Thapsigargin-induced apoptosis involves Cabin1-MEF2-mediated induction of Nur77.
Thapsigargin (TG), which inhibits endoplasmic reticulum-dependent Ca(2 +)-ATPase and thereby increases cytosolic Ca(2 +), has been reported to cause apoptosis in T lymphocytes another cell types. In this study, we investigated the molecular mechanisms that are involved in the apoptosis induced by TG in T cell hybridomas. Exposure to TG results in rapid induction of the orphan steroid receptor, Nur77, accompanied by apoptosis of T cell hybridomas. The expression of Nur77 in response to TG treatment is sensitive to cyclosporin A, implicating that activation of calcineurin is necessary for Nur77 expression. The TG-induced Nur77 expression is also inhibited by overexpression of Cabin1, an endogenous inhibitor of calcineurin and a corepressor of the transcription factor MEF2, suggesting that MEF2 activation is required for Nur77 expression. These results suggest that induction of Nur77 expression and apoptosis by TG are mediated by the same signaling pathways that are involved in T cell receptor-mediated thymocyte apoptosis, including the calcineurin pathway and Cabin1-MEF2 pathway.
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Center for Cancer Research, Departments of Biology and Chemistry, Massachusetts Institute of Technology, Cambridge 02139, USA.
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D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis; D019703:Calcineurin / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D015398:Signal Transduction; D019284:Thapsigargin / Q000378:metabolism / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C491861:CABIN1 protein, human; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D019284:Thapsigargin; D019703:Calcineurin; D000252:Calcium-Transporting ATPases