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J. Biol. Chem., Vol. 280, Issue 41, 34577-34589, October 14, 2005

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Sterol Regulatory Element-binding Proteins Activate Insulin Gene Promoter Directly and Indirectly through Synergy with BETA2/E47^*

Michiyo Amemiya-Kudo, Junko Oka, Tomohiro Ide, Takashi Matsuzaka, Hirohito Sone, Tomohiro Yoshikawa¶, Naoya Yahagi¶, Shun Ishibashi¶, Jun-ichi Osuga¶, Nobuhiro Yamada, Toshio Murase, and Hitoshi Shimano1

From the Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Toranomon 2-2-2, Minato-ku, Tokyo 105-8470, Japan, ^¶Department of Diabetes and Metabolic Diseases, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan, and Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki 305-8575, Japan

Insulin gene expression is regulated by pancreatic cell-specific factors, PDX-1 and BETA2/E47. Here we have demonstrated that the insulin promoter is a novel target for SREBPs established as lipid-synthetic transcription factors. Promoter analyses of rat insulin I gene in non- cells revealed that nuclear SREBP-1c activates the insulin promoter through three novel SREBP-binding sites (SREs), two of which overlap with E-boxes, binding sites for BETA2/E47. SREBP-1c activation of the insulin promoter was markedly enhanced by co-expression of BETA2/E47. This synergistic activation by SREBP-1c/BETA2/E47 was not mediated through SREs but through the E-boxes on which BETA2/E47 physically interacts with SREBP-1c, suggesting a novel function of SREBP as a co-activator. These two cis-DNA regions, E1 and E2, with an appropriate distance separating them, were mandatory for the synergism, which implicates formation of SREBP-1c·BETA2·E47 complex in a DNA looping structure for efficient recruitment of CREB-binding protein/p300. However, in the presence of PDX1, the synergistic action of SREBP-1c with BETA2/E47 was canceled. SREBP-1c-mediated activation of the insulin promoter and expression became overt in cell lines and isolated islets when endogenous PDX-1 expression was low. This cryptic SREBP-1c action might play a compensatory role in insulin expression in diabetes with cell lipotoxicity.

Received for publication, June 21, 2005

^* This work was supported by grants-in-aid from the Ministry of Science, Education, Culture, 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: Dept. of Internal Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki, Japan 305-8575. Tel.: 81-29-853-3053; Fax: 81-29-853-3174; E-mail: shimano-tky{at}umin.ac.jp.

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