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Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway

Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway
Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway
Translationally controlled tumour protein TCTP (gene symbol: TPT1) is a highly-conserved, cyto-protective protein implicated in many physiological and disease processes, in particular cancer, where it is associated with poor patient outcomes. To understand the mechanisms underlying the accumulation of high TCTP levels in cancer cells, we studied the signalling pathways that control translation of TCTP mRNA, which contains a 5?-terminal oligopyrimidine tract (5?-TOP). In HT29 colon cancer cells and in HeLa cells, serum increases the expression of TCTP two- and four-fold, respectively, and this is inhibited by rapamycin or mTOR kinase inhibitors. Polysome profiling and mRNA quantification indicate that these effects occur at the level of mRNA translation. Blocking this pathway upstream of mTOR complex 1 (mTORC1) by inhibiting Akt also prevented increases in TCTP levels in both HeLa and HT29 colon cancer cells, whereas knockout of TSC2, a negative regulator of mTORC1, led to derepression of TCTP synthesis under serum starvation. Overexpression of eIF4E enhanced the polysomal association of the TCTP mRNA, although it did not protect its translation from inhibition by rapamycin. Conversely, expression of a constitutively-active mutant of the eIF4E inhibitor 4E-BP1, which is normally inactivated by mTORC1, inhibited of TCTP mRNA translation in HEK293 cells. Our results demonstrate that TCTP mRNA translation is regulated by signalling through the PI3-K/Akt/mTORC1 pathway. This explains why TCTP levels are frequently increased in cancers, since mTORC1 signalling is hyperactive in ~ 80% of tumours.
translationally controlled tumour protein TCTP, PI 3-kinase pathway, Akt, mTOR complex 1, initiation factor eIF4E, TOP mRNA
0898-6568
1-12
Bommer, Ulrich-Axel
7287b374-fe10-4859-a8da-e7637ce585a5
Iadevaia, Valentina
1124252e-5709-4a5e-8a4b-956ced0c9611
Chen, Jiezhong
fa1de702-e04c-4fa5-bcd1-f35cb54c2329
Knoch, Bianca
70d16748-faf2-4a10-ae54-a69ab9f5f149
Engel, Martin
ccfbc8d2-e2d5-47a8-a66f-e6f456099fa7
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3
Bommer, Ulrich-Axel
7287b374-fe10-4859-a8da-e7637ce585a5
Iadevaia, Valentina
1124252e-5709-4a5e-8a4b-956ced0c9611
Chen, Jiezhong
fa1de702-e04c-4fa5-bcd1-f35cb54c2329
Knoch, Bianca
70d16748-faf2-4a10-ae54-a69ab9f5f149
Engel, Martin
ccfbc8d2-e2d5-47a8-a66f-e6f456099fa7
Proud, Christopher G.
59dabfc8-4b44-4be8-a17f-578a58550cb3

Bommer, Ulrich-Axel, Iadevaia, Valentina, Chen, Jiezhong, Knoch, Bianca, Engel, Martin and Proud, Christopher G. (2015) Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway. Cellular Signalling, 1-12. (doi:10.1016/j.cellsig.2015.04.011). (PMID:25936523)

Record type: Article

Abstract

Translationally controlled tumour protein TCTP (gene symbol: TPT1) is a highly-conserved, cyto-protective protein implicated in many physiological and disease processes, in particular cancer, where it is associated with poor patient outcomes. To understand the mechanisms underlying the accumulation of high TCTP levels in cancer cells, we studied the signalling pathways that control translation of TCTP mRNA, which contains a 5?-terminal oligopyrimidine tract (5?-TOP). In HT29 colon cancer cells and in HeLa cells, serum increases the expression of TCTP two- and four-fold, respectively, and this is inhibited by rapamycin or mTOR kinase inhibitors. Polysome profiling and mRNA quantification indicate that these effects occur at the level of mRNA translation. Blocking this pathway upstream of mTOR complex 1 (mTORC1) by inhibiting Akt also prevented increases in TCTP levels in both HeLa and HT29 colon cancer cells, whereas knockout of TSC2, a negative regulator of mTORC1, led to derepression of TCTP synthesis under serum starvation. Overexpression of eIF4E enhanced the polysomal association of the TCTP mRNA, although it did not protect its translation from inhibition by rapamycin. Conversely, expression of a constitutively-active mutant of the eIF4E inhibitor 4E-BP1, which is normally inactivated by mTORC1, inhibited of TCTP mRNA translation in HEK293 cells. Our results demonstrate that TCTP mRNA translation is regulated by signalling through the PI3-K/Akt/mTORC1 pathway. This explains why TCTP levels are frequently increased in cancers, since mTORC1 signalling is hyperactive in ~ 80% of tumours.

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Accepted/In Press date: 25 April 2015
e-pub ahead of print date: 30 April 2015
Keywords: translationally controlled tumour protein TCTP, PI 3-kinase pathway, Akt, mTOR complex 1, initiation factor eIF4E, TOP mRNA
Organisations: Centre for Biological Sciences

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Local EPrints ID: 376910
URI: https://eprints.soton.ac.uk/id/eprint/376910
ISSN: 0898-6568
PURE UUID: 2843668c-b1dd-424d-aaae-32d20bad9eea

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Date deposited: 12 May 2015 15:45
Last modified: 17 Jul 2017 21:05

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