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Molecular and Cellular Biology, April 2004, p. 2831-2841, Vol. 24, No. 7
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.7.2831-2841.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Overexpression of Inducible Cyclic AMP Early Repressor Inhibits Transactivation of Genes and Cell Proliferation in Pancreatic ß Cells

Akari Inada,^1,2, Yoshiyuki Hamamoto,^1,2 Yoshiyuki Tsuura,¹ Jun-ichi Miyazaki,³ Shinya Toyokuni,⁴ Yu Ihara,¹ Koichiro Nagai,⁵ Yuichiro Yamada,¹ Susan Bonner-Weir,^2* and Yutaka Seino¹

Department of Diabetes and Clinical Nutrition,¹ Department of Pathology and Biology of Disease,⁴ Department of Geriatric, Graduate School of Medicine, Kyoto University, Kyoto 606-8507,⁵ Division of Stem Cell Regulation Research G6, Medical School, Osaka University, Suita, Osaka 565-0871, Japan,³ Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215²

Received 29 September 2003/ Returned for modification 18 December 2003/ Accepted 5 January 2004

Transcriptional control mediated by the cyclic AMP-responsive element (CRE) represents an important mechanism of gene regulation. To test our hypothesis that increased inducible cyclic AMP early repressor (ICER) I inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic ß cells, we generated transgenic mice with ß-cell-directed expression of ICER I, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER I expression in ß cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of ß cells. The decrease in ß cells appears to result from impaired proliferation rather than from increased apoptosis after birth. Cyclin A gene expression is impaired by the strong inhibition of ICER; the suppression of cyclin A results in a substantially decreased proliferation of ß cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic ß-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of ß-cell mass.

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* Corresponding author. Mailing address: Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA 02215. Phone: (617) 732-2581. Fax: (617) 732-2650. E-mail: susan.bonner-weir{at}joslin.harvard.edu.

Present address: Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215.

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Molecular and Cellular Biology, April 2004, p. 2831-2841, Vol. 24, No. 7
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.7.2831-2841.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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