Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions.
Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions.
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DOI：
10.1093/nar/gkp1034
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发表时间：
2010-01
影响因子：
14.9
通讯作者：
Lee SC
中科院分区：
文献类型：
--
作者：
Chen YJ;Tan BC;Cheng YY;Chen JS;Lee SC
细胞通过诱导对存活或凋亡重要的mRNA子集的翻译来响应环境应激。应激诱导的ATF 4的下游转录靶CHOP在应激下也以uORF依赖的方式受到调控。低浓度的茴香霉素在转录和翻译水平上诱导CHOP表达。为了专门研究CHOP表达的翻译方面，并进一步阐明应激诱导的翻译起始的调控机制，我们开发了CMV启动子调控的uORFchop驱动的报告平台。在这里，我们发现茴香霉素诱导的CHOP表达依赖于磷酸化的eIF 4 E/S209和eIF 2 α/S51。与磷酸化eIF 2 α/S51相反，磷酸化eIF 4 E/S209不参与毒胡萝卜素诱导的CHOP表达。使用各种激酶抑制剂和突变体的研究发现，p38 MAPK-Mnk和mTOR信号通路都有助于应激反应报告基因和CHOP表达。我们还表明，茴香霉素诱导的翻译是紧密调控的合作伙伴的结合偏好eIF 4 E。此外，突变uORF序列消除了茴香霉素诱导的chop mRNA与磷酸化eIF 4 E和多核糖体的关联，从而证明了这种顺式调节元件在赋予转录物应激响应性翻译诱导因子中的重要性。值得注意的是，尽管胰岛素处理激活了ERK-Mnk和mTOR通路，并因此激活了eIF 4 E/S209磷酸化，但它未能诱导磷酸化eIF 2 α/S51和报告基因翻译，因此确定了应激反应翻译中的关键决定因素。
Cells respond to environmental stress by inducing translation of a subset of mRNAs important for survival or apoptosis. CHOP, a downstream transcriptional target of stress-induced ATF4, is also regulated translationally in a uORF-dependent manner under stress. Low concentration of anisomycin induces CHOP expression at both transcriptional and translational levels. To study specifically the translational aspect of CHOP expression, and further clarify the regulatory mechanisms underlying stress-induced translation initiation, we developed a CMV promoter-regulated, uORFchop-driven reporter platform. Here we show that anisomycin-induced CHOP expression depends on phosphorylated eIF4E/S209 and eIF2α/S51. Contrary to phospho-eIF2α/S51, phospho-eIF4E/S209 is not involved in thapsigargin-induced CHOP expression. Studies using various kinase inhibitors and mutants uncovered that both the p38MAPK-Mnk and mTOR signaling pathways contribute to stress-responsive reporter and CHOP expression. We also demonstrated that anisomycin-induced translation is tightly regulated by partner binding preference of eIF4E. Furthermore, mutating the uORF sequence abolished the anisomycin-induced association of chop mRNA with phospho-eIF4E and polysomes, thus demonstrating the significance of this cis-regulatory element in conferring on the transcript a stress-responsive translational inducibility. Strikingly, although insulin treatment activated ERK-Mnk and mTOR pathways, and consequently eIF4E/S209 phosphorylation, it failed to induce phospho-eIF2α/S51 and reporter translation, thus pinpointing a crucial determinant in stress-responsive translation.
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影响因子：
5.5
作者：
Cherla, Rama P.;Lee, Sang-Yun;Tesh, Vernon L.
通讯作者：
Tesh, Vernon L.
DOI：
10.1083/jcb.153.5.1011
发表时间：
2001-05-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Novoa I;Zeng H;Harding HP;Ron D
通讯作者：
Ron D
影响因子：
11.4
作者：
Gomez, E;Mohammad, SS;Pavitt, GD
通讯作者：
Pavitt, GD
影响因子：
4.8
作者：
LeFebvre, Aaron K.;Korneeva, Nadejda L.;Rhoads, Robert E.
通讯作者：
Rhoads, Robert E.
影响因子：
5.3
作者：
Imataka, H;Sonenberg, N
通讯作者：
Sonenberg, N