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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells
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A genomewide study identifies the Wnt signaling pathway as a major target of p53 in murine embryonic stem cells

机译：全基因组研究确定Wnt信号通路是小鼠胚胎干细胞中p53的主要靶标

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摘要

Both p53 and the Wnt signaling pathway play important roles in regulating the differentiation of mouse embryonic stem cells (mESCs). However, it is not known whether they directly and/or functionally crosstalk in mESCs. Here we report a surprising anti-differentiation function of p53 in mESCs through directly regulating the Wnt signaling pathway. A chromatin-immunoprecipitation-based microarray (ChlP-chip) and gene expression microarray assays reveal that the Wnt signaling pathway is significantly (P value, 0.000048) overrepresented in p53-regulated genes in mESCs. The expression of five Wnt ligand genes is robustly induced by various genotoxic and nongenotoxic insults in a p53-dependent manner. Moreover, the induction of these Wnt genes is greatly attenuated in mouse embryonic fibroblast (MEF) cells and ESC-derived neural stem/progenitor cells, suggesting that the induction is mESC specific. It is established that the activation of the Wnt signaling pathway inhibits the differentiation of mESCs. Consistent with this notion, we detected an antidifferentiation activity from the conditioned medium (CM) collected from UV (UV)-treated mESCs. This antidifferentiation activity can be lowered by either the addition of Wnt antagonists into the CM or the reduction of p53 levels in UV-treated mESCs. Therefore, reminiscent of its dual functions on death and survival in somatic cells, p53 appears to regulate both prodifferentiation and antidifferentiation programs in mESCs. Our findings uncover a direct and functional connection between p53 and the Wnt signaling pathway, and expand the catalog of p53 regulated genes in mESCs.
机译：p53和Wnt信号通路均在调节小鼠胚胎干细胞（mESCs）的分化中起重要作用。但是，尚不清楚它们是否在mESC中直接和/或在功能上串扰。在这里，我们报道了通过直接调节Wnt信号通路在mESCs中p53的令人惊讶的抗分化功能。基于染色质免疫沉淀的微阵列（ChlP芯片）和基因表达微阵列分析显示，Wnt信号通路在mESC中的p53调控基因中明显过高（P值，0.000048）。五个Wnt配体基因的表达被多种遗传毒性和非遗传毒性损伤以p53依赖性方式强烈诱导。此外，这些Wnt基因的诱导在小鼠胚胎成纤维细胞（MEF）细胞和ESC衍生的神经干/祖细胞中大大减弱，表明该诱导是mESC特异性的。已经确定，Wnt信号传导途径的激活抑制了mESC的分化。与此想法一致，我们从紫外线（UV）处理的mESC收集的条件培养基（CM）中检测到了抗分化活性。可以通过在CM中添加Wnt拮抗剂或在经紫外线处理的mESC中降低p53水平来降低这种抗分化活性。因此，让人联想到其在体细胞中的死亡和存活双重功能，p53似乎可以调节mESCs中的预分化和抗分化程序。我们的发现揭示了p53与Wnt信号通路之间的直接功能联系，并扩展了mESC中p53调控基因的目录。

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    Kyoung-Hwa Lee; Mangmang Li; Aleksandra M. Michalowski; Xinyue Zhang; Hongling Liao; Lingyi Chen; Yang Xu; Xiaolin Wu; Jing Huang;

  • 作者单位

    Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892;

    Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892;

    Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892;

    Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892;

    Laboratory of Molecular Technology, Scientific Application International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21702;

    College of Life Sciences, Nankai University, Tianjin, 300071, China;

    Division of Biological Science, University of California, San Diego, La Jolla, CA 92093-0322;

    Laboratory of Molecular Technology, Scientific Application International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21702;

    Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, MD 20892;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    transcription; epigenetic; modifications; DNA binding; neural stem cells;

    机译：转录表观遗传修改;DNA结合;神经干细胞;

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