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
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DOI：
10.1016/j.cellsig.2015.04.011
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发表时间：
2015-08-01
影响因子：
4.8
通讯作者：
Proud, Christopher G.
中科院分区：
文献类型：
--
作者：
Bommer, Ulrich-Axel;Iadevaia, Valentina;Proud, Christopher G.
翻译控制的肿瘤蛋白TCTP(基因代码：TPT1)是一种高度保守的细胞保护蛋白，参与许多生理和疾病过程，特别是癌症，在癌症中，它与不良的患者预后有关。为了了解癌细胞中高水平TCTP积聚的机制，我们研究了控制TOP mRNA翻译的信号通路，TOP mRNA包含一个5‘末端的寡嘧啶(5’-TOP)链。在HT29结肠癌细胞和HeLa细胞中，血清分别将TCTP的表达增加两倍和四倍，这可被雷帕霉素或mTOR激酶抑制剂抑制。多聚体图谱和信使核糖核酸定量分析表明，这些影响发生在信使核糖核酸翻译水平。通过抑制Akt来阻断mTOR复合体1(MTORC1)上游的这一途径，也可以防止HeLa和HT29结肠癌细胞中TCTP水平的增加，而敲除mTORC1的负调控因子TSC2，导致血清饥饿下TCTP合成的抑制。EIF4E的过表达增强了TCTP mRNA的多体结合，尽管它不能保护其翻译免受雷帕霉素的抑制。相反，eIF4E抑制剂4E-BP1的结构性活性突变体的表达(通常被mTORC1灭活)抑制了HEK293细胞中TCTP的mRNA翻译。我们的结果表明，TCTP mRNA的翻译受PI3-K/Akt/mTORC1途径信号的调节。这解释了为什么TCTP水平在癌症中经常增加，因为mTORC1信号在类似80%的肿瘤中是过度活跃的。(C)由Elsevier Inc.出版的皇冠版权所有2015年。保留所有权利。
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 TOP 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 similar to 80% of tumours. (C) Crown Copyright 2015 Published by Elsevier Inc. All rights reserved.