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J. Biol. Chem., Vol. 283, Issue 5, 2543-2553, February 1, 2008

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Stress-induced Translation of ATF5 mRNA Is Regulated by the 5'-Untranslated Region^*

From the Laboratory of Environmental Molecular Physiology, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo 192-0392, Japan

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'-UTR and 5'-UTRβ, derived from exon1 and exon1β. 5'-UTR 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'-UTR or 5'-UTRβ represses translation from the downstream ATF5 ORF. Moreover, 5'-UTR-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'-UTR restored the basal expression and abolished the positive regulation by amino acid limitation or arsenite exposure. We demonstrated that phosphorylation of eukaryotic initiation factor 2 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 2 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.

Received for publication, September 17, 2007 , and in revised form, November 6, 2007.

^* This work was supported by a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: School of Life Science, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan. Tel.: 81-426-76-7018; Fax: 81-426-76-6811; E-mail: shigeru{at}ls.toyaku.ac.jp.

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