1. IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.
- Author
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Ursø B, Ilondo MM, Holst PA, Christoffersen CT, Ouwens M, Giorgetti S, Van Obberghen E, Naor D, Tornqvist H, and De Meyts P
- Subjects
- Adaptor Proteins, Signal Transducing, Animals, Cattle, Enzyme Activation, Female, Humans, Insulin Receptor Substrate Proteins, Lymphoma, T-Cell, Mice, Mice, Inbred BALB C, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation drug effects, Receptor, IGF Type 1 deficiency, Signal Transduction drug effects, Tumor Cells, Cultured drug effects, Tumor Cells, Cultured enzymology, Tyrosine metabolism, Growth Hormone pharmacology, Insulin pharmacology, Mitogens pharmacology, Phosphatidylinositol 3-Kinases metabolism, Phosphoproteins metabolism
- Abstract
Insulin and growth hormone (GH) induce mitogenic and metabolic signals in cells, GH either directly or indirectly via IGF-I production. We have studied a spontaneous murine T-cell lymphoma (LB cells) devoid of IGF-1 receptors in which proliferation is maintained by insulin [Int. J. Cancer 50 (1992) 80], and show that GH is more potent than insulin, with both GH and insulin dose-response curves for thymidine incorporation being bell-shaped. Binding showed somatogenic rather than lactogenic GH receptors. Insulin stimulated phosphorylation of the insulin receptor and of a 160-kDa protein, identified as the IRS-4 protein. This phosphorylated IRS-4 associated with PI3-kinase, which was activated along with the downstream p70(S6) kinase, whereas the Ras-MAPK pathway was not. Using selective inhibitors, the PI3-kinase, but not p70(S6) kinase or MEK, was found to be involved in insulin-stimulated DNA synthesis. GH induced tyrosine phosphorylation of IRS-4 and nuclear translocation of STAT5. The LB cells constitute a new model for studying GH and insulin signalling without interference of IGF-1 receptors.
- Published
- 2003
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