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TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation
Authors:Chio Iok In Christine  Sasaki Masato  Ghazarian Danny  Moreno Juan  Done Susan  Ueda Takeshi  Inoue Satoshi  Chang Yu-Ling  Chen Nien Jung  Mak Tak Wah
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.
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.
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