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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-06-1779. This Article Full Text (PDF) All Versions of this Article: 2002-06-1779v1 101/2/585    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Marchetti, M. C. Articles by Riccardi, C. Search for Related Content PubMed PubMed Citation Articles by Marchetti, M. C. Articles by Riccardi, C. Social Bookmarking                   What's this? Submitted June 26, 2002 Accepted August 14, 2002 Dexamethasone-induced apoptosis of thymocytes: role of glucocorticoid receptor-associated Src kinase and caspase-8 activation Maria Cristina Marchetti, Barbara Di Marco, Grazia Cifone, Graziella Migliorati, and Carlo Riccardi* Department Clinical and Experimental Medicine, Section of Pharmacology, University of Perugia, Perugia, Italy Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy * Corresponding author; email: riccardi{at}unipg.it. Glucocorticoid hormones (GCH) regulate normal and neoplastic lymphocyte development by exerting anti-proliferation and/or apoptotic effects. We have previously shown that dexamethasone (DEX)-activated thymocyte apoptosis requires a sequence of events including interaction with the glucocorticoid receptor (GR), phosphatidylinositol-specific phospholipase C (PI-PLC) and acidic sphingomyelinase (aSMase) activation. We analysed the mechanisms of GCH-activated apoptosis by focusing on: 1) GR-associated Src kinase, 2) cytochrome c release, 3) caspase-8, -9 and -3 activation. We show here that PI-PLC binds to GR-associated Src kinase, as indicated by co-immunoprecipitation experiments. Moreover, DEX treatment induces PI-PLC phosphorylation and activation. DEX-induced PI-PLC phosphorylation, activation and apoptosis are inhibited by PP1, a Src kinase inhibitor, thus suggesting that Src-mediated PI-PLC activation is involved in DEX-induced apoptosis. Caspase-9, -8, -3 activation and cytochrome c release can be detected 1-2 hours after DEX treatment. Caspase-9 inhibition does not counter cytochrome c release, caspase-8 and caspase-3 activation and apoptosis. Caspase-8 inhibition counters cytochrome c release, caspase-9 and caspase-3 activation and apoptosis, thus suggesting that caspase-8 inhibitor can directly inhibit caspase-9 and/or that DEX-induced caspase-8 activation is up-stream to mitochondria and can regulate caspase-3 directly or via cytochrome c release and the consequent caspase-9/caspase-3 activation. DEX-induced caspase-8 activation, like the ceramide-induced, correlates with the formation of FADD/caspase-8 complex. Caspase-8 activation is countered by inhibition of macromolecular synthesis and of Src kinase, PI-PLC and aSMase activation, suggesting it is downstream in the DEX-activated apoptotic pathway of thymocytes. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: P. Obexer, J. Hagenbuchner, M. Rupp, C. Salvador, M. Holzner, M. Deutsch, V. Porto, R. Kofler, T. Unterkircher, and M. J. 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