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Molecular and Cellular Biology, June 2006, p. 4553-4563, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.01412-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Regulation of Insulin Secretion and ß-Cell Mass by Activating Signal Cointegrator 2{dagger}

Seon-Yong Yeom,1,{ddagger} Geun Hyang Kim,1,{ddagger} Chan Hee Kim,1 Heun Don Jung,1 So-Yeon Kim,2 Joong-Yeol Park,3 Youngmi Kim Pak,1,3 Dong-Kwon Rhee,4 Shao-Qing Kuang,5 Jianming Xu,5 Duck Jong Han,6 Dae-Kyu Song,2 Jae Woon Lee,7 Ki-Up Lee,3* and Seung-Whan Kim1,3*

Asan Institute for Life Sciences,1 Department of Internal Medicine,3 Department of Physiology, Keimyung University School of Medicine, Daegu, South Korea,2 College of Pharmacy, Sungkyunkwan University, Suwon, South Korea,4 Department of Molecular and Cellular Biology,5 Department of Surgery, University of Ulsan College of Medicine, Seoul, South Korea,6 Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, Texas7

Received 26 July 2005/ Returned for modification 16 September 2005/ Accepted 30 March 2006

Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic ß-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/– mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/– mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/– islets. These results suggest that ASC-2 regulates insulin secretion and ß-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

* Corresponding author. Mailing address for Seung-Whan Kim: Asan Institute for Life Sciences, University of Ulsan College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, South Korea. Phone: 82-2-3010-4141. Fax: 82-2-3010-4182. E-mail: swkim7{at}amc.seoul.kr. Mailing address for Ki-Up Lee: Department of Internal Medicine, University of Ulsan College of Medicine, 388-1 Pungnap-2dong, Songpa-gu, Seoul 138-736, South Korea. Phone: 82-2-3010-3243. Fax: 82-2-3010-6962. E-mail: kulee{at}amc.seoul.kr.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} S.-Y.Y. and G.H.K. contributed equally to this work.

Molecular and Cellular Biology, June 2006, p. 4553-4563, Vol. 26, No. 12
0270-7306/06/$08.00+0     doi:10.1128/MCB.01412-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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