Pancreatic tumours escape from translational control through 4E-BP1 loss
Pancreatic tumours escape from translational control through 4E-BP1 loss
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DOI：
10.1038/onc.2013.100
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发表时间：
2014-03-13
期刊：
影响因子：
8
通讯作者：
Pyronnet, S.
中科院分区：
文献类型：
--
作者：
Martineau, Y.;Azar, R.;Pyronnet, S.
MRNA帽结合蛋白eIF4E(真核细胞翻译起始因子4E)允许核糖体募集到被覆盖的mRNAs，其磷酸化形式在细胞转化中起着重要作用。然而，eIF4E的致癌功能被抑制性eIF4E结合蛋白1和2的低磷酸化形式所拮抗。eIF4E结合蛋白1和2(4E-BP1和2)是蛋白激酶mTOR的两个主要靶点，对于mTOR抑制剂的抗增殖作用是必不可少的。在此，我们报告了胰腺特异性和大量表达4E-BP1(4E-BP2几乎检测不到)。然而，4E-BP1在超过一半的人胰腺导管腺癌(PDAC)中表达消失。4E-BP1关闭是在PDAC的小鼠遗传模型中概括的，该模型基于胰腺特异的Kras突变，Kras是人类胰腺肿瘤中更频繁突变的癌基因。4E-BP1下调促进eIF4E磷酸化，促进胰腺癌细胞体外增殖和体内肿瘤的发展。此外，4E-BP1的缺失和4E-BP2的缺失使eIF4E的磷酸化、蛋白质合成和细胞增殖抵抗mTOR的抑制。然而，最近开发的一种化合物可以更好地限制增殖，该化合物模拟4E-BP1和2的功能，而不依赖于mTOR抑制。
The mRNA cap-binding protein eIF4E (eukaryotic translation initiation factor 4E) permits ribosome recruitment to capped mRNAs, and its phosphorylated form has an important role in cell transformation. The oncogenic function of eIF4E is, however, antagonised by the hypophosphorylated forms of the inhibitory eIF4E-binding proteins 1 and 2. eIF4E-binding protein 1 and 2 (4E-BP1 and 2) are two major targets of the protein kinase mTOR, and are essential for the antiproliferative effects of mTOR inhibitors. Herein, we report that pancreas expresses specifically and massively 4E-BP1 (4E-BP2 is nearly undetectable). However, 4E-BP1 expression is extinguished in more than half of the human pancreatic ductal adenocarcinomas (PDAC). 4E-BP1 shutoff is recapitulated in a mouse genetic model of PDAC, which is based on a pancreas-specific mutation of Kras, the more frequently mutated oncogene in human pancreatic tumours. 4E-BP1 downregulation enhances eIF4E phosphorylation and facilitates pancreatic cancer cell proliferation in vitro and tumour development in vivo. Furthermore, 4E-BP1 loss combined with the absence of 4E-BP2 renders eIF4E phosphorylation, protein synthesis and cell proliferation resistant to mTOR inhibition. However, proliferation can be better limited by a recently developed compound that mimics the function of 4E-BP1 and 2 independently of mTOR inhibition.