{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:55:18Z","timestamp":1792086918162,"version":"4.4.0"},"reference-count":63,"publisher":"Rockefeller University Press","issue":"8","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,4,19]]},"abstract":"<jats:p>Resistance to death receptor\u2013mediated apoptosis is supposed to be important for the deregulated growth of B cell lymphoma. Hodgkin\/Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin's lymphoma (cHL), resist CD95-induced apoptosis. Therefore, we analyzed death receptor signaling, in particular the CD95 pathway, in these cells. High level CD95 expression allowed a rapid formation of the death-inducing signaling complex (DISC) containing Fas-associated death domain\u2013containing protein (FADD), caspase-8, caspase-10, and most importantly, cellular FADD-like interleukin 1\u03b2\u2013converting enzyme-inhibitory protein (c-FLIP). The immunohistochemical analysis of the DISC members revealed a strong expression of CD95 and c-FLIP overexpression in 55 out of 59 cases of cHL. FADD overexpression was detectable in several cases. Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane. Elevated c-FLIP expression in HRS cells depends on nuclear factor (NF)-\u03baB. Despite expression of other NF-\u03baB\u2013dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor\u2013related apoptosis-inducing ligand\u2013induced apoptosis. Therefore, c-FLIP is a key regulator of death receptor resistance in HRS cells.<\/jats:p>","DOI":"10.1084\/jem.20031080","type":"journal-article","created":{"date-parts":[[2004,4,12]],"date-time":"2004-04-12T20:54:12Z","timestamp":1081803252000},"page":"1041-1052","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":175,"title":["c-FLIP Mediates Resistance of Hodgkin\/Reed-Sternberg Cells to Death Receptor\u2013induced Apoptosis"],"prefix":"10.1084","volume":"199","author":[{"given":"Stephan","family":"Mathas","sequence":"first","affiliation":[{"name":"1Max-Delbru\u0308ck-Center for Molecular Medicine, 13125 Berlin, Germany"},{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Lietz","sequence":"additional","affiliation":[{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis","family":"Anagnostopoulos","sequence":"additional","affiliation":[{"name":"3Universita\u0308tsklinikum Benjamin Franklin, Institute for Pathology, Free University, 12200 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Hummel","sequence":"additional","affiliation":[{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkhard","family":"Wiesner","sequence":"additional","affiliation":[{"name":"4Institute of Molecular Pharmacology, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Janz","sequence":"additional","affiliation":[{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franziska","family":"Jundt","sequence":"additional","affiliation":[{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkhard","family":"Hirsch","sequence":"additional","affiliation":[{"name":"3Universita\u0308tsklinikum Benjamin Franklin, Institute for Pathology, Free University, 12200 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Korinna","family":"Jo\u0308hrens-Leder","sequence":"additional","affiliation":[{"name":"3Universita\u0308tsklinikum Benjamin Franklin, Institute for Pathology, Free University, 12200 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Peter","family":"Vornlocher","sequence":"additional","affiliation":[{"name":"5Ribopharma AG, 95326 Kulmbach, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Bommert","sequence":"additional","affiliation":[{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"Stein","sequence":"additional","affiliation":[{"name":"3Universita\u0308tsklinikum Benjamin Franklin, Institute for Pathology, Free University, 12200 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernd","family":"Do\u0308rken","sequence":"additional","affiliation":[{"name":"1Max-Delbru\u0308ck-Center for Molecular Medicine, 13125 Berlin, Germany"},{"name":"2Humboldt-University, Charite\u0301, Robert-Ro\u0308ssle-Klinik, 13125 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2004,4,12]]},"reference":[{"key":"2023072512284665900_BIB1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S0092-8674(01)00237-9","volume":"104","year":"2001","journal-title":"Cell."},{"key":"2023072512284665900_BIB2","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/sj.cdd.4401186","volume":"10","year":"2003","journal-title":"Cell Death Differ."},{"key":"2023072512284665900_BIB3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S1074-7613(02)00502-2","volume":"18","year":"2003","journal-title":"Immunity."},{"key":"2023072512284665900_BIB4","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/40657","volume":"388","year":"1997","journal-title":"Nature."},{"key":"2023072512284665900_BIB5","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/35095508","volume":"1","year":"2001","journal-title":"Nat. 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