Correction of radioresistant DNA synthesis in ataxia telangiectasia fibroblasts by prostaglandin E2 treatment
| Autor: | Razmik Mirzayans, Malcolm C. Paterson |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
DNA Replication
Epidemiology Health Toxicology and Mutagenesis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Radiation Tolerance Dinoprostone Ataxia Telangiectasia Oxytocics Ca2+/calmodulin-dependent protein kinase medicine Humans Prostaglandin E2 Protein kinase A Cells Cultured Genetics (clinical) DNA synthesis Tumor Suppressor Proteins Fibroblasts medicine.disease Cell biology DNA-Binding Proteins Cell culture Immunology Ataxia-telangiectasia Ectopic expression Signal transduction Signal Transduction medicine.drug |
| Zdroj: | Environmental and Molecular Mutagenesis. 38:191-199 |
| ISSN: | 1098-2280 0893-6692 |
| Popis: | Cultured cells from patients inheriting the rare cancer-prone and radiotherapy-sensitive disorder ataxia telangiectasia (AT) exhibit defects in the activation of cell-cycle checkpoints after exposure to ionizing radiation. In particular, the failure of AT cells to arrest transiently the DNA de novo replication machinery immediately after irradiation—so-called radioresistant DNA synthesis (RDS)—is often taken as a molecular hallmark of the disease. Recently we reported that: (i) the radiation-responsive S-phase checkpoint operating in normal human cells is mediated by a signal transduction pathway involving Ca2+/calmodulin-dependent protein kinase II (CaMKII); and (ii) the RDS phenotype of AT cells is associated with failure to mobilize Ca2+ from intracellular stores, which is required for activation of the CaMKII-dependent S-phase arrest. In the present study, we demonstrate that the RDS phenotype of AT dermal fibroblasts can be rectified in the absence of ectopic expression of functional ATM, the 350-kDa protein kinase encoded by the gene mutated in AT. Correction of RDS was observed when AT fibroblasts were coincubated with normal fibroblasts under conditions in which the 2 different cell cultures shared the same medium but were completely separated physically. The RDS trait was also rectified when AT fibroblasts were briefly incubated with prostaglandin E2 in the absence of normal feeder cells, signifying that this ubiquitous eicosanoid can serve as the diffusible “RDS-correction factor” for AT cells in the aforementioned cocultivation studies. It would therefore appear that prostaglandin E2 can assume the role of an extracellular signaling modulator of the S-phase checkpoint in AT cells exposed to ionizing radiation, inducing DNA synthesis shutdown via an alternative, ATM-independent signal transduction pathway. Environ. Mol. Mutagen. 38:191–199, 2001 © 2001 Wiley-Liss, Inc. |
| Databáze: | OpenAIRE |
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