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首页> 外文期刊>Cell death and differentiation >PIDDosome-independent tumor suppression by Caspase-2
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PIDDosome-independent tumor suppression by Caspase-2

机译：Caspase-2抑制PIDDosome依赖性肿瘤

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摘要

The PIDDosome, a multiprotein complex constituted of the p53-induced protein with a death domain (PIDD), receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD) and pro-Caspase-2 has been defined as an activating platform for this apoptosis-related protease. PIDD has been implicated in p53-mediated cell death in response to DNA damage but also in DNA repair and nuclear factor kappa-light-chain enhancer (NF-B) activation upon genotoxic stress, together with RIP-1 kinase and Nemo/IKKγ. As all these cellular responses are critical for tumor suppression and deregulated expression of individual PIDDosome components has been noted in human cancer, we investigated their role in oncogenesis induced by DNA damage or oncogenic stress in gene-ablated mice. We observed that Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development. In contrast, Caspase-2 showed tumor suppressive capacity in response to aberrant c-Myc expression, which did not rely on PIDD, the BH3-only protein Bid (BH3 interacting domain death agonist) or the death receptor ligand Trail (TNF-related apoptosis-inducing ligand), but associated with reduced rates of p53 loss and increased extranodal dissemination of tumor cells. In contrast, Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.
机译：PIDDosome是一种多蛋白复合物，由具有死亡域（PIDD）的p53诱导蛋白，具有死亡域（RAIDD）的受体相互作用蛋白（RIP）相关的ICH-1 / CED-3同源蛋白和前胱天蛋白酶组成-2已被定义为该凋亡相关蛋白酶的激活平台。 PIDD与RIP-1激酶和Nemo /IKKγ一起参与了p53介导的对DNA损伤的细胞死亡，但也涉及DNA修复和遗传毒性胁迫下的核因子kappa轻链增强子（NF-B）活化。由于所有这些细胞应答对于抑制肿瘤至关重要，并且已在人类癌症中注意到单个PIDDosome组分的表达失控，因此我们研究了它们在基因消融小鼠中由DNA损伤或致癌应激诱导的肿瘤发生中的作用。我们观察到，Pidd或Caspase-2未能抑制由γ射线或3-甲基胆固醇驱动的纤维肉瘤发展触发的淋巴瘤形成。相反，Caspase-2表现出对c-Myc异常表达的反应的肿瘤抑制能力，这不依赖于PIDD，仅BH3蛋白Bid（BH3相互作用域死亡激动剂）或死亡受体配体Trail（TNF相关凋亡） -诱导配体），但与p53丢失率降低和肿瘤细胞的结外扩散增加有关。相反，Pidd缺乏症与异常的M期进展和疾病发作延迟相关，表明这两种蛋白质在c-Myc触发的致癌应激中差异性结合，从而导致无瘤生存的相反作用。

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