Stress-induced translation of ATF5 mRNA is regulated by the 5'-untranslated region.
Activating transcription factor (ATF) 5 is a transcription factor belonging to the ATF/cAMP-response element-binding protein gene family. We previously reported that ATF5 mRNA expression increased in response to amino acid limitation. The ATF5 gene allows transcription of mRNAs with at least two alternative 5'-untranslated regions (5'-UTRs), 5'-UTRalpha and 5'-UTRbeta, derived from exon1alpha and exon1beta. 5'-UTRalpha contains highly conserved sequences, in which the upstream open reading frames (uORFs) uORF1 and uORF2 are found in many species. This study was designed to investigate the potential role of 5'-UTRs in translational control. These 5'-UTRs differentially determined translation efficiency from mRNA. The presence of 5'-UTRalpha or 5'-UTRbeta represses translation from the downstream ATF5 ORF. Moreover, 5'-UTRalpha-regulated translational repression is released by amino acid limitation or NaAsO(2) exposure. This release was not seen for 5'-UTRbeta. Mutation of uAUG2 in the uORF2 of 5'-UTRalpha restored the basal expression and abolished the positive regulation by amino acid limitation or arsenite exposure. We demonstrated that phosphorylation of eukaryotic initiation factor 2alpha was required for amino acid limitation-induced translational regulation of ATF5. Furthermore, arsenite exposure activated the exogenously expressed heme-regulated inhibitor kinase and induced the phosphorylation of eukaryotic initiation factor 2alpha in nonerythroid cells. These results suggest that translation of ATF5 is regulated by the alternative 5'-UTR region of its mRNA, and ATF5 may play a role in protecting cells from amino acid limitation or arsenite-induced oxidative stress.
Laboratory of Environmental Molecular Physiology, School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, Japan.
Yujiro
Y
Watatani
Kenji
K
Ichikawa
Noriko
N
Nakanishi
Maki
M
Fujimoto
Hitoshi
H
Takeda
Natsumi
N
Kimura
Hidenori
H
Hirose
Shigeru
S
Takahashi
Yuji
Y
Takahashi
D020121:5' Untranslated Regions; D051696:Activating Transcription Factors / Q000235:genetics*; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D018053:Arsenites / Q000494:pharmacology; D001483:Base Sequence; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016366:Open Reading Frames; D018384:Oxidative Stress; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics*; D012689:Sequence Homology, Nucleic Acid
D020121:5' Untranslated Regions; C507532:ATF5 protein, human; D051696:Activating Transcription Factors; D000596:Amino Acids; D018053:Arsenites; D017931:DNA Primers; D015852:Eukaryotic Initiation Factor-2; D012333:RNA, Messenger; C015001:arsenite