title: Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand (TRAIL) in human melanoma cells.
abstract: Induction of apoptosis in cells by TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is believed to be regulated by expression of two death-inducing and two inhibitory (decoy) receptors on the cell surface. In previous studies we found no correlation between expression of decoy receptors and susceptibility of human melanoma cells to TRAIL-induced apoptosis. In view of this, we studied the localization of the receptors in melanoma cells by confocal microscopy to better understand their function. We show that the death receptors TRAIL-R1 and R2 are located in the trans-Golgi network, whereas the inhibitory receptors TRAIL-R3 and -R4 are located in the nucleus. After exposure to TRAIL, TRAIL-R1 and -R2 are internalized into endosomes, whereas TRAIL-R3 and -R4 undergo relocation from the nucleus to the cytoplasm and cell membranes. This movement of decoy receptors was dependent on signals from TRAIL-R1 and -R2, as shown by blocking experiments with Abs to TRAIL-R1 and -R2. The location of TRAIL-R1, -R3, and -R4 in melanoma cells transfected with cDNA for these receptors was similar to that in nontransfected cells. Transfection of TRAIL-R3 and -R4 increased resistance of the melanoma lines to TRAIL-induced apoptosis even in melanoma lines that naturally expressed these receptors. These results indicate that abnormalities in "decoy" receptor location or function may contribute to sensitivity of melanoma to TRAIL-induced apoptosis and suggest that further studies are needed on the functional significance of their nuclear location and TRAIL-induced movement within cells.
authors.affiliation: Department of Oncology and Immunology, John Hunter Hospital, Newcastle, Australia.
authors.forename: X D
authors.initials: XD
authors.lastname: Zhang
authors.forename: A V
authors.initials: AV
authors.lastname: Franco
authors.forename: T
authors.initials: T
authors.lastname: Nguyen
authors.forename: C P
authors.initials: CP
authors.lastname: Gray
authors.forename: P
authors.initials: P
authors.lastname: Hersey
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D020126:Brefeldin A / Q000494:pharmacology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D058851:GPI-Linked Proteins; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D008024:Ligands; D008545:Melanoma / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D015398:Signal Transduction / Q000276:immunology; D013347:Subcellular Fractions / Q000276:immunology / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014162:Transfection; D014407:Tumor Cells, Cultured; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D051017:Apoptosis Regulatory Proteins; D015853:Cysteine Proteinase Inhibitors; D018076:DNA, Complementary; D058851:GPI-Linked Proteins; D007976:Leupeptins; D008024:Ligands; D008562:Membrane Glycoproteins; D011500:Protein Synthesis Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053320:Receptors, Tumor Necrosis Factor, Member 10c; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C108661:TNFRSF10C protein, human; C505653:TNFSF10 protein, human; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C063261:acetylleucyl-leucyl-norleucinal; D020126:Brefeldin A