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Inhibition of Protein Synthesis in Apoptosis

Differential Requirements by the Tumor Necrosis Factor Family and a DNA-damaging Agent for Caspases and the Double-stranded RNA-dependent Protein Kinase¹

Department of Biochemistry and Immunology, Cellular and Molecular Sciences Group, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE [I. W. J., M. B., V. J. T., M. J. C.], and Biochemistry Group, School of Biological Sciences, University of Sussex, Brighton BN1 9QG, United Kingdom [S. M.], United Kingdom

Exposure of mammalian cells to agents that induce apoptosis results in a rapid and substantial inhibition of protein synthesis. In MCF-7 breast cancer cells, tumor necrosis factor (TNF) and TNF-related apoptosis-inducing ligand inhibit overall translation by a mechanism that requires caspase (but not necessarily caspase-3) activity. This inhibition is associated with the increased phosphorylation of eukaryotic initiation factor (eIF2) , increased association of eIF4E with the inhibitory eIF4E-binding protein (4E-BP1), and specific cleavages of eIF4B and eIF2. All of these changes require caspase activity. The cleavage of eIF4GI, which specifically needs caspase-3 activity, is dispensable for the inhibition of translation in MCF-7 cells. Similar experiments with embryonic fibroblasts from control mice and animals defective for expression of the double-stranded RNA-regulated protein kinase (PKR) reveal requirements for both caspase activity and PKR for inhibition of protein synthesis in response to TNF. In contrast, treatment of cells with the DNA-damaging agent etoposide inhibits protein synthesis equally well in the presence of a pan-specific caspase inhibitor and in the presence or absence of PKR. Surprisingly, the ability of etoposide to cause increased association of eIF4E with 4E-BP1 does require PKR activity. However, our data suggest that neither increased phosphorylation of eIF2 nor increased [eIF4E.4E-BP1] complex formation is essential for the inhibition of overall translation by the DNA-damaging agent.

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