Calcineurin functions in Ca(2+)-activated cell death in mammalian cells.
Calcineurin is a calcium-dependent protein phosphatase that functions in T cell activation. We present evidence that calcineurin functions more generally in calcium-triggered apoptosis in mammalian cells deprived of growth factors. Specifically, expression of epitope-tagged calcineurin A induces rapid cell death upon calcium signaling in the absence of growth factors. We show that this apoptosis does not require new protein synthesis and therefore calcineurin must operate through existing substrates. Co-expression of the Bcl-2 protooncogene efficiently blocks calcineurin-induced cell death. Significantly, we demonstrate that a calcium-independent calcineurin mutant induces apoptosis in the absence of calcium, and that this apoptotic response is a direct consequence of calcineurin's phosphatase activity. These data suggest that calcineurin plays an important role in mediating the upstream events in calcium-activated cell death.
Shibasaki
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F
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
McKeon
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F
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019703:Calcineurin; D002118:Calcium / Q000502:physiology*; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line / Q000166:cytology / Q000201:enzymology; D006224:Cricetinae; D015870:Gene Expression / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D009154:Mutation; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000502:physiology; D013379:Substrate Specificity
D002148:Calmodulin-Binding Proteins; D006133:Growth Substances; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011505:Protein-Tyrosine Kinases; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; D002118:Calcium