S100 beta induces apoptotic cell death in cultured astrocytes via a nitric oxide-dependent pathway.
S100 beta is a calcium binding protein expressed primarily by astrocytes in the brain. In initiating studies of the toxic signalling pathways activated by high concentrations of S100 beta, we previously demonstrated that treatment of astrocytes with microM S100 beta results in a potent stimulation of the mRNA level and enzyme activity of inducible nitric oxide (NO) synthase, an enzyme previously implicated in glial pathology. We provide evidence here that NO formation stimulated by S100 beta can lead to cell death in astrocytes, with characteristics defined for apoptosis. Incubation of astrocytes with S100 beta for 48 h results in an increased percentage of astrocytes undergoing apoptotic cell death, as determined with the TUNEL technique, assays of DNA fragmentation and lactate dehydrogenase release. The cell death induced in responses to S100 beta addition correlates with the levels of NO formation, and an inhibitor of nitric oxide synthase attenuates the NO formation elicited by S100 beta, as well as the cell death. Therefore, we propose that S100 beta has the potential to be trophic or toxic. Although S100 beta may be involved in development, homeostasis and repair, chronic overexpression of the protein may mediate toxic responses or even cell death.
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611, USA.
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Hu
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Van Eldik
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001253:Astrocytes / Q000166:cytology* / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins
D002135:Calcium-Binding Proteins; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D009414:Nerve Growth Factors; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D010396:Penicillamine; D019331:NG-Nitroarginine Methyl Ester