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Title: ATM-dependent expression of the insulin-like growth factor-I receptor in a pathway regulating radiation response.

Authors: Peretz, S; Jensen, R; Baserga, R; Glazer, P M

Published In Proc Natl Acad Sci U S A, (2001 Feb 13)

Abstract: 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.

PubMed ID: 11172010 Exiting the NIEHS site

MeSH Terms: Ataxia Telangiectasia Mutated Proteins; Cell Cycle Proteins; Cell Line, Transformed; Cell Survival; DNA, Complementary; DNA-Binding Proteins; Gene Expression Regulation*; Humans; Leucine Zippers*; Promoter Regions, Genetic; Protein Serine-Threonine Kinases/genetics; Protein Serine-Threonine Kinases/metabolism; Protein Serine-Threonine Kinases/physiology*; Receptor, IGF Type 1/genetics*; Receptor, IGF Type 1/metabolism; Tumor Suppressor Proteins

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