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J. Biol. Chem., Vol. 279, Issue 16, 16767-16777, April 16, 2004

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The Gtx Homeodomain Transcription Factor Exerts Neuroprotection Using Its Homeodomain^*

Yuichi Hashimoto, Osahiko Tsuji, Kohsuke Kanekura, Sadakazu Aiso¶, Takako Niikura||, Masaaki Matsuoka**, and Ikuo Nishimoto

From the Departments of Pharmacology and ^¶Anatomy, KEIO University School of Medicine, 35 Shinanomachi, Tokyo 160-8582, Japan

Certain cases of familial Alzheimer's disease are caused by mutants of amyloid- precursor protein (APP), including V642I-APP, K595N/M596L-APP (NL-APP), A617G-APP, and L648P-APP. By using an unbiased functional screening with transfection and expression of a human brain cDNA library, we searched for genes that protect neuronal cells from toxicity by V642I-APP. One protective clone was identical to the human GTX, a neuronal homeobox gene. Human Gtx (hGtx) inhibited caspase inhibitor-sensitive neuronal cell death not only by V642I-APP but also by L648P-, NL-, A617G-APP, apolipoprotein E4, and A. The region of hGtx responsible for this rescue function was specified to be its homeodomain (Lys¹⁴⁸-His²⁰⁷). The rescue function was shared by DLX4, a distal-less family gene with a homeodomain only 38.3% homologous to that of hGtx, suggesting that this function would be generally shared by homeodomains. The neuroprotective function of hGtx was attributable to hGtx-stimulated production and secretion of insulin-like growth factor-I. This study provides molecular clues to understand how neuronal cells developmentally regulate themselves against cell death as well as to develop reagents effective in curative therapeutics of Alzheimer's disease.

Received for publication, December 12, 2003 , and in revised form, January 28, 2004.

^* This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (M. M.) and Keio Gijuku Academic Development Funds (Y. H. & M. M.). 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.

Both authors contributed equally to this work.

^|| To whom correspondence may be addressed. Tel.: 81-3-3359-8909; Fax: 81-3-5363-8428; E-mail: niikurat{at}sc.itc.keio.ac.jp.

^** To whom correspondence may be addressed. Tel.: 81-3-3359-8909; Fax: 81-3-5363-8428; E-mail: sakimatu{at}sc.itc.keio.ac.jp.

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