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Molecular and Cellular Biology, October 2006, p. 7747-7759, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.02353-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Increased Pancreatic ß-Cell Proliferation Mediated by CREB Binding Protein Gene Activation{triangledown}

Mehboob A. Hussain,1,{ddagger}* Delia L. Porras,2,{dagger} Matthew H. Rowe,2,{dagger} Jason R. West,2,{dagger} Woo-Jin Song,1 Weston E. Schreiber,1 and Fredric E. Wondisford1,{ddagger}*

Departments of Pediatrics and Medicine, Metabolism Division, Johns Hopkins University, Baltimore, Maryland,1 Department of Medicine, Section of Endocrinology, University of Chicago Hospital, Chicago, Illinois2

Received 9 December 2005/ Returned for modification 3 February 2006/ Accepted 28 July 2006

The cyclic AMP (cAMP) signaling pathway is central in ß-cell gene expression and function. In the nucleus, protein kinase A (PKA) phosphorylates CREB, resulting in recruitment of the transcriptional coactivators p300 and CREB binding protein (CBP). CBP, but not p300, is phosphorylated at serine 436 in response to insulin action. CBP phosphorylation disrupts CREB-CBP interaction and thus reduces nuclear cAMP action. To elucidate the importance of the cAMP-PKA-CREB-CBP pathway in pancreatic ß cells specifically at the nuclear level, we have examined mutant mice lacking the insulin-dependent phosphorylation site of CBP. In these mice, the CREB-CBP interaction is enhanced in both the absence and presence of cAMP stimulation. We found that islet and ß-cell masses were increased twofold, while pancreas weights were not different from the weights of wild-type littermates. ß-Cell proliferation was increased both in vivo and in vitro in isolated islet cultures. Surprisingly, glucose-stimulated insulin secretion from perfused, isolated mutant islets was reduced. However, ß-cell depolarization with KCl induced similar levels of insulin release from mutant and wild-type islets, indicating normal insulin synthesis and storage. In addition, transcripts of pgc1a, which disrupts glucose-stimulated insulin secretion, were also markedly elevated. In conclusion, sustained activation of CBP-responsive genes results in increased ß-cell proliferation. In these ß cells, however, glucose-stimulated insulin secretion was diminished, resulting from concomitant CREB-CBP-mediated pgc1a gene activation.

* Corresponding author. Mailing address: Metabolism Division, Department of Pediatrics and Medicine, Johns Hopkins University, 600 N. Wolfe Street, CMSC 10-113, Baltimore, MD 21287. Phone: (410) 502-5761. Fax: (410) 502-5776. E-mail for Mehboob A. Hussain: mhussai4{at}jhmi.edu. E-mail for Frederic E. Wondisford: fwondisford{at}jhmi.edu.

{triangledown} Published ahead of print on 14 August 2006.

{ddagger} These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

Molecular and Cellular Biology, October 2006, p. 7747-7759, Vol. 26, No. 20
0270-7306/06/$08.00+0     doi:10.1128/MCB.02353-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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