| The insulin-like growth factor-I receptor (IGF-IR) is a tyrosine kinase, transmembrane receptor expressed in most body tissues and required for normal growth of cells. As tumors develop, abnormalities in vascularization lead to a heterogeneous environment which includes areas of hypoxia, low pH and low glucose. We have found that the overexpression of the IGF-IR confers a selective growth advantage under hypoxic conditions and promotes increased clonogenic survival in cells exposed to hypoxia, low pH and low glucose. Furthermore, cells lacking the receptor due to targeted disruption of the IGF-IR gene do not survive as well as normal cells in such conditions. In addition, we find that, regardless of receptor levels present, cells activate the IGF-IR promoter in response to hypoxia, and immunoblot analyses show increased receptor protein levels in cell exposed to hypoxia. This increase in IGF-IR does not appear to be regulated by the p53 protein. Furthermore, we have found that a soluble IGF-IR can result in decreased cellular survival in cells exposed to radiation, supporting a role for the IGF-IR in radiation response. In addition, we have shown that the ATM gene, mutated in the syndrome of ataxia telangiectasia, is able to regulate IGF-IR expression. AT cells express low levels of IGF-IR, and complementing these cells with the ATM cDNA results in increased levels of IGF-IR promoter activity and protein levels. Inhibiting ATM results in a decrease in IGF-IR levels. Furthermore, increasing the levels of IGF-IR in AT cells increases the radioresistance of these cells and inhibiting IGF-IR abolishes this effect, suggesting that the reduced expression of IGF-IR contributes to the radiosensitivity seen in AT cells. The regulation of IGF-IR by ATM appears to be specific, and places the IGF-IR gene downstream of ATM in the DNA-damage sensing pathway. These results suggest a role for IGF-IR in tumor progression, and establish a fundamental link between ATM function and IGF-IR expression. |
