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An antagonist decoy receptor and a death domain-containing receptor for TRAIL
1Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Abstract:
TRAIL, also called Apo2L, is a cytotoxic protein that induces apoptosis of many transformed cell lines but not of normal tissues, even though its death domain-containing receptor, DR4, is expressed on both cell types. An antagonist decoy receptor (designated as TRID for TRAIL receptor without an intracellular domain) that may explain the resistant phenotype of normal tissues was identified. TRID is a distinct gene product with an extracellular TRAIL-binding domain and a transmembrane domain but no intracellular signaling domain. TRID transcripts were detected in many normal human tissues but not in most cancer cell lines examined. Ectopic expression of TRID protected mammalian cells from TRAIL-induced apoptosis, which is consistent with a protective role. Another death domain-containing receptor for TRAIL (designated as death receptor-5), which preferentially engaged a FLICE (caspase-8)-related death protease, was also identified.
Insights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis. A novel decoy receptor, TRAIL receptor without an intracellular domain (TRID), protects normal cells from TRAIL-induced apoptosis, explaining tissue resistance.
Area of Science:
- Molecular biology
- Cell biology
- Immunology
Background:
- Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) induces apoptosis in transformed cells but not normal tissues.
- Both normal and transformed cells express the TRAIL receptor, DR4, suggesting other mechanisms confer resistance in normal tissues.
Purpose of the Study:
- To identify the mechanism responsible for normal tissue resistance to TRAIL-induced apoptosis.
- To characterize a novel decoy receptor for TRAIL.
Main Methods:
- Identification and characterization of a novel TRAIL receptor.
- Analysis of TRID gene expression in normal human tissues and cancer cell lines.
- Functional studies involving ectopic expression of TRID in mammalian cells.
Main Results:
- A novel decoy receptor, TRAIL receptor without an intracellular domain (TRID), was identified.
- TRID lacks an intracellular signaling domain but binds TRAIL.
- TRID transcripts were found in normal tissues but not most cancer cell lines.
- Ectopic TRID expression conferred resistance to TRAIL-induced apoptosis.
Conclusions:
- TRID acts as an antagonist decoy receptor, explaining normal tissue resistance to TRAIL.
- TRID represents a potential therapeutic target for cancer treatment by blocking TRAIL-mediated apoptosis resistance.