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Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1

机译:唐氏综合症抑制肿瘤生长和钙调神经磷酸酶抑制剂DSCR1的作用

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摘要

The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway5"10. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscrl is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrkla, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals.
机译:唐氏综合症患者中许多癌症类型的发生率显着降低,并且据认为,这种广泛的癌症保护作用是通过增加21号染色体多余231个多余基因中的一个或多个基因的表达而实现的。是唐氏综合症候选项区1(DSCR1,也称为RCAN1),它编码一种蛋白,该蛋白通过钙调神经磷酸酶途径抑制血管内皮生长因子(VEGF)介导的血管生成信号[5]。10。组织和在唐氏综合症的小鼠模型中的研究。此外,我们证明了由单个额外的转基因拷贝的Dscrl提供的适度表达增加足以赋予小鼠明显的肿瘤生长抑制作用,并且这种抗药性是钙调神经磷酸酶途径的抑制导致肿瘤血管生成的缺陷。我们也提供证据表明DSCR1降低钙调神经磷酸酶的活性另一个21号染色体基因Dyrkla的二聚醚可能足以显着减少血管生成。这些数据提供了降低唐氏综合症癌症发病率的机制,并将钙调神经磷酸酶信号通路及其调节剂DSCR1和DYRK1A鉴定为所有个体中潜在的癌症治疗靶标。

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  • 来源
    《Nature》 |2009年第25期|1126-11301162|共6页
  • 作者单位

    Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA These authors contributed equally to this work.;

    Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA These authors contributed equally to this work.;

    Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA These authors contributed equally to this work.;

    Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA.;

    Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.;

    Department of Anatomy, Physiology and Genetic, Neuroscience, Molecular and Cellular Biology Program, School of Medicine, Uniformed Services University of the Health Services, Bethesda, Maryland 20814, USA.;

    Department of Medicine, Division of Pediatric Hematology Oncology, Children's Hospital Boston, and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.;

    Department of Medicine, Division of Pediatric Hematology Oncology, Children's Hospital Boston, and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.;

    Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Boston, Maryland 02114, USA.;

    Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, 153-8904, Japan.;

    Department of Pediatrics and The Brain Institute, The University of Utah, Salt Lake City, Utah 84108, USA.;

    Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA.;

    Department of Medicine, Division of Pediatric Hematology Oncology, Children's Hospital Boston, and Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.;

    Center for Vascular Biology Research, Division of Molecular and Vascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.;

    Department of Anatomy, Physiology and Genetic, Neuroscience, Molecular and Cellular Biology Program, School of Medicine, Uniformed Services University of the Health Services, Bethesda, Maryland 20814, USA.;

    Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA.;

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