https://scholars.lib.ntu.edu.tw/handle/123456789/623790
標題: | Differential regulation of CHOP translation by phosphorylated eIF4E under stress conditions | 作者: | Chen, Yi-Jiun Tan, Bertrand Chin-Ming Cheng, Ya-Yun JIN-SHING CHEN Lee, Sheng-Chung |
關鍵字: | INITIATION-FACTOR 4G; UNFOLDED PROTEIN RESPONSE; MESSENGER-RNA TRANSLATION; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; FACTOR 4E; KINASES; ACTIVATION; INHIBITION; UPSTREAM | 公開日期: | 一月-2010 | 出版社: | OXFORD UNIV PRESS | 卷: | 38 | 期: | 3 | 起(迄)頁: | 764 | 來源出版物: | Nucleic acids research | 摘要: | 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, uORF(chop)-driven reporter platform. Here we show that anisomycin-induced CHOP expression depends on phosphorylated eIF4E/S209 and eIF2alpha/S51. Contrary to phospho-eIF2alpha/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-eIF2alpha/S51 and reporter translation, thus pinpointing a crucial determinant in stress-responsive translation. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/623790 | ISSN: | 0305-1048 | DOI: | 10.1093/nar/gkp1034 |
顯示於: | 醫學系 |
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