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Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7

机译:对抗微管蛋白化学疗法的敏感性由MCL1和FBW7调节

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摘要

Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics1. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarci-nomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms2. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with thee tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiqui-tylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemo-therapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in onco-genesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.
机译:微管在基本的细胞过程中起着关键作用,是抗微管蛋白化学疗法的靶标1。针对各种恶性肿瘤,包括卵巢和乳腺腺癌,非小细胞肺癌,白血病和淋巴瘤,广泛使用针对微管的药物如紫杉醇和长春新碱。这些药物将细胞停在有丝分裂中,并随后通过定义不明确的机制诱导细胞死亡2。抗性肿瘤细胞用于逃避抗微管蛋白剂诱导的死亡的策略也不清楚。在这里,我们显示了前生存蛋白MCL1(参考文献3)是由抗微管蛋白化学疗法触发的凋亡的重要调节剂。在有丝分裂阻滞期间,通过翻译后机制,MCL1蛋白水平显着下降,从而增强细胞死亡。 MCL1的磷酸化指导其与肿瘤抑制蛋白FBW7的相互作用,该蛋白是泛素连接酶复合物的底物结合成分。然后,MCL1的多泛酰化作用将其靶向蛋白酶体降解。 MCL1的降解在缺乏FBW7或FBW7功能缺失突变的患者源性肿瘤细胞中被阻断,从而赋予抗微管蛋白药物抗性并促进化学治疗诱导的多倍体。此外,原发性肿瘤样品富含FBW7失活和MCL1水平升高,强调了这些蛋白在癌基因发生中的重要作用。我们的研究结果表明,从蛋白质水平,信使RNA水平和遗传状态方面分析肿瘤的FBW7和MCL1状态可能有助于预测患者对抗微管蛋白化学疗法的反应。

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  • 来源
    《Nature》 |2011年第7336期|p.110-114|共5页
  • 作者单位

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA;

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia;

    Department of Protein Chemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA,Department of Protein Chemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    Department of Bioinformatics, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    Department of Bioinformatics, Genentech, South San Francisco, California 94080, USA;

    Department of Physiological Chemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA;

    Department of Biochemical Pharmacology, Genentech, South San Francisco, California 94080, USA;

    Department of Biochemical Pharmacology, Genentech, South San Francisco, California 94080, USA;

    Department of Structural Biology, Abbott Laboratories, Abbott Park, Illinois 60064, USA;

    Department of Protein Chemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA;

    Department of Research Oncology, Genentech, South San Francisco, California 94080, USA;

    The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia,Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia;

    Department of Physiological Chemistry, Genentech, South San Francisco, California 94080, USA;

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