title: Regulation of fas/fas ligand-mediated apoptosis by nuclear factor of activated T cells in megakaryocytes.
abstract: Signal transduction pathways in megakaryocytes, a rare population of bone marrow cells, are poorly understood. We have previously shown that the calcineurin-dependent transcription factor Nuclear Factor of Activated T cells (NFAT) is expressed in megakaryocytes and is required for the transcription of specific megakaryocytic genes. The biological role of NFAT in megakaryocytes, however, is unknown. Here we show that activation of the calcineurin/NFAT pathway in megakaryocytes forces the cells to go into apoptosis. Calcineurin/NFAT activation in megakaryocytes leads to membrane expression of Fas ligand (FASLG), a pro-apoptotic member of the tumour necrosis factor superfamily. Expression of FASLG was augmented in cells stably overexpressing NFATC2 and suppressed in cells either pretreated with the calcineurin inhibitor ciclosporin A (CsA) or expressing the specific peptide inhibitor of NFAT, VIVIT. In cocultures with Fas-expressing Jurkat T cells, the presence of activated megakaryocytic cells, but not of unstimulated cells or cells stimulated in the presence of CsA, significantly induced apoptosis in Jurkat cells in a Fas/FASLG- and NFAT-dependent manner. These results represent the first evidence for a biological function of the calcineurin/NFAT pathway in megakaryocytes, and suggest that the biological role of megakaryocytes may include the induction of apoptosis in bystander cells.
authors.affiliation: Department of Medicine I, Dresden University of Technology, Dresden, Germany.
authors.forename: Laleh S
authors.initials: LS
authors.lastname: Arabanian
authors.forename: Satu
authors.initials: S
authors.lastname: Kujawski
authors.forename: Ivonne
authors.initials: I
authors.lastname: Habermann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Ehninger
authors.forename: Alexander
authors.initials: A
authors.lastname: Kiani
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019703:Calcineurin / Q000378:metabolism; D061207:Calcium Ionophores / Q000494:pharmacology; D002460:Cell Line; D018920:Coculture Techniques; D053222:Fas Ligand Protein / Q000378:metabolism*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D061207:Calcium Ionophores; D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; D019014:fas Receptor; D015759:Ionomycin; D019703:Calcineurin