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A novel receptor for Apo2L/TRAIL contains a truncated death domain
S A Marsters1, J P Sheridan, R M Pitti
1Department of Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080-4918, USA.
Abstract:
Apo2 ligand (Apo2L [1], also called TRAIL for tumor necrosis factor (TNF)-related apoptosis-inducing ligand [2]) belongs to the TNF family and activates apoptosis in tumor cells. Three closely related receptors bind Apo2L: DR4 and DR5, which contain cytoplasmic death domains and signal apoptosis, and DcR1, a decoy receptor that lacks a cytoplasmic tail and inhibits Apo2L function [3-5]. By cross-hybridization with DcR1, we have identified a fourth Apo2L receptor, which contains a cytoplasmic region with a truncated death domain. We subsequently named this protein decoy receptor 2 (DcR2). The DcR2 gene mapped to human chromosome 8p21, as did the genes encoding DR4, DR5 and DcR1. A single DcR2 mRNA transcript showed a unique expression pattern in human tissues and was particularly abundant in fetal liver and adult testis. Upon overexpression, DcR2 did not activate apoptosis or nuclear factor-kappaB; however, it substantially reduced cellular sensitivity to Apo2L-induced apoptosis. These results suggest that DcR2 functions as an inhibitory Apo2L receptor.
Insights
Researchers identified decoy receptor 2 (DcR2), a new Apo2L receptor. This receptor inhibits Apo2L-induced apoptosis, suggesting a role in regulating cell death pathways.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Apo2 ligand (Apo2L), also known as tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), is a member of the TNF family.
- Apo2L induces apoptosis in tumor cells through specific receptors.
- Known receptors include DR4, DR5 (apoptosis-signaling receptors), and DcR1 (a decoy receptor inhibiting Apo2L function).
Purpose of the Study:
- To identify and characterize novel Apo2L receptors.
- To investigate the function and expression pattern of the newly identified receptor, DcR2.
- To determine if DcR2 plays a role in regulating Apo2L-mediated apoptosis.
Main Methods:
- Cross-hybridization with DcR1 to identify new receptors.
- Gene mapping of DcR2 to human chromosome 8p21.
- Analysis of DcR2 mRNA expression patterns in human tissues.
- Overexpression studies to assess DcR2's effect on apoptosis and NF-kappaB activation.
Main Results:
- A fourth Apo2L receptor, named decoy receptor 2 (DcR2), was identified.
- The DcR2 gene is located on human chromosome 8p21, along with DR4, DR5, and DcR1.
- DcR2 exhibits a unique mRNA expression pattern, abundant in fetal liver and adult testis.
- Overexpression of DcR2 did not induce apoptosis or NF-kappaB but significantly reduced sensitivity to Apo2L-induced apoptosis.
Conclusions:
- DcR2 functions as an inhibitory Apo2L receptor.
- The identification of DcR2 expands the understanding of Apo2L receptor interactions.
- DcR2 may play a critical role in modulating apoptosis in specific tissues like the testis.