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A new internal-ribosome-entry-site motif potentiates XIAP- mediated cytoprotection

Nature Cell Biology volume 1, pages 190–192 (1999)Cite this article

Programmed cell death (apoptosis) plays a critical part in regulating cell turnover during embryogenesis, metamorphosis, tissue homeostasis and viral infection1. Dysregulation of apoptosis occurs in such pathologies as cancer, autoimmunity, immunodeficiency and neurodegeneration. Proteins of the inhibitor-of-apoptosis (IAP) family are intrinsic cellular suppressors of apoptosis and are represented by highly conserved members found from insect viruses to mammals2,3,4. The most potent mammalian IAP is the X-linked IAP, or XIAP5, whose mechanism of action involves direct inhibition of caspases 3 and 7, key proteases of the apoptotic cascade6. Cellular control of XIAP expression should be fundamental to a cell’s ability to modulate its responses to apoptotic stimuli. However, XIAP messenger RNA is expressed in most tissues and cells at fairly constant levels5, indicating that translational control of XIAP levels may be an important regulatory mechanism. Here we characterize the primary genomic structure and function of XIAP, and show that XIAP expression is controlled at the translational level, specifically through an internal ribosome-entry site (IRES).

To determine which part of the 5′ UTR is responsible for translation initiation, we generated constructs containing deletions of the human XIAP 5′ UTR (Fig. 1b). The region that retained full IRES activity was the nucleotide segment –162 to –1 upstream of the initiation codon; this segment was as effective as the larger 5′ UTR. The smallest construct contained only 83 nucleotides of the 5′ UTR, but its activity was 25% that of the full-length UTR, being 30-fold higher than that of the bicistronic reporter containing no IRES. In monocistronic plasmids, the 5′ UTR in the sense orientation did not reduce translation of the reporter gene. However, when the IRES was in the antisense orientation or was mutated (see below), expression was substantially reduced, indicating that XIAP translation may be fully dependent on the IRES (Fig. 1b).

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Figure 1: The 5′ UTR of mouse and human XIAP mRNA contains functional IRES elements.
Figure 2: XIAP-IRES-directed translation is resistant to cellular stress.

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Acknowledgements

We thank G. Belsham and P. Liston for plasmids pCMV-2A and pCI-lacZ; J.-Y. Xuan and C. Neville for sequencing; and R. Farahani and M. Legace for the mouse and human XIAP genomic clones. We acknowledge support from the Medical Research Council (MRC) of Canada, the Canadian Networks of Centers of Excellence and the Howard Hughes Medical Institute (HHMI). M.H. is a recipient of an MRC Postdoctoral Fellowship. R.G.K. is a recipient of an MRC Senior Scientist Award, a Fellow of the Royal Society of Canada, and an HHMI International Research Scholar.

Correspondence and requests for materials should be addressed to R.G.K.

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Authors and Affiliations

  1. Solange Gauthier-Karsh Molecular Genetics Laboratory, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, K1H 8L1, Ontario, Canada

    Martin Holcik & Robert G. Korneluk

  2. Apoptogen Inc., Ottawa, K1H 8M5, Ontario, Canada

    Charles Lefebvre & Robert G. Korneluk

  3. Department of Oncology, McGill University, Montreal, PQ H3G 1A4, Canada

    Chiaoli Yeh & Terry Chow

  4. Department of Microbiology and Immunology, University of Ottawa, Ottawa, K1H 8M5, Ontario, Canada

    Robert G. Korneluk

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  1. Martin Holcik
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  5. Robert G. Korneluk
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Correspondence to Robert G. Korneluk.

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Holcik, M., Lefebvre, C., Yeh, C. et al. A new internal-ribosome-entry-site motif potentiates XIAP- mediated cytoprotection. Nat Cell Biol 1, 190–192 (1999). https://doi.org/10.1038/11109

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