Overexpression of Inducible Cyclic AMP Early Repressor Inhibits Transactivation of Genes and Cell Proliferation in Pancreatic β Cells
Open Access
- 1 April 2004
- journal article
- research article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 24 (7), 2831-2841
- https://doi.org/10.1128/mcb.24.7.2831-2841.2004
Abstract
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) Iγ inhibits function of CRE-binding proteins and thus disrupts CRE-mediated transcription in pancreatic β cells, we generated transgenic mice with β-cell-directed expression of ICER Iγ, a powerful repressor that is greatly increased in diabetes. Three transgenic lines clearly show that increased ICER Iγ expression in β cells results in early severe diabetes. From birth islets were severely disorganized with a significantly increased proportion of α cells throughout the islet. Diabetes results from the combined effects of impaired insulin expression and a decreased number of β cells. The decrease in β 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 β cells in the postnatal period. These results suggest that CRE and CRE-binding factors have an important role in pancreatic β-cell physiology not only directly by regulation of gene trans-activation but also indirectly by regulation of β-cell mass.Keywords
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