Morley, S. J., Jeffrey, I., Bushell, M. , Pain, V. M. and Clemens, M. J. (2000) Differential requirements for caspase-8 activity in the mechanism of phosphorylation of eIF2α, cleavage of eIF4GI and signaling events associated with the inhibition of protein synthesis in apoptotic Jurkat T cells. FEBS Letters, 477(3), pp. 229-236. (doi: 10.1016/S0014-5793(00)01805-6) (PMID:10908726)
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Abstract
Previously we have reported that induction of apoptosis in Jurkat cells results in an inhibition of overall protein synthesis with the selective and rapid cleavage of eukaryotic initiation factor (eIF) 4GI. For the cleavage of eIF4GI, caspase‐3 activity is both necessary and sufficient in vivo, in a process which does not require signaling through the p38 MAP kinase pathway. We now show that activation of the Fas/CD95 receptor promotes an early, transient increase in the level of eIF2α phosphorylation, which is temporally correlated with the onset of the inhibition of translation. This is associated with a modest increase in the autophosphorylation of the protein kinase activated by double‐stranded RNA. Using a Jurkat cell line that is deficient in caspase‐8 and resistant to anti‐Fas‐induced apoptosis, we show that whilst the cleavage of eIF4GI is caspase‐8‐dependent, the enhancement of eIF2α phosphorylation does not require caspase‐8 activity and occurs prior to the cleavage of eIF4GI. In addition, activation of the Fas/CD95 receptor results in the caspase‐8‐dependent dephosphorylation and degradation of p70S6K, the enhanced binding of 4E‐BP1 to eIF4E, and, at later times, the cleavage of eIF2α. These data suggest that apoptosis impinges upon the activity of several polypeptides which are central to the regulation of protein synthesis and that multiple signaling pathways are involved in vivo.
Item Type: | Articles |
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Additional Information: | This research was supported by project and equipment grants from The Wellcome Trust (040800, 050703, 045619, 056778) and the Cancer Prevention Research Trust (M.J.C.). S.J.M. is a Senior Research Fellow of The Wellcome Trust. |
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Bushell, Professor Martin |
Authors: | Morley, S. J., Jeffrey, I., Bushell, M., Pain, V. M., and Clemens, M. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | FEBS Letters |
Publisher: | Wiley |
ISSN: | 0014-5793 |
ISSN (Online): | 1873-3468 |
Published Online: | 18 July 2000 |
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