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Blood, 15 May 2005, Vol. 105, No. 10, pp. 4070-4077. Prepublished online as a Blood First Edition Paper on February 3, 2005; DOI 10.1182/blood-2004-10-4075. This Article Full Text (PDF) All Versions of this Article: 2004-10-4075v1 105/10/4070    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 Sun, Y. Articles by Fadeel, B. Search for Related Content PubMed PubMed Citation Articles by Sun, Y. Articles by Fadeel, B. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 25, 2004 Accepted January 24, 2005 Plasma membrane sequestration of apoptotic protease-activating factor-1 in human B lymphoma cells: a novel mechanism of chemoresistance Yu Sun, Sten Orrenius, Shazib Pervaiz, and Bengt Fadeel* Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Physiology, National University of Singapore, Singapore, Singapore Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden Department of Physiology, National University of Singapore, Singapore, Singapore Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden * Corresponding author; email: bengt.fadeel{at}imm.ki.se. Burkitt's lymphoma (BL) is a highly aggressive B cell neoplasm harboring chromosomal rearrangements of the c-myc oncogene. BL cells frequently resist apoptosis induction by chemotherapeutic agents; however, the mechanism of unresponsiveness has not been elucidated. Here we show that cytochrome c fails to stimulate apoptosome formation and caspase activation in cytosolic extracts of human BL-derived cell lines, due to insufficient levels of apoptotic protease-activating factor-1 (Apaf-1). Enforced expression of Apaf-1 increased its concentration in the cytosolic compartment, restored cytochrome c-dependent caspase activation, and rendered the prototypic Raji BL cell line sensitive to etoposide- and staurosporine-induced apoptosis. Surprisingly, in non-transfected BL cells, the bulk of Apaf-1 was found to associate with discrete domains in the plasma membrane. Disruption of lipid raft domains and/or the actin cytoskeleton of Raji cells liberated Apaf-1 and restored sensitivity to cytochrome c-dependent apoptosis, indicating that constitutive Apaf-1 retained its ability to promote caspase activation. Moreover, disruption of lipid rafts sensitized BL cells to apoptosis induced by etoposide. Together, our findings suggest that ectopic (non-cytosolic) localization of Apaf-1 may constitute a novel mechanism of chemoresistance in B lymphoma. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Jitkaew, A. Trebinska, E. Grzybowska, G. Carlsson, A. Nordstrom, J. Lehtio, A.-S. Frojmark, N. Dahl, and B. Fadeel N{alpha}-Tosyl-L-phenylalanine Chloromethyl Ketone Induces Caspase-dependent Apoptosis in Transformed Human B Cell Lines with Transcriptional Down-regulation of Anti-apoptotic HS1-associated Protein X-1 J. Biol. Chem., October 9, 2009; 284(41): 27827 - 27837. 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