TY - JOUR
T1 - Inhibition of lymphotoxin-β receptor-mediated cell death by survivin-ΔEx3
AU - You, Ren In
AU - Chen, Mei Chieh
AU - Wang, Hsei Wei
AU - Chou, Yang Chieh
AU - Lin, Chi Hung
AU - Hsieh, Shie Liang
PY - 2006/3/15
Y1 - 2006/3/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-05-2479
DO - 10.1158/0008-5472.CAN-05-2479
M3 - Article
C2 - 16540654
AN - SCOPUS:33645531325
VL - 66
SP - 3051
EP - 3061
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -