TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation
Author: ["Iok In Christine Chio","Masato Sasaki","Danny Ghazarian","Juan Moreno","Susan Done","Takeshi Ueda","Satoshi Inoue","Yu-Ling Chang","Nien Jung Chen","Tak Wah Mak"]
Publication: Nature Cell Biology
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Abstract
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 p19Arf tumour suppressor protein. Our data indicate that TRADD shuttles dynamically from the cytoplasm into the nucleus to modulate the interaction between p19Arf and its E3 ubiquitin ligase ULF, thereby promoting p19Arf 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 p19Arf post-translational regulation. Mak and colleagues report that TRADD, an adaptor protein important in tumour necrosis factor receptor (TNFR) signalling, contributes to tumour suppression independently of TNFR. They show that nuclear TRADD binds to the tumour suppressor p19Arf and inhibits its interaction with the E3 ubiquitin ligase ULF, leading to p19Arf stability and promoting cell senescence.
Cite this article
Chio, I., Sasaki, M., Ghazarian, D. et al. TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation. Nat Cell Biol 14, 625–633 (2012). https://doi.org/10.1038/ncb2496
