Abstract
Ataxia-telangiectasia mutated is a protein kinase that is critical for the maintenance of genomic stability and proper cellular response to redox imbalance. Previous studies indicate that ataxia-telangiectasia mutated is also required for expression of the insulin-like growth factor-1 receptor in human fibroblasts. As insulin-like growth factor-1 receptor is critical in mammary gland development, we sought to determine the relationship between ataxia-telangiectasia mutated and insulin-like growth factor-1 receptor using mouse as a model system. Knockdown of ataxia-telangiectasia mutated in cultured mouse mammary epithelial cells resulted in a significant reduction in insulin-like growth factor-1 receptor mRNA levels. Using a conditional knockout mouse model, we observed that loss of ataxia-telangiectasia mutated resulted in a severe decrease in both insulin-like growth factor-1 receptor mRNA and protein expression. These results support the observation that insulin-like growth factor-1 receptor expression is ataxia-telangiectasia mutated -dependent in the mammary epithelium, and given the critical role that insulin-like growth factor-1 receptor plays in mammary gland development, suggests that ataxia-telangiectasia mutated may be critical in the development of this organ as well.
Highlights
Ataxia-telangiectasia mutated (ATM) is a central protein kinase activated in response to DNA damage and redox imbalance [1]
3.1 ATM knockdown results in decreased Insulin-like growth factor (IGF)-1R expression in cultured mouse mammary epithelial cells
4.1 ATM is required for IGF-1R expression The Glaser laboratory was first to report that, in fibroblasts cultured from a human A-T patient, expression of the IGF-1R protein and mRNA were notably diminished [15]
Summary
Ataxia-telangiectasia mutated (ATM) is a central protein kinase activated in response to DNA damage and redox imbalance [1]. ATM expression is commonly observed in sporadic breast cancers [6, 7]. Release of growth hormone (GH) from the pituitary, stimulates the expression of both isoforms of IGF (i.e. IGF1 and IGF2) by the liver as well as numerous cell types within the body [8]. Insulin receptor substrates 1 and 2 (IRS1 and IRS2), which act as signaling adaptors for both IGF-1R and the insulin receptor (InsR), dock with tyrosine phosphorylated IGF-1R at the cytosolic face of the receptor and activate numerous downstream signaling cascades such as the PI3K-AKT and RAS-MAPK-ERK1 signaling axes [10]
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