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Papers In Press, published online ahead of print July 24, 2003
Department of Clinical and Experimental Medicine, University of Catania, Catanzaro, Catanzaro 88100
Corresponding Author: belfiore{at}unicz.it
The human insulin receptor (IR) exists in two isoforms (IR-A and IR-B). IR-A is a short isoform, generated by the skipping of exon 11, a small exon encoding for 12 aminoacid residues at the carboxyl terminus of the IR a-subunit. Recently, we found that IR-A is the predominant isoform in fetal tissues and malignant cells and binds with a high affinity not only insulin but also IGF-II. In order to investigate whether the activation of IR-A by the two ligands differentially activate post-receptor molecular mechanisms, we studied gene expression in response to IR-A activation by either insulin or IGF-II, using microarray technology. To avoid the interfering effect of the IGF-IR, IGF-II binding to the IR-A was studied in IGF-IR deficient murine fibroblasts (R- cells) transfected with the human IR-A cDNA (R-/IR-A cells). Gene expression was studied at 0.5, 3 and 8 hr. We found that 214 transcripts were similarly regulated by insulin and IGF-II while 45 genes were differentially transcribed. Eighteen of these differentially regulated genes were responsive to only one of the two ligands (12 to insulin and 6 to IGF-II). Twenty-seven transcripts were regulated by both insulin and IGF-II but a significant difference between the two ligands was present at least in one time point. Interestingly, IGF-II was a more potent and/or persistent regulator than insulin for these genes. Results were validated by measuring the expression of 12 genes by quantitative Real-Time RT-PCR. In conclusion, we show that insulin and IGF-II, acting via the same receptor, may differentially affect gene expression in cells. These studies provide a molecular basis for understanding some of the biological differences between the two ligands and may help to clarify the biological role of IR-A in embryonic/fetal growth and the selective biological advantage that malignant cells producing IGF-II may acquire via IR-A overexpression.
J. Biol. Chem, 10.1074/jbc.M304980200
Submitted on May 13, 2003
Revised on July 17, 2003
Accepted on July 24, 2003
Differential gene expression induced by insulin and IGF-ii through the insulin receptor isoform A
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