title: Expression of a kinase-deficient IGF-I-R suppresses tumorigenicity of rhabdomyosarcoma cells constitutively expressing a wild type IGF-I-R.
abstract: Previous results have shown that the insulin-like growth factor type I receptor (IGF-I-R) plays a critical role in the control of rhabdomyosarcoma (RMS) growth. The purpose of this study was to investigate whether a mutated IGF-I-R, when expressed in RMS cells, may interfere with the function of the endogenous wild-type IGF-I-R. We also examined whether the expression of a mutated IGF-I-R may induce phenotypic changes in RMS cells. We used here the mutated IGF-I-R with a lysine to arginine residue 1003 substitution, called IGF-I-KR, which carries a mutation in the ATP-binding domain of the intracellular beta subunit, while the extracellular, ligand binding alpha subunit remains unchanged. We observed that the expression of this mutated IGF-I-KR markedly decreased the response of RMS cells to stimulation with IGF-I. While stimulation with IGF-I increases the autophosphorylation of IGF-I-R in the parent cells, stimulation with IGF-I failed to produce a comparable increase in autophosphorylation in the cells expressing the mutated IGF-I-KR. We also observed a decreased plating efficiency of cells expressing the mutated IGF-I-KR. Consistently, a decrease of RMS growth in vivo was observed in an animal model. Our data suggest that the IGF/IGF-I-R signaling pathway may be inhibited by expressing a mutated IGF-I-KR and that such a mutant gene could be utilized in developing novel therapeutic strategies to suppress RMS growth. 1998.
authors.affiliation: Molecular Oncology Section, Pediatric Branch, National Cancer Institute, Bethesda, MD 20892, USA. KALEBICT@CTEP.NCI.NIH.GOV
authors.forename: T
authors.initials: T
authors.lastname: Kalebic
authors.forename: V
authors.initials: V
authors.lastname: Blakesley
authors.forename: C
authors.initials: C
authors.lastname: Slade
authors.forename: S
authors.initials: S
authors.lastname: Plasschaert
authors.forename: D
authors.initials: D
authors.lastname: Leroith
authors.forename: L J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D002455:Cell Division / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D046911:Macromolecular Substances; D009154:Mutation; D014411:Neoplastic Stem Cells; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure*; D013268:Stimulation, Chemical; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D046911:Macromolecular Substances; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1