Peintner L, Dorstyn L, Kumar S, Aneichyk T, Villunger A, Manzl C
Division of Developmental Immunology, Medical University of Innsbruck, 6020 Innsbruck, Austria.
Centre for Cancer Biology - An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5001, Australia.
Cell Death Differ. 2015 Nov;22(11):1803-11. doi: 10.1038/cdd.2015.31. Epub 2015 Apr 10.
The receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD/CRADD) functions as a dual adaptor and is a constituent of different multi-protein complexes implicated in the regulation of inflammation and cell death. Within the PIDDosome complex, RAIDD connects the cell death-related protease, Caspase-2, with the p53-induced protein with a death domain 1 (PIDD1). As such, RAIDD has been implicated in DNA-damage-induced apoptosis as well as in tumorigenesis. As loss of Caspase-2 leads to an acceleration of tumor onset in the Eμ-Myc mouse lymphoma model, whereas loss of Pidd1 actually delays onset of this disease, we set out to interrogate the role of Raidd in cancer in more detail. Our data obtained analyzing Eμ-Myc/Raidd(-/-) mice indicate that Raidd is unable to protect from c-Myc-driven lymphomagenesis. Similarly, we failed to observe a modulatory effect of Raidd deficiency on DNA-damage-driven cancer. The role of Caspase-2 as a tumor suppressor and that of Pidd1 as a tumor promoter can therefore be uncoupled from their ability to interact with the Raidd scaffold, pointing toward the existence of alternative signaling modules engaging these two proteins in this context.
含死亡结构域的受体相互作用蛋白相关ICH-1/CED-3同源蛋白（RAIDD/CRADD）作为一种双重衔接蛋白，是参与炎症和细胞死亡调控的不同多蛋白复合物的组成成分。在PIDDosome复合物中，RAIDD将细胞死亡相关蛋白酶Caspase-2与含死亡结构域的p53诱导蛋白1（PIDD1）连接起来。因此，RAIDD与DNA损伤诱导的细胞凋亡以及肿瘤发生有关。由于在Eμ-Myc小鼠淋巴瘤模型中，Caspase-2的缺失会导致肿瘤发生加速，而Pidd1的缺失实际上会延迟该疾病的发生，我们着手更详细地探究Raidd在癌症中的作用。我们分析Eμ-Myc/Raidd(-/-)小鼠获得的数据表明，Raidd无法保护机体免受c-Myc驱动的淋巴瘤发生。同样，我们未观察到Raidd缺陷对DNA损伤驱动的癌症有调节作用。因此，Caspase-2作为肿瘤抑制因子以及Pidd1作为肿瘤促进因子的作用，可以与其与Raidd支架相互作用的能力脱钩，这表明在这种情况下存在与这两种蛋白相互作用的替代信号模块。
