title: TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation.
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 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.
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2M9, Canada.
authors.forename: Iok In Christine
authors.initials: II
authors.lastname: Chio
authors.forename: Masato
authors.initials: M
authors.lastname: Sasaki
authors.forename: Danny
authors.initials: D
authors.lastname: Ghazarian
authors.forename: Juan
authors.initials: J
authors.lastname: Moreno
authors.forename: Susan
authors.initials: S
authors.lastname: Done
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Nien Jung
authors.initials: NJ
authors.lastname: Chen
authors.forename: Tak Wah
authors.initials: TW
authors.lastname: Mak
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational; D053199:TNF Receptor-Associated Death Domain Protein / Q000172:deficiency / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002352:Carrier Proteins; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D053199:TNF Receptor-Associated Death Domain Protein; C481226:Tradd protein, mouse; D016159:Tumor Suppressor Protein p53; C530813:TRIP12 protein, human; C570199:Trip12 protein, mouse; D044767:Ubiquitin-Protein Ligases