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The function of GADD34 is a recovery from a shutoff of protein synthesis induced by ER stress—elucidation by GADD34‐deficient mice
Author(s) -
Kojima Eiji,
Takeuchi Akihide,
Haneda Masataka,
Yagi Fumiko,
Hasegawa Tadao,
Yamaki Ken-Ichi,
Takeda Kiyoshi,
Akira Shizuo,
Shimokata Kaoru,
Isobe Ken-Ichi
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-1184fje
Subject(s) - unfolded protein response , tunicamycin , chemistry , chop , endoplasmic reticulum , microbiology and biotechnology , knockout mouse , phosphorylation , protein biosynthesis , thapsigargin , transfection , biology , biochemistry , gene
ABSTRACT GADD34 is a protein that is induced by stresses such as DNA damage. The function of mammalian GADD34 has been proposed by in vitro transfection, but its function in vivo has not yet been elucidated. Here we generated and analyzed GADD34 knockout mice. Despite their embryonic stage‐ and tissue‐specific expressions, GADD34 knockout mice showed no abnormalities at fetal development and in early adult life. However, in GADD34 −/− mouse embryonic fibroblasts (MEFs), recovery from a shutoff of protein synthesis was delayed when MEFs were exposed to endoplasmic reticulum (ER) stress. The phosphorylation of eukaryotic translation initiation factor 2 α (eIF2α) at Ser51 induced by thapsigargin or DTT was prolonged in GADD34 −/− MEF, although following treatment with tunicamycin, the eIF2α phosphorylation level did not change in either GADD34 +/+ or GADD34 −/− cells. ER stress stimuli induced expressions of Bip (binding Ig protein) and CHOP (C/EBP homologous protein) in MEF of wild‐type mice. These expressions were strongly reduced in GADD34 −/− MEF, which suggests that GADD34 up‐regulates Bip and CHOP. These results indicate that GADD34 works as a sensor of ER stress stimuli and recovers cells from shutoff of protein synthesis.