TRADD contributes to tumour suppression by regulating ULF-dependent p19 Arf ubiquitylation

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


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.

Original languageEnglish
Pages (from-to)625-633
Number of pages9
JournalNature Cell Biology
Issue number6
StatePublished - Jun 2012


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