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

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, 27 8: 1557-1568. doi:10.1016/j.cellsig.2015.04.011


Author Bommer, Ulrich-Axel
Iadevaia, Valentina
Chen, Jiezhong
Knoch, Bianca
Engel, Martin
Proud, Christopher G.
Title Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway
Journal name Cellular Signalling   Check publisher's open access policy
ISSN 1873-3913
0898-6568
Publication date 2015-08
Sub-type Article (original research)
DOI 10.1016/j.cellsig.2015.04.011
Open Access Status Not yet assessed
Volume 27
Issue 8
Start page 1557
End page 1568
Total pages 12
Place of publication Philadelphia, PA, United States
Publisher Elsevier,
Collection year 2016
Language eng
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 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.
Keyword Akt
Initiation factor eIF4E
MTOR complex 1
PI 3-kinase pathway
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Biomedical Sciences Publications
 
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