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Effects of physiological and synthetic IAP antagonism on c-IAP-dependent signaling

Oncogene volume 34, pages 5472–5481 (2015)Cite this article

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Abstract

Cellular inhibitor of apoptosis proteins 1 and 2 (c-IAP1/2) have central roles in signal transduction mediated by numerous receptors that participate in inflammatory and immune responses. In certain pathways, such as activation of NF-κB, their degradation is a major regulatory event and is physiologically induced by activation of receptors. In addition, a number of synthetic compounds have been developed that also target the c-IAPs and induce their degradation. However, the extent of a synthetic IAP antagonist’s ability to mirror the transcriptional program by a physiological signal remains unclear. Here we take a systems approach to compare the transcriptional programs triggered by activation of CD30, a well-characterized receptor previously shown to induce the degradation of the c-IAPs, to SM-164, a synthetic IAP antagonist that specifically triggers c-IAP degradation. Employing a technique that allows the specific analysis of newly transcribed RNA, we have generated comparative transcriptome profiles for CD30 activation and SM-164 treatment. Analysis of these profiles revealed that the genes regulated by each stimulus were not completely shared, indicating novel functions of IAP antagonists and consequences of c-IAP1/2 degradation. The data identified a role for c-IAP1/2 in the regulation of the ribosome and protein synthesis, which was subsequently confirmed by biological assays. These findings expand our knowledge of the roles of c-IAP1/2 in signaling and provide insight into the mechanism of synthetic IAP antagonists, furthering our understanding of their therapeutic potential.

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Acknowledgements

We thank Drs Shaomeng Wang (University of Michigan, Ann Arbor, MI, USA) for the kind gift of SM-164, Judith Sebolt-Leopold (University of Michigan) for the gift of Trametinib, Niall Kenneth (Newcastle University, Newcastle upon Tyne, UK) for his insightful suggestions, Elizabeth Lawlor (University of Michigan, Ann Arbor, MI, USA) for her critical reading of the manuscript, Thomas Wilson (University of Michigan, Ann Arbor, MI, USA) for use of his data analysis software, the members of the Duckett laboratory for their helpful advice and the personnel at the University of Michigan Molecular and Behavioral Neuroscience Institute computing cluster and the University of Michigan Sequencing Core for their technical assistance. This work was supported in part by NIH R01CA142809 (to CSD), NIH 1R01HG006786 (to ML) and NIH T32AI007413 (to AJK).

Author Contributions

AJK and CSD designed the research. AJK and MTP performed the research. AJK, AV, ML and CSD analyzed the data. AJK and CSD wrote the manuscript.

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Authors and Affiliations

  1. Graduate Program in Immunology, The University of Michigan, Ann Arbor, MI, USA

    A J Kocab

  2. Department of Pathology, The University of Michigan, Ann Arbor, MI, USA

    A J Kocab & C S Duckett

  3. Department of Radiation Oncology, The University of Michigan, Ann Arbor, MI, USA

    A Veloso, M T Paulsen & M Ljungman

  4. Department of Computational Medicine and Bioinformatics, Bioinformatics Program, The University of Michigan, Ann Arbor, MI, USA

    A Veloso

  5. Department of Environmental Health Sciences, School of Public Health, The University of Michigan, Ann Arbor, MI, USA

    M Ljungman

  6. Department of Internal Medicine, The University of Michigan, Ann Arbor, MI, USA

    C S Duckett

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  1. A J Kocab
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  2. A Veloso
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Correspondence to C S Duckett.

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Kocab, A., Veloso, A., Paulsen, M. et al. Effects of physiological and synthetic IAP antagonism on c-IAP-dependent signaling. Oncogene 34, 5472–5481 (2015). https://doi.org/10.1038/onc.2015.3

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