Induced ICER Igamma down-regulates cyclin A expression and cell proliferation in insulin-producing beta cells.

We have previously found that cyclin A expression is markedly reduced in pancreatic beta-cells by cell-specific overexpression of repressor inducible cyclic AMP early repressor (ICER Igamma) in transgenic mice. Here we further examined regulatory effects of ICER Igamma on cyclin A gene expression using Min6 cells, an insulin-producing cell line. The cyclin A promoter luciferase assay showed that ICER Igamma directly repressed cyclin A gene transcription. In addition, upon ICER Igamma overexpression, cyclin A mRNA levels markedly decreased, thereby confirming an inhibitory effect of ICER Igamma on cyclin A expression. Suppression of cyclin A results in inhibition of BrdU incorporation. Under normal culture conditions endogenous cyclin A is abundant in these cells, whereas ICER is hardly detectable. However, serum starvation of Min6 cells induces ICER Igamma expression with a concomitant very low expression level of cyclin A. Cyclin A protein is not expressed unless the cells are in active DNA replication. These results indicate a potentially important anti-proliferative effect of ICER Igamma in pancreatic beta cells. Since ICER Igamma is greatly increased in diabetes as well as in FFA- or high glucose-treated islets, this effect may in part exacerbate diabetes by limiting beta-cell proliferation.