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J. Biol. Chem., Vol. 280, Issue 15, 15047-15052, April 15, 2005

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A Crucial Role of MafA as a Novel Therapeutic Target for Diabetes^*

Hideaki Kaneto, Taka-aki Matsuoka, Yoshihisa Nakatani, Takeshi Miyatsuka, Munehide Matsuhisa, Masatsugu Hori, and Yoshimitsu Yamasaki

From the Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan

MafA, a recently isolated pancreatic -cell-specific transcription factor, is a potent activator of insulin gene transcription. In this study, we show that MafA overexpression, together with PDX-1 (pancreatic and duodenal homeobox factor-1) and NeuroD, markedly increases insulin gene expression in the liver. Consequently, substantial amounts of insulin protein were induced by such combination. Furthermore, in streptozotocin-induced diabetic mice, MafA overexpression in the liver, together with PDX-1 and NeuroD, dramatically ameliorated glucose tolerance, while combination of PDX-1 and NeuroD was much less effective. These results suggest a crucial role of MafA as a novel therapeutic target for diabetes.

Received for publication, October 22, 2004 , and in revised form, January 4, 2005.

^* This work was supported in part by grants from the Ministry of Education 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.

This article was selected as a Paper of the Week.

These two authors contributed equally to this work.

To whom correspondence may be addressed. Tel.: 81-6-6879-3633; Fax: 81-6-6879-3639; E-mail: kaneto{at}medone.med.osaka-u.ac.jp (for H. K.) or takaaki{at}medone.med.osaka-u.ac.jp (for T.-A. M.).

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