Extracellular Ca2+ - related signaling and gene expression in ataxia telangiectasia cells.

M Pienkowska, PhD, K Brown, RH Bakheet, BSc, RS Al-Hijailan, MSc, F Al-Mohanna, PhD, MC Paterson PhD, and KS Famulski, PhD, DSc.

Dept of Biological and Medical Research, King Faisal Specialist and Research Centre, Riyadh, Saudi Arabia,

AIMS: Ataxia-telangiectasia (A-T) is a hereditary chromosomal instability syndrome. The pleiotropic manifestation of symptoms suggests that the gene product underlying A-T, an ATM kinase, is involved in multiple signaling pathways. We had previously demonstrated that A-T fibroblasts mobilize the intracellular Ca2+ [Ca2+]i in response to ionizing radiation or growth factors insufficiently, probably due to aberrant sensing of the extracellular Ca2+ [Ca2+]o. To extend our findings we aimed to characterize the activity of the [Ca2+]o receptor and Ca2+ - related gene expression in A-T cells. Methods: [Ca2+]i was monitored using Fura-2 AM and OpenLab, a dual excitation imaging system (ImproVision, Coventry, UK). Phosphorylation of kinases ERK1/2 was detected with an anti-phospho antibody (Cell Signaling Technology, Beverly, MA). Gene expression was evaluated with the aid of Atlastm Human Arrays, Clontech, Palo Alto, CA. Results and conclusions: We found that low concentrations of [Ca2+]o activated [Ca2+]i mobilization and ERK kinases in A-T fibroblasts. Moreover, spermine, a well known [Ca2+]o receptor (CaR) agonist, evoked a Ca2+ transient that differed from the one induced in normal cells. The expression of CaR message, however, was identical in normal and A-T fibroblasts. Thus, it can be proposed that the ATM kinase serves to control signaling from CaR to cognate response pathways. Lack of this proper control in A-T cells results in an altered expression of at least 30 genes, the products of which are involved in signal transduction, cytoskeleton formation and protein and energy metabolism.

KEY WORDS: Ataxia telangiectasia, extracellular Ca^(2+), intracellular Ca^(2+), extracellular calcium receptor, gene expression.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Chromosomal Aberrations.