Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation

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dc.contributor.author Kozel, Caitlin
dc.contributor.author Thompson, Brytteny
dc.contributor.author Hustak, Samantha
dc.contributor.author Moore, Chelsea
dc.contributor.author Nakashima, A.
dc.contributor.author Singh, Chingakham Ranjit
dc.contributor.author Reid, Megan
dc.contributor.author Cox, Christian
dc.contributor.author Papadopoulos, E.
dc.contributor.author Luna, R. E.
dc.contributor.author Anderson, Abbey
dc.contributor.author Tagami, H.
dc.contributor.author Hiraishi, Hiroyuki
dc.contributor.author Slone, Emily A.
dc.contributor.author Yoshino, K.
dc.contributor.author Asano, Masayo
dc.contributor.author Gillaspie, Sarah
dc.contributor.author Nietfeld, Jerome
dc.contributor.author Perchellet, Jean-Pierre
dc.contributor.author Rothenburg, Stefan
dc.contributor.author Masai, H.
dc.contributor.author Wagner, G.
dc.contributor.author Beeser, Alexander
dc.contributor.author Kikkawa, U.
dc.contributor.author Fleming, Sherry D.
dc.contributor.author Asano, Katsura
dc.date.accessioned 2017-11-30T21:40:24Z
dc.date.available 2017-11-30T21:40:24Z
dc.identifier.uri http://hdl.handle.net/2097/38318
dc.description Citation: Kozel, C., Thompson, B., Hustak, S., Moore, C., Nakashima, A., Singh, C. R., . . . Asano, K. (2016). Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation. Nucleic Acids Research, 44(18), 8704-8713. doi:10.1093/nar/gkw559
dc.description.abstract 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.
dc.relation.uri https://doi.org/10.1093/nar/gkw559
dc.rights Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)
dc.rights.uri https://creativecommons.org/licenses/by-nc/4.0/
dc.subject Guanine-Nucleotide Exchange
dc.subject Start Codon Recognition
dc.subject Multifactor
dc.subject Complex
dc.subject Eif5-Mimic Protein
dc.subject Mammalian-Cells
dc.title Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation
dc.type Article
dc.date.published 2016
dc.citation.doi 10.1093/nar/gkw559
dc.citation.epage 8713
dc.citation.issn 0305-1048
dc.citation.issue 18
dc.citation.jtitle Nucleic Acids Research
dc.citation.spage 8704
dc.citation.volume 44
dc.description.embargo 2018
dc.contributor.authoreid kasano
dc.contributor.authoreid sdflemin
dc.contributor.authoreid sr1hsv
dc.contributor.authoreid jcnietfe
dc.contributor.authoreid csingh
dc.contributor.kstate Asano, Katsura
dc.contributor.kstate Fleming, Sherry D.
dc.contributor.kstate Rothenburg, Stefan
dc.contributor.kstate Nietfeld, Jerome
dc.contributor.kstate Singh, Chingakham Ranjit

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Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Except where otherwise noted, the use of this item is bound by the following: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

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