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TRADD contributes to tumour suppression by regulating ULF-dependent p19Arf ubiquitylation

Nature Cell Biology volume 14, pages 625–633 (2012)Cite this article

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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.

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Figure 1: Tradd deficiency promotes tumorigenesis in a TNF-independent and cell intrinsic manner.
Figure 2: Tradd deficiency attenuates HRasV12-induced growth arrest and senescence in MEFs.
Figure 3: Tradd deficiency reduces p19Arf protein accumulation induced by HRasV12 activation.
Figure 4: Nuclear TRADD impairs p19Arf ubiquitylation through its carboxyl-terminal sequences.
Figure 5: Nuclear TRADD regulates p19Arf ubiquitylation through disruption of the interaction between ULF and p19Arf.
Figure 6: Stabilization of p19Arf mediated by nuclear TRADD is required for HRasV12-induced senescence.

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Acknowledgements

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.

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Authors and Affiliations

  1. The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network, 620 University Avenue, Suite 706, Toronto, Ontario M5G 2M9, Canada

    Iok In Christine Chio, Masato Sasaki, Juan Moreno, Susan Done, Satoshi Inoue & Tak Wah Mak

  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada

    Iok In Christine Chio & Tak Wah Mak

  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, Ontario M5G 2M9, Canada

    Danny Ghazarian & Susan Done

  4. Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan

    Takeshi Ueda

  5. Institute of Microbiology and Immunology, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan, China

    Yu-Ling Chang & Nien Jung Chen

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Contributions

I.I.C.C. and T.W.M. designed the study and wrote the manuscript; I.I.C.C. conducted most experiments and analysed the data; M.S., T.U., S.I., N.J.C. and T.W.M. assisted in data analyses; D.G. performed histological analysis of skin tumour samples; J.M. and S.D. performed histological analysis of spontaneous tumour samples and the breast cancer tissue microarray. Y-L.C. cloned the cytoplasmic-specific TRADD construct. All authors discussed the results and agree with the conclusions of the manuscript.

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Correspondence to Tak Wah Mak.

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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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