Correction of radioresistant DNA synthesis in ataxia telangiectasia fibroblasts by prostaglandin E2 treatment.
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.
Mirzayans
R
R
Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada.
Paterson
M C
MC
D001260:Ataxia Telangiectasia / Q000188:drug therapy* / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects* / Q000528:radiation effects; D004268:DNA-Binding Proteins; D015232:Dinoprostone / Q000494:pharmacology* / Q000627:therapeutic use; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D010120:Oxytocics / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011836:Radiation Tolerance; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010120:Oxytocics; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D015232:Dinoprostone