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J. Biol. Chem., Vol. 278, Issue 43, 42178-42189, October 24, 2003

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Differential Gene Expression Induced by Insulin and Insulin-like Growth Factor-II through the Insulin Receptor Isoform A^*

Giuseppe Pandini, Enzo Medico, Enrico Conte¶, Laura Sciacca, Riccardo Vigneri, and Antonino Belfiore||**

From the Dipartimento di Medicina Interna e di Medicine Specialistiche, Cattedra di Endocrinologia, University of Catania, USL 34, Ospedale Garibaldi, 95123 Catania, Institute for Cancer Research and Treatment, University of Torino Medical School, S.P. 142, km 3.95, 10060 Candiolo (TO), ^¶Dipartimento di Scienze Biomediche, University of Catania, 95125 Catania, and ^||Dipartimento di Medicina Molecolare e Clinica, Cattedra di Endocrinologia, University of Catanzaro, Policlinico Mater Domini, 88100 Catanzaro Italy

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 amino acid residues at the carboxyl terminus of the IR -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 insulin-like growth factor-II (IGF-II). 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 h. We found that 214 transcripts were similarly regulated by insulin and IGF-II, whereas 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 reverse transcriptase-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.

Received for publication, May 13, 2003 , and in revised form, July 17, 2003.

^* This work was partially supported by grants from the Associazione Italiana per la Ricerca sul Cancro (to A .B. and to R. V.) and from Ministero Italiano Università e Ricerca (Grant Cofin 2001 to A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^** To whom correspondence should be addressed. Tel.: 39-0961-712-423; Fax: 39-0961-772-748; E-mail: belfiore{at}unicz.it.

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