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 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.
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522 NSW, Australia; Graduate School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong 2522 NSW, Australia. Electronic address: ubommer@uow.edu.au.
Ulrich-Axel
UA
Bommer
Centre for Biological Sciences, University of Southampton, UK.
Valentina
V
Iadevaia
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522 NSW, Australia.
Jiezhong
J
Chen
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522 NSW, Australia.
Bianca
B
Knoch
Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong 2522 NSW, Australia.
Martin
M
Engel
Centre for Biological Sciences, University of Southampton, UK.
Christopher G
CG
Proud
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011132:Polyribosomes / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000077005:Tuberous Sclerosis Complex 2 Protein; D000090324:Tumor Protein, Translationally-Controlled 1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D039561:Eukaryotic Initiation Factor-4E; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; C000715647:TPT1 protein, human; C000624653:TSC2 protein, human; D000077005:Tuberous Sclerosis Complex 2 Protein; D000090324:Tumor Protein, Translationally-Controlled 1; D025521:Tumor Suppressor Proteins; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
Akt; Initiation factor eIF4E; PI 3-kinase pathway; TOP mRNA; Translationally controlled tumour protein TCTP; mTOR complex 1