Death receptor–mediated apoptosis can be modulated by several antiapoptotic proteins, such as the FLICE (FADD [Fas-associated death domain]-like IL-1β–converting enzyme)-inhibitory proteins (FLIPs). The FLIP family includes both cellular and viral members. The Kaposi's sarcoma–associated herpesvirus protein (KSHV)-FLIP is expressed by human herpesvirus 8 (HHV-8), which is associated with malignancies such as Kaposi's sarcoma and certain lymphomas. In this paper, we demonstrate that KSHV-FLIP protects cells from Fas-mediated apoptosis by inhibiting caspase activation and permits clonal growth in the presence of death stimuli in vitro. Furthermore, we show that KSHV-FLIP can act as a tumor progression factor by promoting tumor establishment and growth in vivo. When injected into immunocompetent recipient mouse strains, murine B lymphoma cells (A20) transduced with KSHV-FLIP rapidly develop into aggressive tumors showing a high rate of survival and growth. The tumor-progressive activity of KSHV-FLIP is mediated by prevention of death receptor–induced apoptosis triggered by conventional T cells. Consequently, inhibitors of death receptor signaling can be regarded as a new class of tumor progression factors, and HHV-8–associated tumors may represent naturally occurring examples of the tumorigenic effect of such inhibitors.
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4 October 1999
Article|
October 04 1999
The Inhibitor of Death Receptor Signaling, Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors
Mounira Djerbi,
Mounira Djerbi
aDepartment of Immunology, Wenner-Gren Institute, University of Stockholm, S-10691 Stockholm, Sweden
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Valentina Screpanti,
Valentina Screpanti
aDepartment of Immunology, Wenner-Gren Institute, University of Stockholm, S-10691 Stockholm, Sweden
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Anca Irinel Catrina,
Anca Irinel Catrina
bImmunopathology Laboratory, Institute for Oncology-Pathology, the Karolinska Institute and Hospital, S-17177 Stockholm, Sweden
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Bjarne Bogen,
Bjarne Bogen
cInstitute of Immunology, National Hospital, University of Oslo, N-0172 Oslo, Norway
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Peter Biberfeld,
Peter Biberfeld
bImmunopathology Laboratory, Institute for Oncology-Pathology, the Karolinska Institute and Hospital, S-17177 Stockholm, Sweden
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Alf Grandien
Alf Grandien
aDepartment of Immunology, Wenner-Gren Institute, University of Stockholm, S-10691 Stockholm, Sweden
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Mounira Djerbi
aDepartment of Immunology, Wenner-Gren Institute, University of Stockholm, S-10691 Stockholm, Sweden
Valentina Screpanti
aDepartment of Immunology, Wenner-Gren Institute, University of Stockholm, S-10691 Stockholm, Sweden
Anca Irinel Catrina
bImmunopathology Laboratory, Institute for Oncology-Pathology, the Karolinska Institute and Hospital, S-17177 Stockholm, Sweden
Bjarne Bogen
cInstitute of Immunology, National Hospital, University of Oslo, N-0172 Oslo, Norway
Peter Biberfeld
bImmunopathology Laboratory, Institute for Oncology-Pathology, the Karolinska Institute and Hospital, S-17177 Stockholm, Sweden
Alf Grandien
aDepartment of Immunology, Wenner-Gren Institute, University of Stockholm, S-10691 Stockholm, Sweden
1used in this paper: BCBL, body cavity–based B cell lymphoma; DED, death effector domain; FADD, Fas-associated death domain; FLICE, FADD-like IL-1β–converting enzyme; FLIP, FLICE-inhibitory protein; KSHV, Kaposi's sarcoma–associated herpesvirus; TUNEL, TdT-mediated dUTP–biotin nick-end labeling
M. Djerbi and V. Screpanti contributed equally to this work.
Received:
March 04 1999
Revision Requested:
June 11 1999
Accepted:
July 30 1999
Online ISSN: 1540-9538
Print ISSN: 0022-1007
© 1999 The Rockefeller University Press
1999
The Rockefeller University Press
J Exp Med (1999) 190 (7): 1025–1032.
Article history
Received:
March 04 1999
Revision Requested:
June 11 1999
Accepted:
July 30 1999
Citation
Mounira Djerbi, Valentina Screpanti, Anca Irinel Catrina, Bjarne Bogen, Peter Biberfeld, Alf Grandien; The Inhibitor of Death Receptor Signaling, Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors. J Exp Med 4 October 1999; 190 (7): 1025–1032. doi: https://doi.org/10.1084/jem.190.7.1025
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