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

Abstract

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.

Genetic networks responsive to sodium butyrate in colonic epithelial cells

“…This network includes IGF2 at its center. IGF2 is reported to be involved in the expression of NDRG1, THRA, JUNB and DUSP1 in mutant mouse fibroblasts with a homozygous knockout of IGF1R [37]. The differentially expressed genes or functionally categorized genetic clusters and genetic networks identified here are likely to be involved in cell growth arrest and differentiation induced by SB in colonic epithelial cells.…”

Insulin control of placental gene expression shifts from mother to foetus over the course of pregnancy

“…We identified 371 insulin-responsive genes that were specifically regulated in one compartment of the placenta. Some of the genes had also been identified in other microarray studies, which used different cell models, stimulation and analysis modalities [24][25][26][27][28], or by other methods [9,10], thus representing a robust insulin response common to many cell types.…”

Pharmacodynamic and Antineoplastic Activity of BI 836845, a Fully Human IGF Ligand-Neutralizing Antibody, and Mechanistic Rationale for Combination with Rapamycin

“…By binding to and neutralizing the IGF ligands, BI 836845 blocks activation not only of the IGF-IR, but unlike anti-IGF-IR antibodies also reduces IGF-II-stimulated activation of IR-A. This may be an important advantage, as the expression of this receptor variant is often increased in tumor cells (7,8,10,44) and may play a role in autocrine IGF-IImediated growth stimulation (34,40). In addition, some IGF-IR antibodies have been shown to be weak inhibitors of IGF-II-driven IGF-IR signaling, which is thought to be due to differences in the binding sites of IGF-I and IGF-II on the IGF-I receptor (45).…”

“…7,8). This is of particular interest from an oncologic perspective as IR-A is preferentially expressed in fetal and cancer cells (9,10).…”