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首页> 外文期刊>Cell cycle >The EphB2 tumor suppressor induces autophagic cell death via concomitant activation of the ERK1/2 and PI3K pathways.
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The EphB2 tumor suppressor induces autophagic cell death via concomitant activation of the ERK1/2 and PI3K pathways.

机译：EphB2肿瘤抑制剂通过伴随ERK1 / 2和PI3K途径的激活诱导自噬细胞死亡。

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EphB2 is a tyrosine kinase receptor that has been shown to be a tumor suppressor gene in various cancers. However the mechanisms of this function are unknown. We report that EphB2 induces a form of cell death that does not involve the formation of apoptotic bodies or nuclear fragmentation and is instead accompanied by extensive vacuolization. Transmission electron microscopy demonstrates cytoplasmic vacuoles in EphB2-overexpressing cells that resembled autophagosomes. Using an EYFP-LC3 fusion protein and immunoblotting, we detected LC3 aggregation and conversion from form I to form II, both hallmarks of autophagy, in EphB2-transfected cells. Silencing of the autophagy regulating genes ATG5 or ATG7 using shRNAs, strongly prevented EphB2-induced cell death, further confirming its autophagic nature. EphB2 expression results in mitochondrial depolarization and translocation of cytochrome c from the mitochondria to the cytosol. Mapping of signaling pathways revealed novel information about the mechanisms of action of EphB2. We demonstrated that the MAPK pathway is important in the pro-death action of EphB2, through ERK1/2 phosphorylation and inhibition of this pathway using PD98059 counters EphB2-driven cell death. In addition, we found that inhibition of class III PI3K pathway, using the autophagy inhibitor 3MA, but not class I PI3K inhibition using LY294002, also effectively blocks EphB2- induced cell death. Finally, EphB2 expression inactivates Akt, which is a known inhibitor of autophagy. In conclusion, the EphB2 receptor induces an autophagic cell death that is mediated through the ERK1/2 and PI3K/Akt pathways.
机译：EphB2是酪氨酸激酶受体，其已被证明是各种癌症中的肿瘤抑制基因。然而，这个功能的机制是未知的。我们认为EphB2诱导细胞死亡形式，不涉及形成凋亡体或核碎片，而是伴随着广泛的真空。透射电子显微镜表现出类似于自噬体的EphB2过表达细胞中的细胞质泡沫塑料。使用EYFP-LC3融合蛋白和免疫印迹，我们在EPHB2转染细胞中检测到II形式I的LC3聚集和转化为II的形式II。使用ShRNA沉默自噬调节基因ATG5或ATG7，强烈地防止EphB2诱导的细胞死亡，进一步证实其自噬性质。 EphB2表达导致线粒体去极化和细胞色素C的易位从线粒体到胞嘧啶。信号传导途径的映射揭示了关于EPHB2的作用机制的新颖信息。我们证明MAPK途径在EPHB2的前死亡作用中是重要的，通过ERK1 / 2磷酸化和使用PD98059计数器EphB2驱动的细胞死亡抑制该途径。此外，我们发现使用自噬抑制剂3MA的III类PI3K途径的抑制，但不使用LY294002的I类PI3K抑制，也有效阻断EPHB2诱导的细胞死亡。最后，EphB2表达灭活AKT，这是一种已知的自噬抑制剂。总之，EphB2受体诱导通过ERK1 / 2和PI3K / AKT途径介导的自噬细胞死亡。

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  • 来源
    《Cell cycle》 |2010年第2期|共10页
  • 作者

    Kandouz M; Haidara K; Zhao J; Brisson ML; Batist G;

  • 作者单位

    Montreal Centre for Experimental Therapeutics in Cancer Segal Cancer Centre Lady Davis Institute for Medical Research Sir Mortimer B. Davis-Jewish General Hospital McGill University Montreal QC Canada.;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;
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