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J. Biol. Chem., Vol. 283, Issue 32, 22063-22075, August 8, 2008

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Int6/eIF3e Promotes General Translation and Atf1 Abundance to Modulate Sty1 MAPK-dependent Stress Response in Fission Yeast^*

Tsuyoshi Udagawa¹, Naoki Nemoto¹, Caroline R. M. Wilkinson, Jana Narashimhan^¶, Li Jiang^¶, Stephen Watt^||, Aaron Zook, Nic Jones, Ronald C. Wek^¶, Jürg Bähler^||, and Katsura Asano²

From the Molecular Cellular and Developmental Biology Program, Division of Biology, Kansas State University, Manhattan, Kansas 66506, the Cancer Research UK Cell Regulation Laboratory, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, United Kingdom, the ^¶Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202, and the ^||Cancer Research UK Fission Yeast Functional Genomics Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH United Kingdom

int-6 is one of the frequent integration sites for mouse mammary tumor viruses. Although its product is the e-subunit of translation initiation factor eIF3, other evidence indicates that it interacts with proteasomes or other proteins to regulate protein stability. Here we report that the fission yeast int6⁺ is required for overcoming stress imposed by histidine starvation, using the drug 3-aminotriazole (3AT). Microarray and complementary Northern studies using wild-type, int6 or gcn2 mutants indicate that 3AT-treated wild-type yeast induces core environmental stress response (CESR) genes in addition to typical general amino acid control (GAAC) genes whose transcription depends on the eIF2 kinase, Gcn2. In agreement with this, Sty1 MAPK and its target transcription factor Atf1, which signal the CESR, are required for overcoming 3AT-induced starvation. We find that Int6 is required for maintaining the basal level of Atf1 and for rapid transcriptional activation of the CESR on 3AT-insult. Pulse labeling experiments indicate that int6 significantly slows down de novo protein synthesis. Moreover, Atf1 protein half-life was reduced in int6 cells. These effects would account for the compromised Atf1 activity on 3AT-induced stress. Thus, the robust protein synthesis promoted by intact eIF3 appears to be a part of the requisites for sound Sty1 MAPK-dependent signaling governed by the activity of the Atf1 transcription factor.

Received for publication, December 10, 2007 , and in revised form, May 22, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM67481 (to K. A.) and GM49164 (to R. W.). This work was also supported by NCRR K-INBRE Pilot Grant P20 RR016475, an Innovative Award from the Kansas State University Terry Johnson Cancer Center (to K. A.) and Cancer Research UK Grant C9546/A6517 (to J. B.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S2 and Table S1.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. E-mail: kasano{at}ksu.edu.

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