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Characterization of a GCN2/eIF2alpha independent pathway that regulates the expression of eukaryotic initiation factor 4E‐binding protein 1
Author(s) -
Mazor Kevin Michael,
Stipanuk Martha
Publication year - 2013
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/fasebj.27.1_supplement.370.7
Subject(s) - atf4 , eif2 , integrated stress response , eukaryotic initiation factor , eif4a1 , initiation factor , protein biosynthesis , microbiology and biotechnology , signal transduction , translational regulation , biology , messenger rna , downregulation and upregulation , eif4ebp1 , eukaryotic translation initiation factor 4 gamma , translation (biology) , chemistry , biochemistry , gene
Lack of essential amino acids is known to activate the eIF2α/ATF4 stress signaling pathway via activation of GCN2 (eIF2α kinase 4) by nonaminoacylated tRNAs. In previous studies, we have observed that eukaryotic initiation factor 4E‐binding protein 1 (4EBP1) expression is upregulated in methionine (Met)‐deficient cells even in the absence of an active GCN2/eIF2α signaling pathway. To further characterize this GCN2/eIF2α‐independent pathway, we compared the effects of Met and histidine (His) deficiency in murine embryonic fibroblasts (MEFs). In wild‐type MEFs, either –His or –Met medium resulted in increases in 4EBP1 mRNA and protein abundance as well as ATF4 mRNA levels. This upregulation of 4EBP1 and ATF4 was also seen in MEFs lacking GCN2 or with mutant eIF2α when they were cultured in –Met medium, but not when cultured in –His medium. These results imply the existence of a GCN2‐and eIF2α phosphorylationin‐dependent pathway that is capable of increasing the expression of both 4EBP1 and ATF4 in response to Met but not His deficiency. Supported by Grants DK‐083473 and T32DK007158 (NIDDK) and by the Division of Nutritional Sciences.