Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma

Clifford G Tepper, Michael F Seldin

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Abstract

Ligation of the Fas receptor induces death-inducing signaling complex (DISC) formation, caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/APO-1-associated death domain protein (FADD), and caspase-8 (FLICE/MACH/Mch5). The apoptotic pathway distal to the DISC is intact because ceramide analogs, staurosporine, and granzyme B activate caspase-3 and induce apoptosis. Fas resistance was not explained by the putative death-attenuating caspase-8 isoforms. However, while Fas-activated cytosolic extracts from sensitive cells were capable of processing both procaspase-8 and procaspase-3 into active subunit forms, resistant cell extracts did not possess either of these activities. Accordingly, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed higher transcript levels for the FLICE-inhibitory protein (FLIP(L)) in resistant cells and the ratio of caspase-8 to FLIP(L) measured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines. In addition, modification of the caspase-8/FLIP(L) ratio by caspase-8 or FLIP(L) overexpression was able to alter the susceptibility status of the cell lines tested. Our results imply that the relative levels of caspase-8 and FLIP(L) are an important determinant of susceptibility to Fas-mediated apoptosis.

Original languageEnglish (US)
Pages (from-to)1727-1737
Number of pages11
JournalBlood
Volume94
Issue number5
StatePublished - Sep 1 1999

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CASP8 and FADD-Like Apoptosis Regulating Protein
Burkitt Lymphoma
Caspase 8
Human Herpesvirus 4
Viruses
Carcinogenesis
Modulation
Death Domain Receptor Signaling Adaptor Proteins
Cells
Apoptosis
Polymerase chain reaction
RNA-Directed DNA Polymerase
Cell Extracts
Reverse Transcriptase Polymerase Chain Reaction
Cell Line
Caspase 3
CD95 Antigens
Granzymes
Staurosporine
Ceramides

ASJC Scopus subject areas

  • Hematology

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Modulation of caspase-8 and FLICE-inhibitory protein expression as a potential mechanism of Epstein-Barr virus tumorigenesis in Burkitt's lymphoma. / Tepper, Clifford G; Seldin, Michael F.

In: Blood, Vol. 94, No. 5, 01.09.1999, p. 1727-1737.

Research output: Contribution to journalArticle

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abstract = "Ligation of the Fas receptor induces death-inducing signaling complex (DISC) formation, caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/APO-1-associated death domain protein (FADD), and caspase-8 (FLICE/MACH/Mch5). The apoptotic pathway distal to the DISC is intact because ceramide analogs, staurosporine, and granzyme B activate caspase-3 and induce apoptosis. Fas resistance was not explained by the putative death-attenuating caspase-8 isoforms. However, while Fas-activated cytosolic extracts from sensitive cells were capable of processing both procaspase-8 and procaspase-3 into active subunit forms, resistant cell extracts did not possess either of these activities. Accordingly, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed higher transcript levels for the FLICE-inhibitory protein (FLIP(L)) in resistant cells and the ratio of caspase-8 to FLIP(L) measured by competition RT-PCR analysis directly correlated with susceptibility to Fas-mediated apoptosis of all cell lines. In addition, modification of the caspase-8/FLIP(L) ratio by caspase-8 or FLIP(L) overexpression was able to alter the susceptibility status of the cell lines tested. Our results imply that the relative levels of caspase-8 and FLIP(L) are an important determinant of susceptibility to Fas-mediated apoptosis.",
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