The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2M9, Canada.
Nat Cell Biol. 2012 May 6;14(6):625-33. doi: 10.1038/ncb2496.
Tumour necrosis factor receptor (TNFR)-associated death domain (TRADD) protein is a central adaptor in the TNFR1 signalling complex that mediates both cell death and inflammatory signals. Here, we report that Tradd deficiency in mice accelerated tumour formation in a chemical-induced carcinogenesis model independently of TNFR1 signalling. In vitro, primary cells lacking TRADD were less susceptible to HRas-induced senescence and showed a reduced level of accumulation of the p19(Arf) tumour suppressor protein. Our data indicate that TRADD shuttles dynamically from the cytoplasm into the nucleus to modulate the interaction between p19(Arf) and its E3 ubiquitin ligase ULF, thereby promoting p19(Arf) protein stability and tumour suppression. These results reveal a previously unknown tumour-suppressive role for nuclear TRADD, augmenting its long-established cytoplasmic functions in inflammatory and immune signalling cascades. Our findings also make an important contribution to the rapidly expanding field of p19(Arf) post-translational regulation.
肿瘤坏死因子受体（TNFR）相关死亡结构域（TRADD）蛋白是 TNFR1 信号复合物中的一个中心衔接蛋白，介导细胞死亡和炎症信号。在这里，我们报告说，在化学诱导的致癌发生模型中，小鼠中 Tradd 的缺失独立于 TNFR1 信号而加速了肿瘤的形成。在体外，缺乏 TRADD 的原代细胞对 HRas 诱导的衰老的敏感性较低，并且 p19(Arf)肿瘤抑制蛋白的积累水平降低。我们的数据表明，TRADD 从细胞质到细胞核动态穿梭，以调节 p19(Arf)与其 E3 泛素连接酶 ULF 之间的相互作用，从而促进 p19(Arf)蛋白的稳定性和肿瘤抑制作用。这些结果揭示了核 TRADD 的先前未知的肿瘤抑制作用，增强了其在炎症和免疫信号级联反应中的长期确立的细胞质功能。我们的研究结果也为 p19(Arf) 翻译后调节的快速发展领域做出了重要贡献。
