Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.
Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.
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EIF5或其蛋白质模拟5MP的过表达EIF2函数，并通过延迟重新定位诱导ATF4翻译。
DOI：
10.1093/nar/gkw559
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发表时间：
2016-10-14
影响因子：
14.9
通讯作者：
Asano K
中科院分区：
文献类型：
--
作者：
Kozel C;Thompson B;Hustak S;Moore C;Nakashima A;Singh CR;Reid M;Cox C;Papadopoulos E;Luna RE;Anderson A;Tagami H;Hiraishi H;Slone EA;Yoshino KI;Asano M;Gillaspie S;Nietfeld J;Perchellet JP;Rothenburg S;Masai H;Wagner G;Beeser A;Kikkawa U;Fleming SD;Asano K
ATF4是一种癌前转录因子，其翻译被eIF2磷酸化激活，再启动延迟，涉及两个uORF在mRNA前导。然而，在酵母中，eIF2的磷酸化作用可以通过eIF5的过表达来模拟，eIF5将eIF5转化为翻译抑制物，从而促进酵母ATF4类似物Gcn4的翻译。此外，被称为eIF5模拟蛋白(5MP)的调节蛋白可以与eIF2结合并抑制一般翻译。在这里，我们发现5MP1在人类细胞中过表达会导致5MP1：eIF2复合体的强烈形成，与eIF5过表达产生的eIF5：eIF2复合体几乎相当。人类第二类基因eIF5、5MP1和5MP2的过表达促进了ATF4在某些类型的人类细胞中的表达，包括纤维肉瘤。5MP过表达还可诱导果蝇ATF4的表达。纤维肉瘤中5MP1基因的敲除可减少ATF4的表达及其在裸鼠体内的成瘤作用。由于5MP2在涎腺粘液表皮样癌中过度表达，我们认为eIF5和5MP的过表达通过延迟重新启动诱导ATF4和可能在其mRNA前导带有uORF的其他基因的翻译，从而提高正常细胞和癌细胞在应激条件下的生存。
ATF4 is a pro-oncogenic transcription factor whose translation is activated by eIF2 phosphorylation through delayed re-initiation involving two uORFs in the mRNA leader. However, in yeast, the effect of eIF2 phosphorylation can be mimicked by eIF5 overexpression, which turns eIF5 into translational inhibitor, thereby promoting translation of GCN4, the yeast ATF4 equivalent. Furthermore, regulatory protein termed eIF5-mimic protein (5MP) can bind eIF2 and inhibit general translation. Here, we show that 5MP1 overexpression in human cells leads to strong formation of 5MP1:eIF2 complex, nearly comparable to that of eIF5:eIF2 complex produced by eIF5 overexpression. Overexpression of eIF5, 5MP1 and 5MP2, the second human paralog, promotes ATF4 expression in certain types of human cells including fibrosarcoma. 5MP overexpression also induces ATF4 expression in Drosophila. The knockdown of 5MP1 in fibrosarcoma attenuates ATF4 expression and its tumor formation on nude mice. Since 5MP2 is overproduced in salivary mucoepidermoid carcinoma, we propose that overexpression of eIF5 and 5MP induces translation of ATF4 and potentially other genes with uORFs in their mRNA leaders through delayed re-initiation, thereby enhancing the survival of normal and cancer cells under stress conditions.
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影响因子：
7.7
作者：
Andreev DE;O'Connor PB;Fahey C;Kenny EM;Terenin IM;Dmitriev SE;Cormican P;Morris DW;Shatsky IN;Baranov PV
通讯作者：
Baranov PV
DOI：
10.4161/trla.28387
发表时间：
2014
期刊：
Translation (Austin, Tex.)
影响因子：
--
作者：
Asano K
通讯作者：
Asano K
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
14.9
作者：
Sokabe M;Fraser CS;Hershey JW
通讯作者：
Hershey JW
影响因子：
14.9
作者：
Singh CR;Watanabe R;Zhou D;Jennings MD;Fukao A;Lee B;Ikeda Y;Chiorini JA;Campbell SG;Ashe MP;Fujiwara T;Wek RC;Pavitt GD;Asano K
通讯作者：
Asano K