Inhibition of lymphotoxin-β receptor-mediated cell death by survivin-ΔEx3

Ren In You, Mei Chieh Chen, Hsei Wei Wang, Yang Chieh Chou, Chi Hung Lin, Shie Liang Hsieh

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21 Citations (Scopus)

Abstract

TNFSF14/LIGHT is a member of the tumor necrosis factor superfamily that binds to lymphotoxin-β receptor (LTβR) 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 LTβR-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-ΔEx3 could inhibit LTβR-mediated caspase-3 activation. However, only survivin-ΔEx3 could protect cells from LTβR-mediated cell death. The differential protective effects of survivin-ΔEx3 and KSHV-K7 can be attributed to the fact that survivin-ΔEx3, but not KSHV-K7, is able to maintain mitochondrial membrane potential and inhibit second mitochondria-derived activator of caspase/DIABLO release. Moreover, survivin-ΔEx3 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 LTβR. Furthermore, survivin-ΔEx3 protects LTβR-mediated cell death in caspase-3-deficient MCF-7 cells. Thus, survivin-ΔEx3 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 LTβR-mediated cell death.

Original languageEnglish
Pages (from-to)3051-3061
Number of pages11
JournalCancer Research
Volume66
Issue number6
DOIs
Publication statusPublished - Mar 15 2006

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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