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TGF\u03b2 induced caspase-8 activation in these cells as shown by the cleavage of specific substrates, including Bid, and the appearance of cleaved fragments of caspase-8. Our data show that TGF\u03b2 induces an apoptotic pathway involving sequential caspase-8 activation, loss of mitochondrial membrane potential, and caspase-9 and -3 activation. Caspase-8 activation was Fas-associated death domain protein (FADD)-independent because cells expressing a dominant negative mutant of FADD were still sensitive to TGF\u03b2-induced caspase-8 activation and apoptosis. This FADD-independent pathway of caspase-8 activation is regulated by p38. Indeed, TGF\u03b2-induced activation of p38 and two different inhibitors specific for this mitogen-activated protein kinase pathway (SB203580 and PD169316) prevented TGF\u03b2-mediated caspase-8 activation as well as the loss of mitochondrial membrane potential and apoptosis. Overall, our data show that p38 activation by TGF\u03b2 induced an apoptotic pathway via FADD-independent activation of caspase-8.<\/jats:p>","DOI":"10.1091\/mbc.12.10.3139","type":"journal-article","created":{"date-parts":[[2013,7,3]],"date-time":"2013-07-03T00:03:26Z","timestamp":1372809806000},"page":"3139-3151","source":"Crossref","is-referenced-by-count":76,"title":["p38-mediated Regulation of an Fas-associated Death Domain Protein-independent Pathway Leading to Caspase-8 Activation during TGF\u03b2-induced Apoptosis in Human Burkitt Lymphoma B Cells BL41"],"prefix":"10.1091","volume":"12","author":[{"given":"Nicolas","family":"Schrantz","sequence":"first","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U542 and Claude Bernard Research Center, Hopital Paul Brousse, 94807 Villejuif, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Fran\u00e7oise","family":"Bourgeade","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U542 and Claude Bernard Research Center, Hopital Paul Brousse, 94807 Villejuif, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahul","family":"Mouhamad","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U542 and Claude Bernard Research Center, Hopital Paul Brousse, 94807 Villejuif, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00e9rald","family":"Leca","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U542 and Claude Bernard Research Center, Hopital Paul Brousse, 94807 Villejuif, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surendra","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Women and Infant's Hospital, Brown University, Providence, Rhode Island 02905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aim\u00e9","family":"Vazquez","sequence":"additional","affiliation":[{"name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U542 and Claude Bernard Research Center, Hopital Paul Brousse, 94807 Villejuif, France; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1076","reference":[{"key":"B1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1002\/(SICI)1097-4644(199701)64:1<33::AID-JCB6>3.0.CO;2-0","volume":"64","author":"Alnemri E.S.","year":"1997","journal-title":"J. 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