Essential role of NAT1/p97/DAP5 in embryonic differentiation and the retinoic acid pathway
Essential role of NAT1/p97/DAP5 in embryonic differentiation and the retinoic acid pathway
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DOI：
10.1093/emboj/19.20.5533
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发表时间：
2000-10-16
期刊：
影响因子：
11.4
通讯作者：
Innerarity, TL
中科院分区：
文献类型：
--
作者：
Yamanaka, S;Zhang, XY;Innerarity, TL
NAT 1/p97/DAP 5是一个新发现的与翻译起始因子eIF 4G具有同源性的蛋白。在体外和转染细胞中的研究表明，NAT 1可能抑制整体翻译，从而抑制细胞增殖。在这里，我们通过破坏小鼠体内的NAT 1基因来研究其体内功能。NAT 1（-/-）胚胎在原肠胚形成期间死亡，表明NAT 1在胚胎发生中起关键作用。未分化的NAT 1（-/-）胚胎干细胞在形态、增殖、翻译和基因表达谱方面均正常。然而，NAT 1（-/-）细胞表现出受损的分化能力：它们对维甲酸诱导的分化具有抗性，并且由它们衍生的畸胎瘤由未分化和低分化组织组成。在NAT 1（-/-）细胞中，视黄酸应答基因的表达，如细胞周期抑制剂p21（WAF 1），被选择性地削弱。合成视黄酸反应元件的转录也受损。这些数据表明，这种翻译起始因子同源物控制细胞分化所需的特定基因表达途径。
NAT1/p97/DAP5 is a newly identified protein that shares homology with the translation initiation factor eIF4G. Studies in vitro and in transfected cells indicated that NAT1 might suppress global translation, thereby repressing cellular proliferation. Here we studied the functions of NAT1 in vivo by disrupting its gene in mice. NAT1(-/-) embryos died during gastrulation, indicating a crucial role for NAT1 in embryogenesis. Undifferentiated NAT1(-/-) embryonic stem cells were normal in morphology, proliferation, global translation and gene expression profile. However, NAT1(-/-) cells exhibited an impaired ability to differentiate: they were resistant to differentiation induced by retinoic acid, and teratomas derived from them consisted of undifferentiated and poorly differentiated tissues. The expression of retinoic acid-responsive genes, such as the cell-cycle inhibitor p21(WAF1), was selectively impaired in NAT1(-/-) cells. Transcription from synthetic retinoic acid-responsive elements was also impaired. These data demonstrated that this translation initiation factor homolog controls specific gene expression pathways required for cellular differentiation.