Over-expression of Reticulon 3 (RTN3) enhances TRAIL-mediated apoptosis via up-regulation of death receptor 5 (DR5) and down-regulation of c-FLIP.
Reticulons (RTNs) are a group of integral membrane proteins that have no homology to other known apoptosis-related domains. Herein, we found that RTN3 overexpressing Caki cells were sensitive to TRAIL-mediated apoptosis. RTN3-induced down-regulation of c-FLIP was recovered by pan-caspase inhibitor, z-VAD to basal levels in TRAIL-treated cells. The forced expression of c-FLIP attenuated the TRAIL-mediated apoptosis in RTN3 over-expressing cells. In addition, RTN3 over-expression provoked the enhanced protein levels in DR4 and DR5 as well as levels in DR5 surface protein but slight increase in DR4 surface protein. RTN3-mediated enhancement of TRAIL-induced apoptosis was markedly blocked by the DR5/Fc chimera or DR5 siRNA, indicating that the sensitization by RTN3 was mainly mediated through interactions of TRAIL with its receptors, DR5. Over-expression of RTN3 also enhanced TNF-alpha and Fas-mediated apoptosis. Taken together, over-expression of RTN3 might increase DR5 surface protein and concomitantly more activate caspase pathways, which cause the c-FLIP cleavage and enhancement of TRAIL-mediated apoptosis.
Lee
Jung Tae
JT
Department of Immunology and Chronic Disease Research Center and Institute for Medical Science, School of Medicine, Keimyung University, 194 DongSan-Dong Jung-Gu, Taegu 700-712, South Korea.
Lee
Tae-Jin
TJ
Kim
Cheol-Hee
CH
Kim
Nam-Soon
NS
Kwon
Taeg Kyu
TK
D017209:Apoptosis / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*; D015854:Up-Regulation
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C476198:RTN3 protein, human; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human