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Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy

Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy
Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy
Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency. Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition. eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied. We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy.
eEF2K, translation, glucose starvation
0898-6568
284-293
Moore, Claire E.J.
261a80c7-495b-419c-b04b-d2cf689ecdb9
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Xie, Jianling
547a1c25-893b-4804-b316-8ac81562acac
Pickford, Jo
474ce03e-f3f0-4898-be14-86483b8036a9
Barron, John
9239ddc3-b230-4e1b-8b74-1c4520228422
Regufe da Mota, Sergio
fe39404b-e413-4834-97c6-0f2204b500a9
Versele, Matthias
aec3c485-3fac-4c00-a8df-e209cafba89d
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Moore, Claire E.J.
261a80c7-495b-419c-b04b-d2cf689ecdb9
Wang, Xuemin
d6bb4eb2-5687-46ed-b770-cceb22fd792e
Xie, Jianling
547a1c25-893b-4804-b316-8ac81562acac
Pickford, Jo
474ce03e-f3f0-4898-be14-86483b8036a9
Barron, John
9239ddc3-b230-4e1b-8b74-1c4520228422
Regufe da Mota, Sergio
fe39404b-e413-4834-97c6-0f2204b500a9
Versele, Matthias
aec3c485-3fac-4c00-a8df-e209cafba89d
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3

Moore, Claire E.J., Wang, Xuemin, Xie, Jianling, Pickford, Jo, Barron, John, Regufe da Mota, Sergio, Versele, Matthias and Proud, Christopher G. (2016) Elongation factor 2 kinase promotes cell survival by inhibiting protein synthesis without inducing autophagy. Cellular Signalling, 28 (4), 284-293. (doi:10.1016/j.cellsig.2016.01.005). (PMID:26795954)

Record type: Article

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) inhibits the elongation stage of protein synthesis by phosphorylating its only known substrate, eEF2. eEF2K is tightly regulated by nutrient-sensitive signalling pathways. For example, it is inhibited by signalling through mammalian target of rapamycin complex 1 (mTORC1). It is therefore activated under conditions of nutrient deficiency. Here we show that inhibiting eEF2K or knocking down its expression renders cancer cells sensitive to death under nutrient-starved conditions, and that this is rescued by compounds that block protein synthesis. This implies that eEF2K protects nutrient-deprived cells by inhibiting protein synthesis. Cells in which signalling through mTORC1 is highly active are very sensitive to nutrient withdrawal. Inhibiting mTORC1 protects them. Our data reveal that eEF2K makes a substantial contribution to the cytoprotective effect of mTORC1 inhibition. eEF2K is also reported to promote another potentially cytoprotective process, autophagy. We have used several approaches to test whether inhibition or loss of eEF2K affects autophagy under a variety of conditions. We find no evidence that eEF2K is involved in the activation of autophagy in the cell types we have studied. We conclude that eEF2K protects cancer cells against nutrient starvation by inhibiting protein synthesis rather than by activating autophagy.

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Accepted/In Press date: 15 January 2016
e-pub ahead of print date: 18 January 2016
Published date: April 2016
Keywords: eEF2K, translation, glucose starvation
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 386416
URI: http://eprints.soton.ac.uk/id/eprint/386416
ISSN: 0898-6568
PURE UUID: 048b9810-fda0-4909-97c4-b5dc5b11cf19
ORCID for Sergio Regufe da Mota: ORCID iD orcid.org/0000-0002-8127-5246

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Date deposited: 01 Feb 2016 13:47
Last modified: 16 Dec 2019 20:08

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Contributors

Author: Claire E.J. Moore
Author: Xuemin Wang
Author: Jianling Xie
Author: Jo Pickford
Author: John Barron
Author: Sergio Regufe da Mota ORCID iD
Author: Matthias Versele
Author: Christopher G. Proud

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