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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Plk4 is required for cytokinesis and maintenance of chromosomal stability
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Plk4 is required for cytokinesis and maintenance of chromosomal stability

机译：Plk4是胞质分裂和维持染色体稳定性所必需的

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摘要

Aneuploidy is a characteristic feature of established cancers and can promote tumor development. Aneuploidy may arise directly, through unequal distribution of chromosomes into daughter cells, or indirectly, through a tetraploid intermediate. The polo family kinase Plk4/Sak is required for late mitotic progression and is haploinsufficient for tumor suppression in mice. Here we show that loss of heterozygosity (LOH) occurs at the Plk4 locus in 50% of human hepatocellular carcinomas (HCC) and is present even in preneoplastic cirrhotic liver nodules. LOH at Plk4 is associated with reduced Plk4 expression in HCC tumors but not with mutations in the remaining allele. Plk4~(+/-) murine embryonic fibroblasts (MEFs) at early passage show a high incidence of multinucleation, supernumerary centrosomes, and a near-tetraploid karyotype. Underlying these phenotypes is a high rate of primary cytokinesis failure, associated with aberrant actomyosin ring formation, reduced RhoA activation, and failure to localize the RhoA guanine nucleotide exchange factor Ect2 to the spindle midbody. We further show that Plk4 normally localizes to the midbody and binds to and phosphorylates Ect2 in vitro. With serial passaging Plk4~(+/-) MEFs rapidly immortalize, acquiring an increasing burden of non-clonal and clonal gross chromosomal irregularities, and form tumors in vivo. Our results indicate that haploid levels of Plk4 disrupt RhoGTPase function during cytokinesis, resulting in aneuploidy and tumorigenesis, thus implicating early LOH at Plk4 as one of the drivers of human hepatocellular carcinogenesis. These findings represent an advance in our understanding of genetic predisposition to HCC, which continues to increase in incidence globally and particularly in North America.
机译：非整倍性是已建立的癌症的特征，可以促进肿瘤的发展。非整倍性可通过染色体不均匀地分布到子细胞中而直接产生，或通过四倍体中间体间接产生。马球家族激酶Plk4 / Sak是晚期有丝分裂进程所必需的，并且单倍不足以抑制小鼠中的肿瘤。在这里，我们显示杂合性（LOH）的丧失发生在50％的人类肝细胞癌（HCC）的Plk4基因座上，甚至在肿瘤前性肝硬化肝结节中也存在。 Plk4处的LOH与HCC肿瘤中Plk4表达减少有关，但与其余等位基因中的突变无关。早期传代的Plk4〜（+/-）鼠胚胎成纤维细胞（MEF）显示出高的多核化，多余的中心体和近四倍体核型。这些表型的基础是高比例的原发性胞质分裂失败，与异常的放线菌素环形成，RhoA激活减少以及无法将RhoA鸟嘌呤核苷酸交换因子Ect2定位于纺锤体中体有关。我们进一步显示，Plk4通常位于中体，并在体外与Ect2结合并磷酸化。通过连续传代的Plk4〜（+/-）MEF永生化，获得越来越多的非克隆和克隆总染色体不规则性负担，并在体内形成肿瘤。我们的结果表明，单倍体水平的Plk4在胞质分裂过程中破坏RhoGTPase功能，导致非整倍性和肿瘤发生，因此牵涉到Plk4的早期LOH是人类肝细胞癌发生的驱动因素之一。这些发现代表了我们对HCC遗传易感性的了解的进步，而HCC的遗传易感性在全球尤其是北美的发病率持续上升。

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  • 作者

    Carla O. Rosario; Michael A. Ko; Yosr Z. Haffani; Rebecca A. Gladdy; Jana Paderova; Aaron Pollett; Jeremy A. Squire; James W. Dennis; Carol J. Swallow;

  • 作者单位

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Laboratory Medicine and Pathobiology,University of Toronto, Toronto, ON M5S 1A1, Canada;

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada lnstitute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada;

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada;

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada lnstitute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada;

    Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada;

    Department of Laboratory Medicine and Pathobiology,University of Toronto, Toronto, ON M5S 1A1, Canada;

    Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON K7L 3N6, Canada;

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Laboratory Medicine and Pathobiology,University of Toronto, Toronto, ON M5S 1A1, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A1, Canada;

    Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada Department of Laboratory Medicine and Pathobiology,University of Toronto, Toronto, ON M5S 1A1, Canada Department of Surgery, University of Toronto, Toronto, ON M5S 1A1, Canada lnstitute of Medical Science, University of Toronto, Toronto, ON M5S 1A1, Canada;

  • 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

    aneuploidy; hepatocellular carcinoma; polo-like kinase; RhoA; Ect2;

    机译：非整倍性肝细胞癌;马球样激酶RhoA;Ect2;

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