The inhibitor of death receptor signaling, FLICE-inhibitory protein defines a new class of tumor progression factors

被引:343
作者
Djerbi, M
Screpanti, V
Catrina, AI
Bogen, B
Biberfeld, P
Grandien, A [1 ]
机构
[1] Univ Stockholm, Wenner Gren Inst, Dept Immunol, S-10691 Stockholm, Sweden
[2] Karolinska Hosp & Inst, Immunopathol Lab, Inst Oncol Pathol, S-17177 Stockholm, Sweden
[3] Univ Oslo, Inst Immunol, N-0172 Oslo, Norway
关键词
apoptosis; Fas receptor; antiapoptotic proteins; herpesvirus; lymphoma;
D O I
10.1084/jem.190.7.1025
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Death receptor-mediated apoptosis can be modulated by several antiapoptotic proteins, such as the FLICE (FADD [Fas-associated death domain]-like IL-1 beta-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.
引用
收藏
页码:1025 / 1031
页数:7
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