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| Status |
Public on Aug 31, 2007 |
| Title |
Death receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Apo2L/TRAIL stimulates cancer-cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyl transferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small cell lung carcinoma and melanoma cell lines (P < 0.00009; n=83), and up to 30% of samples from various human malignancies displayed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-GalNAc-Gal-Sialic acid structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptosis signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a novel link between death receptor O-glycosylation and apoptosis signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.
Keywords: cell type comparison
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| Overall design |
Gene expression for untreated cell lines analyzed. Some cell lines have one replicate profile, some two (Samples with 2 CEL files). Normalized data for replicates was averaged. Analysis involved a regularized t-test to identify genes with expression differences between Apo2L sensitive and resistant lines.
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| Contributor(s) |
Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, Lee D, Goetz MV, Yee SF, Totpal K, Huw L, Katta V, Cavet G, Hymowitz SG, Amler L, Ashkenazi A |
| Citation(s) |
17767167 |
| Submission date |
Jun 29, 2007 |
| Last update date |
Mar 25, 2019 |
| Contact name |
Guy Cavet |
| Organization name |
Genentech, Inc.
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| Street address |
1 DNA Way MS93
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| City |
South San Francisco |
| State/province |
CA |
| ZIP/Postal code |
94080 |
| Country |
USA |
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| Platforms (1) |
| GPL570 |
[HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array |
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| Samples (119)
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| Relations |
| BioProject |
PRJNA101327 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE8332_RAW.tar |
919.2 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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