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Prepublished online as a Blood First Edition Paper on June 7, 2002; DOI 10.1182/blood-2002-03-0686. This Article Full Text (PDF) All Versions of this Article: 2002-03-0686v1 100/4/1310    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 de Botton, S. Articles by Debili, N. Search for Related Content PubMed PubMed Citation Articles by de Botton, S. Articles by Debili, N. Social Bookmarking                   What's this? Submitted March 5, 2002 Accepted April 9, 2002 Platelet formation is the consequence of caspase activation within megakaryocytes Stephane de Botton, Siham Sabri, Eric Daugas, Yael Zermati, Jacques E Guidotti, Olivier Hermine, Guido Kroemer, William Vainchenker, and Najet Debili* INSERM Unite 362, Institut Gustave Roussy, Villejuif, France; Service des maladies du sang, Hopital Claude Huriez, Lille, France INSERM Unite 362, Institut Gustave Roussy, Villejuif, France CNRS UMR 1599, Institut Gustave Roussy, Villejuif, France CNRS UMR 8603, Universte Rene Descartes, Necker, Paris, France INSERM Unite 129, Institut Cochin de Genetique Moleculaire, Paris, France * Corresponding author; email: denali{at}igr.fr. Platelets are formed from mature megakaryocytes (MKs) and arise from the development of long and thin cytoplasmic extension called proplatelets. After platelet release, the senescent MKs (nucleus surrounded by some cytoplasm) undergo cell death by apoptosis. To explore the precise role of apoptosis in proplatelet formation, we grew human MKs from CD34+ cells and assessed the possible role of caspases. Proteolytic maturation of procaspase-3 and procaspase-9 was detected by immunoblots in maturing MKs as well as in proplatelet bearing megakaryocytes and senescent MKs. Cleavage of caspase substrates such as gelsolin or PARP was also detected. Interestingly, activated forms of caspase-3 were detected in maturing megakaryocytes, before proplatelet formation, with a punctuate cytoplasmic distribution, whereas a diffuse staining pattern was seen in senescent and apoptotic MKs. This localized activation of caspase-3 was associated with a mitochondrial membrane permeabilization as assessed by the release of cytochrome c, suggesting an activation of the intrinsic pathway. Moreover, these MKs with localized activated caspase-3 had no detectable DNA fragmentation. In contrast, when apoptosis was induced by staurosporine, diffuse caspase activation was seen, these MKs had signs of DNA fragmentation and no proplatelet formation occurred. The pan-caspase inhibitor z-VAD.fmk as well as more specific inhibitors of caspase-3 and 9 blocked proplatelet formation whereas an inhibitor of calpeptin had no effect. Overexpression of Bcl-2 also inhibited proplatelet formation in maturing megakaryocytes. Thus, localized caspase activation is causal to proplatelet formation. We conclude that proplatelet formation is regulated by a caspase activation limited only to some cellular compartments. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. J. Kuter, G. J. Mufti, B. J. Bain, R. P. Hasserjian, W. Davis, and M. 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