellular signals cause the event. Of interest, addition of the tyrosine phosphatase inhibitor, sodium vanadate, selectively repressed Nanog transcription without any detectable changes in upstream transcriptional regulators Oct3/4 and Sox2. Furthermore, sodium vanadate induced primitive endoderm differentiation, even in the inner cells of ES cell aggregates. Expression of Gata6 and Zfp42, two putative downstream Nanog effectors, was also increased and decreased by the addition of sodium vanadate, respectively, but these changes were eliminated by exogenous Nanog expression. The effects of sodium vanadate were abrogated by Grb2 deficiency or by the addition of the Mek inhibitor, PD98059. Indeed, PD98059 prevented Nanog repression induced by ES cell aggregation as well. Furthermore, transfection of a constitutive active Mek mutant into ES cells induced Nanog repression and primitive endoderm differentiation. These data indicate that the Grb2/Mek pathway primarily mediates Nanog gene repression upon ES cell differentiation into primitive endoderm.
机译：同源盒基因Nanog是胚胎干（ES）细胞自我更新的关键内在决定因素，其抑制作用导致ES细胞选择性分化为原始内胚层。尽管Nanog抑制发生在ES细胞聚集体的最外层，与白血病抑制因子（LIF）/ STAT3途径无关，但很大程度上不确定是由外部线索和细胞内信号引起的。有趣的是，添加酪氨酸磷酸酶抑制剂钒酸钠可选择性抑制Nanog转录，而上游转录调节因子Oct3 / 4和Sox2中没有任何可检测的变化。此外，即使在ES细胞聚集的内部细胞中，钒酸钠也能诱导原始内胚层分化。通过添加钒酸钠分别增加和减少了两个推定的下游Nanog效应子Gata6和Zfp42的表达，但外源性Nanog的表达消除了这些变化。缺乏Grb2或添加Mek抑制剂PD98059可消除钒酸钠的作用。实际上，PD98059也阻止了ES细胞聚集诱导的Nanog抑制。此外，将组成型活性Mek突变体转染到ES细胞中可诱导Nanog抑制和原始内胚层分化。这些数据表明，Grb2 / Mek途径主要在ES细胞分化为原始内胚层后介导Nanog基因抑制。

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