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Inhibition of protein synthesis in apoptosis: differential requirements by the tumor necrosis factor alpha family and a DNA-damaging agent for caspases and the double-stranded RNA-dependent protein kinase.
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posted on 2023-06-07, 22:14 authored by Ian W Jeffrey, Martin Bushell, Vivienne J Tilleray, Simon Morley, Michael J ClemensExposure 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 alpha (TNFalpha) 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) alpha, increased association of eIF4E with the inhibitory eIF4E-binding protein (4E-BP1), and specific cleavages of eIF4B and eIF2alpha. 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 TNFalpha. 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 eIF2alpha nor increased [eIF4E.4E-BP1] complex formation is essential for the inhibition of overall translation by the DNA-damaging agent.
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Publication status
- Published
Journal
Cancer ResearchISSN
0008-5472Issue
8Volume
62Page range
2272-2280Pages
9.0Department affiliated with
- Biochemistry Publications
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- No
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06Usage metrics
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