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

Correspondence: Dr U-A Bommer, Graduate School of Medicine, University of Wollongong, Northfields Avenue, Building 28, Wollongong, New South Wales 2522, Australia. E-mail: ubommer@uow.edu.au

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

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

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

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

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

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

Received 6 April 2009; Revised 21 August 2009; Accepted 28 September 2009; Published online 9 November 2009.

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 eIF2. 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 eIF2 phosphorylation.