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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1
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An integrated genome screen identifies the Wnt signaling pathway as a major target of WT1

机译：整合的基因组筛选将Wnt信号通路确定为WT1的主要靶标

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摘要

WT1, a critical regulator of kidney development, is a tumor suppressor for nephroblastoma but in some contexts functions as an oncogene. A limited number of direct transcriptional targets of WT1 have been identified to explain its complex roles in tumorigenesis and organo-genesis. In this study we performed genome-wide screening for direct WT1 targets, using a combination of ChlP-ChIP and expression arrays. Promoter regions bound by WT1 were highly G-rich and resembled the sites for a number of other widely expressed transcription factors such as SP1, MAZ, and ZNF219. Genes directly regulated by WT1 were implicated in MAPK signaling, axon guidance, and Wnt pathways. Among directly bound and regulated genes by WT1, nine were identified in the Wnt signaling pathway, suggesting that WT1 modulates a subset of Wnt components and responsive genes by direct binding. To prove the biological importance of the interplay between WT1 and Wnt signaling, we showed that WT1 blocked the ability of Wnt8 to induce a secondary body axis during Xenopus embryonic development. WT1 inhibited TCF-mediated transcription activated by Wnt ligand, wild type and mutant, stabilized β-catenin by preventing TCF4 loading onto a promoter. This was neither due to direct binding of WT1 to the TCF binding site nor to interaction between WT1 and TCF4, but by competition of WT1 and TCF4 for CBP. WT1 interference with Wnt signaling represents an important mode of its action relevant to the suppression of tumor growth and guidance of development.
机译：WT1是肾脏发育的关键调节剂，是肾母细胞瘤的肿瘤抑制因子，但在某些情况下起癌基因的作用。 WT1的有限数量的直接转录目标已被确定来解释其在肿瘤发生和器官发生中的复杂作用。在这项研究中，我们结合了ChlP-ChIP和表达阵列，对全基因组WT1靶标进行了全基因组筛选。 WT1结合的启动子区域高度富含G，并且类似于许多其他广泛表达的转录因子（如SP1，MAZ和ZNF219）的位点。 WT1直接调控的基因与MAPK信号传导，轴突指导和Wnt途径有关。在由WT1直接结合和调控的基因中，在Wnt信号通路中鉴定出9个，这表明WT1通过直接结合调节Wnt成分和响应基因的一个子集。为了证明WT1和Wnt信号之间相互作用的生物学重要性，我们表明WT1在爪蟾胚胎发育过程中阻断了Wnt8诱导次生体轴的能力。 WT1通过阻止TCF4加载到启动子上而抑制了Wnt配体，野生型和突变体激活的TCF介导的转录，稳定了β-catenin。这既不是由于WT1与TCF结合位点的直接结合，也不是由于WT1和TCF4之间的相互作用，而是由于WT1和TCF4对CBP的竞争。 WT1对Wnt信号的干扰代表了其作用的一种重要模式，该模式与抑制肿瘤生长和指导发展有关。

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    Marianne K.-H. Kim; Thomas J. McGarry; Pilib O Broin; Jared M. Flatow; Aaron A.-J. Golden; Jonathan D. Licht;

  • 作者单位

    Division of Hematology/Oncology, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL 60611;

    Feinberg Cardiovascular Research Institute, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;

    Department of Information Technology, National University of Ireland, Galway, Republic of Ireland;

    Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL 60611;

    Department of Information Technology, National University of Ireland, Galway, Republic of Ireland;

    Division of Hematology/Oncology, Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611 Robert H. Lurie Cancer Center, Northwestern University, Chicago, IL 60611;

  • 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
  • 中图分类
  • 关键词

    ChIP-ChIP; microarray; tumor suppressor;

    机译：芯片-芯片;微阵列抑癌剂;

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