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.
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We are deeply grateful to K. Yamamoto, Z. Y. Hao and W. J. Lin for their helpful discussions during the initiation of this investigation; to M. Saunders for scientific editing; and to S. McCracken and I. N.g for administrative assistance. This work was supported by grants to T.W.M. from the Canadian Institutes of Health Research. I.I.C.C. is financially supported by the University of Toronto through the Connaught Scholarship and the Ontario Graduate Scholarship.
The authors declare no competing financial interests.
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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
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