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首页> 外文期刊>Nature >The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth
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The Drosophila TNF receptor Grindelwald couples loss of cell polarity and neoplastic growth

机译：果蝇TNF受体格林德瓦耦合细胞极性丧失和肿瘤生长

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摘要

Disruption of epithelial polarity is a key event in the acquisition of neoplastic growth. JNK signalling is known to play an important part in driving the malignant progression of many epithelial tumours, although the link between loss of polarity and JNK signalling remains elusive. In a Drosophila genome-wide genetic screen designed to identify molecules implicated in neoplastic growth(1), we identified grindelwald (grnd), a gene encoding a transmembrane protein with homology to members of the tumour necrosis factor receptor (TNFR) superfamily. Here we show that Grnd mediates the pro-apoptotic functions of Eiger (Egr), the unique Drosophila TNF, and that overexpression of an active form of Grnd lacking the extracellular domain is sufficient to activate JNK signalling in vivo. Grnd also promotes the invasiveness of Ras(V12)/scrib(-/-) tumours through Egr-dependent Matrix metallo-protease-1 (Mmp1) expression. Grnd localizes to the subapical membrane domain with the cell polarity determinant Crumbs (Crb) and couples Crb-induced loss of polarity with JNK activation and neoplastic growth through physical interaction with Veli (also known as Lin-7). Therefore, Grnd represents the first example of a TNFR that integrates signals from both Egr and apical polarity determinants to induce JNK-dependent cell death or tumour growth.
机译：上皮极性的破坏是获得性肿瘤生长的关键事件。尽管极性丧失和JNK信号传导之间的联系仍然难以捉摸，但已知JNK信号传导在驱动许多上皮肿瘤的恶性进展中起重要作用。在旨在鉴定与肿瘤生长相关的分子的果蝇全基因组遗传筛选中（1），我们鉴定了grindelwald（grnd），这是一种编码与肿瘤坏死因子受体（TNFR）超家族成员同源的跨膜蛋白的基因。在这里，我们显示Grnd介导Eiger（Egr），独特的果蝇TNF的促凋亡功能，并且缺少细胞外域的Grnd活性形式的过表达足以激活体内JNK信号传导。 Grnd还通过依赖Egr的基质金属蛋白酶1（Mmp1）表达促进Ras（V12）/ scrib（-/-）肿瘤的侵袭性。 Grnd通过细胞极性决定因子Crumbs（Crb）定位于根尖下膜结构域，并通过与Veli（也称为Lin-7）的物理相互作用将Crb诱导的极性丧失与JNK激活和肿瘤生长相结合。因此，Grnd代表了TNFR的第一个例子，该信号整合了来自Egr和顶端极性决定簇的信号，以诱导JNK依赖性细胞死亡或肿瘤生长。

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  • 来源
    《Nature》 |2015年第7557期|482-486|共5页
  • 作者

    Andersen Ditte S.; Colombani Julien; Palmerini Valentina; Chakrabandhu Krittalak; Boone Emilie; Roethlisberger Michael; Toggweiler Janine; Basler Konrad; Mapelli Marina; Hueber Anne-Odile; Leopold Pierre;

  • 作者单位

    Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France|CNRS, Inst Biol Valrose, F-06108 Nice, France|INSERM, Inst Biol Valrose, F-06108 Nice, France|Inst Biol Valrose, Genet & Physiol Growth Lab, F-06108 Nice, France;

    Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France|CNRS, Inst Biol Valrose, F-06108 Nice, France|INSERM, Inst Biol Valrose, F-06108 Nice, France|Inst Biol Valrose, Genet & Physiol Growth Lab, F-06108 Nice, France;

    European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy;

    Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France|CNRS, Inst Biol Valrose, F-06108 Nice, France|INSERM, Inst Biol Valrose, F-06108 Nice, France|Inst Biol Valrose, Death Receptors Signalling & Canc Therapy Lab, F-06108 Nice, France;

    Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France|CNRS, Inst Biol Valrose, F-06108 Nice, France|INSERM, Inst Biol Valrose, F-06108 Nice, France|Inst Biol Valrose, Genet & Physiol Growth Lab, F-06108 Nice, France;

    Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;

    Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;

    Univ Zurich, Inst Mol Life Sci, CH-8057 Zurich, Switzerland;

    European Inst Oncol, Dept Expt Oncol, I-20139 Milan, Italy;

    Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France|CNRS, Inst Biol Valrose, F-06108 Nice, France|INSERM, Inst Biol Valrose, F-06108 Nice, France|Inst Biol Valrose, Death Receptors Signalling & Canc Therapy Lab, F-06108 Nice, France;

    Univ Nice Sophia Antipolis, Inst Biol Valrose, F-06108 Nice, France|CNRS, Inst Biol Valrose, F-06108 Nice, France|INSERM, Inst Biol Valrose, F-06108 Nice, France|Inst Biol Valrose, Genet & Physiol Growth Lab, F-06108 Nice, France;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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