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Identification of XAF1 as an antagonist of XIAP anti-Caspase activity

Nature Cell Biology volume 3, pages 128–133 (2001)Cite this article

Abstract

The inhibitors of apoptosis (IAPs) suppress apoptosis through the inhibition of the caspase cascade and thus are key proteins in the control of cell death. Here we have isolated the protein XIAP-associated factor 1 (XAF1) on the basis of its ability to bind XIAP, a member of the IAP family. XIAP suppresses caspase activation and cell death in vitro, and XAF1 antagonizes these XIAP activities. Expression of XAF1 triggers a redistribution of XIAP from the cytosol to the nucleus. XAF1 is ubiquitously expressed in normal tissues, but is present at low or undetectable levels in many different cancer cell lines. Loss of control over apoptotic signalling is now recognized as a critical event in the development of cancer. Our results indicate that XAF1 may be important in mediating the apoptosis resistance of cancer cells.

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Figure 1: Interaction analysis of XIAP and XAF1.
Figure 2: XAF1 antagonizes XIAP–caspase interaction.
Figure 3: Xaf1 is underexpressed in many cancer cell lines.
Figure 4: Abolishing XAF1 protein increases apoptotic resistance in cell lines that retain endogenous expression.

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Acknowledgements

We wish to thank the University of California San Francisco / Neurosurgery Tissue Bank for the SF-295 and SF-539 cell lines. P.L. is a Centennial Fellow of the Medical Research Council of Canada. This work was supported by grants to R.G.K. from the Networks of Centers of Excellence Canadian Genetic Diseases Network (CGDN), the Medical Research Council of Canada (MRC), and the Howard Hughes Medical Institute (HHMI). R.G.K. is a recipient of an MRC senior scientist award, a HHMI International Research Scholar, and a Fellow of the Royal Society of Canada.

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  1. Peter Liston and Wai Gin Fong: These authors contributed equally to this work

Authors and Affiliations

  1. Cancer Research Group, Ottawa Regional Cancer Center, 501 Smyth Road, Ottawa, K1H 8L6, Canada

    Peter Liston & Michael W. McBurney

  2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 401 Smyth Road, Ottawa, K1H 8L1, Canada

    Wai Gin Fong, Damiano Conte & Robert G. Korneluk

  3. Aegera Oncology Inc., 451 Smyth Road, Ottawa, K1H 8MS, Canada

    N. Lynn Kelly, Constance G. Craig & Robert G. Korneluk

  4. Medical and Biological Laboratories Co., Naka-ku, 460, Nagoya, Japan

    Shingo Toji & Toshiaki Miyazaki

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  1. Peter Liston
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Correspondence to Robert G. Korneluk.

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Liston, P., Fong, W., Kelly, N. et al. Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nat Cell Biol 3, 128–133 (2001). https://doi.org/10.1038/35055027

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