Overexpression of eIF5 or its protein mimic 5MP perturbs eIF2 function and induces ATF4 translation through delayed re-initiation.
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.
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
Caitlin
C
Kozel
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Brytteny
B
Thompson
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Samantha
S
Hustak
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Chelsea
C
Moore
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
Akio
A
Nakashima
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Chingakham Ranjit
CR
Singh
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Megan
M
Reid
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Christian
C
Cox
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Evangelos
E
Papadopoulos
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Rafael E
RE
Luna
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Abbey
A
Anderson
Graduate School of Natural Sciences, Nagoya City University, Nagoya 467-8501, Japan.
Hideaki
H
Tagami
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Hiroyuki
H
Hiraishi
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Emily Archer
EA
Slone
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
Ken-Ichi
KI
Yoshino
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Masayo
M
Asano
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Sarah
S
Gillaspie
College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
Jerome
J
Nietfeld
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Jean-Pierre
JP
Perchellet
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Stefan
S
Rothenburg
Genome Dynamics Project, Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Hisao
H
Masai
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Gerhard
G
Wagner
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Alexander
A
Beeser
Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
Ushio
U
Kikkawa
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA.
Sherry D
SD
Fleming
Molecular Cellular Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, KS 66506, USA kasano@ksu.edu.
Katsura
K
Asano
D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D063646:Carcinogenesis / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D039621:Eukaryotic Initiation Factor-3; D040061:Eukaryotic Initiation Factor-5 / Q000378:metabolism*; D005354:Fibrosarcoma / Q000473:pathology; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008819:Mice, Nude; D010442:Peptide Chain Initiation, Translational
C568809:BZW2 protein, human; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D039621:Eukaryotic Initiation Factor-3; D040061:Eukaryotic Initiation Factor-5; D051701:Activating Transcription Factor 4