Dominant Negative Inhibition of Tumorigenesis in vivo by Human Insulin-Like Growth Factor I Receptor Mutant

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 91; no. 6; pp. 2181 - 2185
• Main Authors: Prager, Diane, Li, Hsiao-Lin, Asa, Sylvia, Melmed, Shlomo
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.03.1994; National Acad Sciences; National Academy of Sciences
• Subjects: 3T3 cells; Animals; beta subunit; Biological and medical sciences; Carcinogenicity Tests; Cell Division; Cell growth; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Deoxyribonucleic acid; DNA; Fibroblasts; Fibroblasts - cytology; Fundamental and applied biological sciences. Psychology; Hormones; Humans; Hybridity; inhibition; insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Ligands; Medical research; Mice; Mice, Nude; Molecular and cellular biology; mutants; Mutation; Myeloid cells; Phenotype; Rats; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - physiology; Receptors; Somatomedins; Transfection; tumorigenesis; Tumors; Human; Cell proliferation; Heterologous system; Rat; Somatomedin C; Rodentia; DNA synthesis; Cell transformation; Vertebrata; Mammalia; Inhibition; Mutation; Biological receptor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.91.6.2181

Although insulin-like growth factor I (IGF-I) is a mitogenic growth factor, its role in tumorigenesis is unclear. We therefore transfected wild-type and truncated β-subunit mutant (952STOP) human IGF-I receptor cDNAs into Rat-1 fibroblasts. Rat-1 transfectants expressed 2.5- to 7-fold increased IGF-I receptor mass, while the Kdfor IGF-I binding was unchanged. The Rat-1 cells transfected with wild-type receptor cDNA responded to in vitro IGF-I treatment by increased proliferation and DNA synthesis. Cells overexpressing wild-type receptors were also transformed as evidenced by ligand-dependent colony proliferation in soft agar. After injection into athymic nude mice, all wild-type transfectants formed solid sarcomas within 3 weeks, and ex vivo tumor cell assays confirmed continued overexpression of human IGF-I receptors. In contrast, both DNA synthesis and proliferation of952STOP-transfected cells were attenuated below that of untransfected cells.952STOP cells were nonresponsive to IGF-I in vitro and were unable to sustain anchorage-independent growth. No tumors were induced for up to 8 weeks after injection of952STOP transfectants into athymic mice, despite the presence of demonstrable endogenous IGF-I receptors on the952STOP-transfected cells. Therefore,952STOP behaves as a dominant negative inhibitor of endogenous IGF-I receptor function, probably by assembling nonfunctional hybrid rat/mutant human receptor tetramers.