Abstract
Ataxia telangiectasia (AT) is a human hereditary syndrome whose underlying gene product, ataxia telangiectasia mutated (ATM) protein kinase, is involved in multiple intracellular signaling pathways. We demonstrated previously that AT fibroblasts are defective in intracellular Ca2+ mobilization in response to both stress-inducing and mitogenic stimuli. To extend these findings, normal and AT cells were exposed to serum in the presence of different concentrations of extracellular Ca2+ ([Ca2+]o), and release of intracellular Ca2+, activation of calmodulin-dependent protein kinase II and phosphorylation of kinases ERK1 and 2 were monitored. When maintained in high [Ca2+]o (0.42 mM), normal fibroblasts responded to serum introduction more rapidly and efficiently than did AT cells. Unexpectedly, decreasing the [Ca2+]o in the medium had a diametrically opposite effect. Under low [Ca2+]o (0.0022 mM) conditions, normal cells were slow and inefficient in their responses, whereas AT cells showed a substantial improvement in all three end points. These findings demonstrate that loss of ATM kinase function deregulates the extracellular calcium-sensing receptor (CaR). This malfunction presumably arises from a post-transcriptional event, since CaR mRNA proved to be normal in AT cells. Together, our data suggest that ATM may mediate cell response to mitogenic factors by tightly regulating the set point of the CaR and thereby modulating the crosstalk between this metabotropic receptor and growth factor receptors. Alternatively, the faulty sensing of extracellular calcium in AT cells may be secondary to a state of chronic oxidative stress attributable to ATM deficiency.
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Acknowledgements
We thank Dr S Pikula, (Nencki Institute of Experimental Biology, Warsaw, Poland) for his help with the calculations of free calcium concentrations. Excellent technical assistance of Mr Kevin Brown is gratefully acknowledged. This work was supported by King Faisal Specialist Hospital & Research Centre, RAC Research Project # 2010 005.
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Famulski, K., Al-Hijailan, R., Dobler, K. et al. Aberrant sensing of extracellular Ca2+ by cultured ataxia telangiectasia fibroblasts. Oncogene 22, 471–475 (2003). https://doi.org/10.1038/sj.onc.1206167
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DOI: https://doi.org/10.1038/sj.onc.1206167
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