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.
Inada
Akari
A
Section of Islet Transplantation and Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Weir
Gordon C
GC
Bonner-Weir
Susan
S
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D051786:Cyclic AMP Response Element Modulator; D019925:Cyclin A / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D007328:Insulin / Q000096:biosynthesis*; D007515:Islets of Langerhans / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000378:metabolism*
D019925:Cyclin A; D004268:DNA-Binding Proteins; D007328:Insulin; D014157:Transcription Factors; D051786:Cyclic AMP Response Element Modulator