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IG20 (MADD splice variant-5), a proapoptotic protein, interacts with DR4/DR5 and enhances TRAIL-induced apoptosis by increasing recruitment of FADD and caspase-8 to the DISC

Oncogene volume 23, pages 6083–6094 (2004)Cite this article

Abstract

Recently, we identified Insulinoma–Glucagonoma clone 20 (IG20) that can render cells more susceptible to tumor necrosis factor-alpha (TNF-α)-induced apoptosis. In addition, it can slow cell proliferation, and enhance drug- and radiation-induced cell death. TNF-related apoptosis-inducing ligand (TRAIL) can selectively induce apoptosis in some cancer cells and render others susceptible to cotreatment with drugs and irradiation, with little or no effect on most normal cells. In this study, we investigated the potential of IG20 to enhance TRAIL-induced apoptosis and found that it can render cells more susceptible to TRAIL treatment through enhanced activation of caspases. Further, we showed that this effect can be suppressed by caspase inhibitors, p35 and CrmA, and a dominant-negative Fas-associated death domain-containing protein (DN-FADD). Results from colocalization and immunoprecipitation studies showed that IG20 can interact with TRAIL death receptors (DR), DR4 and DR5 and increase recruitment of FADD and caspase-8 into the TRAIL death-inducing signaling complex (DISC). These results indicate that IG20 is a novel protein that can enhance TRAIL-induced apoptosis by facilitating DISC formation.

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Acknowledgements

We thank Dr Vishva M Dixit for the DR4 Flag construct, Dr WS El-Deiry for the DR5-Myc construct, Dr Marcus Peter for the C-15 reagent, Dr Tom Hope and Dr David McDonald, for their help with the deconvolution microscopy, Dr Shashi Kaithamana for the IG20-GFP construct, Dr Prasad Kanteti and Dr David Ucker for critical reading of the manuscript.

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Author notes

  1. Madhu Ramaswamy and Elena V Efimova: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Microbiology and Immunology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, 60612, IL, USA

    Madhu Ramaswamy, Osvaldo Martinez, Nirupama U Mulherkar & Bellur S Prabhakar

  2. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, 60637, 5758 South Maryland Avenue, IL, USA

    Elena V Efimova

  3. Center for Molecular Biology of Oral Diseases, University of Illinois at Chicago, 820 South Paulina Avenue, Chicago, 60612, IL, USA

    Surya P Singh

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  1. Madhu Ramaswamy
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Correspondence to Bellur S Prabhakar.

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Ramaswamy, M., Efimova, E., Martinez, O. et al. IG20 (MADD splice variant-5), a proapoptotic protein, interacts with DR4/DR5 and enhances TRAIL-induced apoptosis by increasing recruitment of FADD and caspase-8 to the DISC. Oncogene 23, 6083–6094 (2004). https://doi.org/10.1038/sj.onc.1207804

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