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Inhibition of Lymphotoxin-ß Receptor–Mediated Cell Death by Survivin-Ex3

¹ Institute and Department of Microbiology and Immunology, National Yang-Ming University; ² Department of Microbiology and Immunology, Taipei Medical University; ³ Immunology Research Center, Taipei Veterans General Hospital; ⁴ Genomics Research Center, Academia Sinica, Taipei, Taiwan

Requests for reprints: Shie-Liang Hsieh, Institute of Microbiology and Immunology, National Yang-Ming University, Shih-Pai, Taipei 11221, Taiwan. Phone: 886-2-28267161; Fax: 886-2-28212880; E-mail: slhsieh{at}ym.edu.tw.

TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-ß receptor (LTßR) to induce cell death via caspase-dependent and caspase-independent pathways. It has been shown that cellular inhibitor of apoptosis protein-1 inhibits cell death by binding to LTßR-TRAF2/TRAF3 complexes and caspases. In this study, we found that both Kaposi's sarcoma–associated herpesvirus K7 (KSHV-K7), a viral inhibitor of apoptosis protein, and the structurally related protein survivin-Ex3 could inhibit LTßR-mediated caspase-3 activation. However, only survivin-Ex3 could protect cells from LTßR-mediated cell death. The differential protective effects of survivin-Ex3 and KSHV-K7 can be attributed to the fact that survivin-Ex3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-Ex3 is able to inhibit production of reactive oxygen species and can translocate from nucleus to cytosol to associate with apoptosis signal-regulating kinase 1 after activation of LTßR. Furthermore, survivin-Ex3 protects LTßR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-Ex3 is able to regulate both caspase-dependent and caspase-independent pathways, whereas inhibition of caspase-independent pathway is both sufficient and necessary for its protective effect on LTßR-mediated cell death. (Cancer Res 2006; 66(6): 3051-61)

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