title: IRS-4 mediated mitogenic signalling by insulin and growth hormone in LB cells, a murine T-cell lymphoma devoid of IGF-I receptors.
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.
authors.affiliation: Department of Receptor Biology, Hagedorn Research Institute, Niels Steensens Vej 6, DK-2820 Gentofte, Denmark. bur@novonordisk.com
authors.forename: Birgitte
authors.initials: B
authors.lastname: Ursø
authors.forename: M Mapoko
authors.initials: MM
authors.lastname: Ilondo
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Holst
authors.forename: Claus T
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: Margriet
authors.initials: M
authors.lastname: Ouwens
authors.forename: Sophie
authors.initials: S
authors.lastname: Giorgetti
authors.forename: E
authors.initials: E
authors.lastname: Van Obberghen
authors.forename: David
authors.initials: D
authors.lastname: Naor
authors.forename: Hans
authors.initials: H
authors.lastname: Tornqvist
authors.forename: Pierre
authors.initials: P
authors.lastname: De Meyts
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002417:Cattle; D004789:Enzyme Activation; D005260:Female; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D016399:Lymphoma, T-Cell; D051379:Mice; D008807:Mice, Inbred BALB C; D008934:Mitogens / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1 / Q000172:deficiency; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D013006:Growth Hormone; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008934:Mitogens; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D017526:Receptor, IGF Type 1; D014443:Tyrosine; C107686:IRS4 protein, human; C491531:Irs4 protein, mouse