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Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses

Oncogene volume 29, pages 763–773 (2010)Cite this article

Abstract

Translationally controlled tumour protein (TCTP) is a highly conserved protein present in all eukaryotic organisms. Various cellular functions and molecular interactions have been ascribed to this protein, many related to its growth-promoting and antiapoptotic properties. TCTP levels are highly regulated in response to various cellular stimuli and stresses. We have shown recently that the double-stranded RNA-dependent protein kinase, PKR, is involved in translational regulation of TCTP. Here we extend these studies by demonstrating that TCTP is downregulated in response to various proapoptotic treatments, in particular agents that induce Ca++ stress, in a PKR-dependent manner. This regulation requires phosphorylation of protein synthesis factor eIF2α. Since TCTP has been characterized as an antiapoptotic and Ca++-binding protein, we asked whether it is involved in protecting cells from Ca++-stress-induced apoptosis. Overexpression of TCTP partially protects cells against thapsigargin-induced apoptosis, as measured using caspase-3 activation assays, a nuclear fragmentation assay, using fluorescence-activated cell sorting analysis, and time-lapse video microscopy. TCTP also protects cells against the proapoptotic effects of tunicamycin and etoposide, but not against those of arsenite. Our results imply that cellular TCTP levels influence sensitivity to apoptosis and that PKR may exert its proapoptotic effects at least in part through downregulation of TCTP via eIF2α phosphorylation.

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Acknowledgements

We thank Drs Charles Weissmann, Randy Kaufman and Donalyn Scheuner for cell lines; Mr Bill Newman for help in performing the initial fluorescence-activated cell sorting analysis experiments; Dr Constantina Constantinou for providing extracts from mouse erythroleukaemia cells and members of Dr Guy Whitley's laboratory for help with the cell-video microscopy facilities. This work was supported by The Wellcome Trust (UAB and MJC), the Cancer Prevention Research Trust (UAB) and the Association for International Cancer Research (MJC).

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  1. U-A Bommer

    Present address: 2Current address: Graduate School of Medicine, University of Wollongong, New South Wales 2522, Australia.,

  2. C Heng

    Present address: 3Current address: Hammersmith Hospital, Imperial College Healthcare NHS Trust, Du Cane Road, London W12 0HS, UK.,

  3. A Perrin

    Present address: 4Current address: INSERM U841-Eq8-Faculté de Médecine, Créteil 94010, France.,

  4. P Dash

    Present address: 5Current address: School of Biological Sciences, University of Reading, Reading RG6 6AJ, UK.,

  5. S Lobov

    Present address: 6Current address: School of Biological Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia.,

  6. M J Clemens

    Present address: 7Current address: Department of Chemistry and Biochemistry, School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK.,

Authors and Affiliations

  1. Division of Basic Medical Sciences, St George's, University of London, London, UK

    U-A Bommer, C Heng, A Perrin, P Dash, S Lobov, A Elia & M J Clemens

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Bommer, UA., Heng, C., Perrin, A. et al. Roles of the translationally controlled tumour protein (TCTP) and the double-stranded RNA-dependent protein kinase, PKR, in cellular stress responses. Oncogene 29, 763–773 (2010). https://doi.org/10.1038/onc.2009.380

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