ATM-Dependent Expression of the Insulin-like Growth Factor-I Receptor in a Pathway Regulating Radiation Response

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 4; pp. 1676 - 1681
• Main Authors: Peretz, Shani, Jensen, Ryan, Baserga, Renato, Glazer, Peter M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 13.02.2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Antibodies; Ataxia Telangiectasia Mutated Proteins; ATM gene; Biological Sciences; Cell Cycle Proteins; Cell growth; Cell Line, Transformed; Cell lines; Cell Survival; Cells; Complementary DNA; DNA, Complementary; DNA-Binding Proteins; Fibroblasts; Gene Expression Regulation; Genes; Genetic vectors; Genetics; Humans; Insulin; Leucine Zippers; Mutation; Neurons; Promoter Regions, Genetic; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Serine-Threonine Kinases - physiology; Radiation tolerance; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; Receptors; Transfection; Tumor Suppressor Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.041416598

The ATM gene is mutated in the syndrome of ataxia telangiectasia (AT), associated with neurologic dysfunction, growth abnormalities, and extreme radiosensitivity. Insulin-like growth factor-I receptor (IGF-IR) is a cell surface receptor with tyrosine kinase activity that can mediate mitogenesis, cell transformation, and inhibition of apoptosis. We report here that AT cells express low levels of IGF-IR and show decreased IGF-IR promoter activity compared with wild-type cells. Complementation of AT cells with the ATM cDNA results in increased IGF-IR promoter activity and elevated IGF-IR levels, whereas expression in wild-type cells of a dominant negative fragment of ATM specifically reduces IGF-IR expression, results consistent with a role for ATM in regulating IGF-IR expression at the level of transcription. When expression of IGF-IR cDNA is forced in AT cells via a heterologous viral promoter, near normal radioresistance is conferred on the cells. Conversely, in ATM cells complemented with the ATM cDNA, specific inhibition of the IGF-IR pathway prevents correction of the radiosensitivity. Taken together, these results establish a fundamental link between ATM function and IGF-IR expression and suggest that reduced expression of IGF-IR contributes to the radiosensitivity of AT cells. In addition, because IGF-I plays a major role in human growth and metabolism and serves as a survival and differentiation factor for developing neuronal tissue, these results may provide a basis for understanding other aspects of the AT syndrome, including the growth abnormalities, insulin resistance, and neurodegeneration.