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Transactivation of the Mouse Sulfonylurea Receptor I Gene by BETA2/NeuroD

Departments of Anatomy (J.-W.K., J.-H.C., S.K., Y.-D.L., H.S.-K.) and Endocrinology (Y.K.), Brain Disease Research Center (H.S.-K.), Ajou University, School of Medicine, Suwon, 442-749, Korea; Department and Institute of Genetic Engineering (Y.R., K.B.), Kyung Hee University, Yongin City, 449–701, Korea; and Departments of Molecular and Cellular Biology (V.S., L.A.-B., J.B.) and Medicine (L.A.-B.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. Haeyoung Suh-Kim, Departments of Anatomy and Endocrinology, Ajou University, Paldal-Gu wonchone-Dong San 5 South Korea, South Korea 442-749. E-mail: hysuh{at}madang.ajou.ac.kr.

The sulfonylurea receptor 1 (SUR1) plays a key role in regulation of insulin secretion in pancreatic ß-cells. In this study we investigated the mechanism for tissue-specific expression of the SUR1 gene. A -138/-20 fragment exhibited basal promoter activity while the -660/-20 fragment contained a regulatory element for tissue-specific expression of the mouse SUR1 gene. A pancreatic ß-cell-specific transcription factor, BETA2 (ß-cell E box transcription factor)/NeuroD, enhanced the promoter activity of the -660/-20 fragment in cooperation with E47. Coexpression of a dominant negative mutant of BETA2/NeuroD, BETA2(1–233), repressed the promoter activity of the -660/-20 fragment. BETA2/NeuroD bound specifically to the E3 element located at -141. The E3 sequence in a heterologous context conferred transactivation by BETA2/NeuroD in HeLa and HIT cells. Mutation of E3 eliminated the stimulatory effect of BETA2/NeuroD. Unlike BETA2/NeuroD, neurogenin 3 (ngn3) could not activate the E3 element in HeLa cells. Overexpression of ngn3 concomitantly increased expression of BETA2/NeuroD and SUR1 in HIT cells but not in HeLa cells. These results indicate that BETA2/NeuroD induces tissue-specific expression of the SUR1 gene through the E3 element. These results also suggest that E3 is specific for BETA2/NeuroD, and the stimulatory effect of ngn3 in HIT cells may require factors specifically expressed in HIT cells.

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