Stress-induced Translation of ATF5 mRNA Is Regulated by the 5′-Untranslated Region

• Published in: The Journal of biological chemistry 2008-02, Vol.283 (5), p.2543-2553
• Main Authors: Watatani, Yujiro, Ichikawa, Kenji, Nakanishi, Noriko, Fujimoto, Maki, Takeda, Hitoshi, Kimura, Natsumi, Hirose, Hidenori, Takahashi, Shigeru, Takahashi, Yuji
• Format: Article
• Language: English
• Subjects: 5' Untranslated Regions; Activating Transcription Factors - genetics; Amino Acids - metabolism; Animals; Arsenites - pharmacology; Base Sequence; Cell Line; Chlorocebus aethiops; COS Cells; DNA Primers - genetics; Eukaryotic Initiation Factor-2 - metabolism; HeLa Cells; Humans; Mice; Molecular Sequence Data; Mutagenesis, Site-Directed; Open Reading Frames; Oxidative Stress; Phosphorylation; Protein Biosynthesis - drug effects; RNA, Messenger - genetics; Sequence Homology, Nucleic Acid
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M707781200

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′-UTRα and 5′-UTRβ, derived from exon1α and exon1β. 5′-UTRα 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′-UTRα or 5′-UTRβ represses translation from the downstream ATF5 ORF. Moreover, 5′-UTRα-regulated translational repression is released by amino acid limitation or NaAsO2 exposure. This release was not seen for 5′-UTRβ. Mutation of uAUG2 in the uORF2 of 5′-UTRα restored the basal expression and abolished the positive regulation by amino acid limitation or arsenite exposure. We demonstrated that phosphorylation of eukaryotic initiation factor 2α 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 2α 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.