Abstract
Upon binding of tumour necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), the agonistic TRAIL receptors DR4 and DR5 activate caspase-8 leading to apoptosis. In primitive neuroectodermal brain tumour (PNET) cell lines, TRAIL-induced apoptosis was recently shown to correlate with caspase-8 mRNA expression (Grotzer MA, Eggert A, Zuzak TJ, et al. Oncogene 2000, 19, 4604-4610). In this study, we analysed the expression of the TRAIL death pathway in 27 primary PNET/medulloblastoma. As shown by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR), all PNET/medulloblastoma evaluated expressed DR5, the adapter protein FADD and caspase-3, but only 48% expressed caspase-8. The mRNA expression of caspase-8 was significantly lower in primary PNET/medulloblastoma compared with normal brain samples. PCR revealed >75% methylation of the caspase-8 promoter region in three of seven PNET cell lines and in 55% of the primary PNET/medulloblastoma evaluated. In the PNET cell lines, the methylation status correlated with the caspase-8 mRNA expression. We conclude that loss of caspase-8 gene expression is common in PNET/medulloblastoma suggesting that suppression of death receptor induced apoptosis may play an important role in the pathogenesis of this common childhood brain tumour.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adolescent
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Apoptosis Regulatory Proteins
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Brain Neoplasms / enzymology*
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / metabolism
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases / metabolism*
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Child
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Child, Preschool
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DNA Methylation
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Fas-Associated Death Domain Protein
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Female
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Humans
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Intracellular Signaling Peptides and Proteins*
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Male
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Medulloblastoma / enzymology
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Membrane Glycoproteins / metabolism
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Neoplasm Proteins / metabolism*
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Neuroectodermal Tumors, Primitive / metabolism*
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RNA, Messenger / metabolism
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RNA, Neoplasm
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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FADD protein, human
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Fas-Associated Death Domain Protein
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Intracellular Signaling Peptides and Proteins
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Membrane Glycoproteins
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Neoplasm Proteins
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RNA, Messenger
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RNA, Neoplasm
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor
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TNF-Related Apoptosis-Inducing Ligand
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TNFRSF10B protein, human
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha
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CASP3 protein, human
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CASP8 protein, human
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CASP9 protein, human
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Caspase 3
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Caspase 8
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Caspase 9
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Caspases