Defective regulation of Ca2+/calmodulin-dependent protein kinase II in gamma-irradiated ataxia telangiectasia fibroblasts.
Recent indirect evidence suggests that a Ca2+/ calmodulin-dependent pathway, which may involve calmodulin-dependent protein kinase II (CaMKII), mediates the S-phase delay manifested by gamma-ray-exposed human fibroblasts. This pathway is severely impaired in ataxia telangiectasia (A-T) cells [Mirzayans et al. (1995) Oncogene 11, 15971. To extend these findings, we assayed CaMKII activity in irradiated normal and A-T fibroblasts. The radiation treatment induced the autonomous activity of the kinase in normal cells. In contrast, this activity was not elevated in either (i) normal cells pretreated with the selective CaMKII antagonist KN-62 or (ii) gamma-irradiated A-T cells. Moreover, A-T fibroblasts, unlike normal cells, failed to mobilize intracellular Ca2+ upon mitogenic stimulation. These findings identify a novel role for CaMKII in radiation-induced signal transduction and suggest its involvement in effecting the S-phase delay. The data also implicate ATM, the product of the gene responsible for A-T, as a key mediator of both intracellular Ca2+ mobilization and CaMKII activation in response not only to genotoxic stress but also to physiological stimuli.
Department of Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. konrad@kfshrc.edu.sa
K S
KS
Famulski
M C
MC
Paterson
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D001260:Ataxia Telangiectasia / Q000201:enzymology*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D002478:Cells, Cultured; D004790:Enzyme Induction / Q000528:radiation effects; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005720:Gamma Rays; D006801:Humans; D008934:Mitogens / Q000494:pharmacology
D008934:Mitogens; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases