Activation of the insulin receptor (IR) by insulin and a synthetic peptide has different effects on gene expression in IR-transfected L6 myoblasts
Résumé
Single chain peptides have been recently produced that display either mimetic or antagonistic properties against the insulin and IGF-1 receptors. We have earlier shown that the insulin mimetic peptide S597 leads to significant differences in receptor activation and initiation of downstream signaling cascades despite similar binding affinity and in vivo hypoglycemic potency. It is still unclear how two ligands can initiate different signaling responses through the insulin receptor (IR). To further investigate how the activation of the IR by insulin and S597 differentially activates post-receptor signaling, we here studied the gene expression profile in response to IR activation by either insulin or S597 using microarray technology. We found striking differences between the patterns induced by these two ligands. Most remarkable was that almost half of the genes differentially regulated by insulin and S597 were involved in cell proliferation and growth. Insulin either selectively regulated the expression of these genes or was a more potent regulator. Furthermore we found that half of the differentially regulated genes interact with the genes involved with the MAPK pathway. These findings support our signaling results obtained earlier and confirm that the main difference between S597 and insulin stimulation resides in the activation of the MAPK pathway. In conclusion we show that insulin and S597 acting via the same receptor differentially affect gene expression in cells resulting in a different mitogenicity of the two ligands, a finding which has critical therapeutic implications.
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