Abstract
Neural stem/progenitor cells (NPCs) are present in the developing and adult central nervous system. NPC apoptosis is an important aspect of normal brain development. We show that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor 2 is highly expressed on human NPCs derived from fetal cortex, yet TRAIL induces only minimal levels of apoptosis in NPCs. Caspase-8 mRNA and protein, an important factor in the TRAIL-mediated death pathway, is present at low levels in human NPCs. In contrast, inhibitors of apoptosis proteins (IAP), such as c-IAP1, are highly expressed. The transcription inhibitor actinomycin D sensitized human NPCs to TRAIL-induced apoptosis. Further, inhibition of cellular inhibitors of apoptosis protein 1 (c-IAP1) expression by small interfering RNA (siRNA) increased TRAIL-mediated caspase-3 activation and apoptosis; thus, c-IAP1 protects NPCs against TRAIL-induced apoptosis and suppresses caspase-3 activation. These findings illustrate the mechanisms for NPC resistance to apoptotic agonists such as TRAIL, and demonstrate a potentially important mechanism in CNS disease states.
Copyright (c) 2005 Wiley-Liss, Inc.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Apoptosis / physiology*
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Apoptosis Regulatory Proteins / metabolism*
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Brain / embryology*
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Brain / growth & development
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Brain / metabolism
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Caspase 3
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Caspase 8
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Caspases / genetics
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Cells, Cultured
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Cerebral Cortex / embryology
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Cerebral Cortex / growth & development
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Cerebral Cortex / metabolism
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Dactinomycin / pharmacology
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Enzyme Activation / drug effects
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Enzyme Activation / genetics
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Fetus
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Humans
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Inhibitor of Apoptosis Proteins / metabolism*
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Membrane Glycoproteins / metabolism*
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Nerve Degeneration / metabolism
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Nerve Degeneration / physiopathology
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Neurons / metabolism*
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Protein Synthesis Inhibitors / pharmacology
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RNA Interference / physiology
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RNA, Messenger / metabolism
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Receptors, TNF-Related Apoptosis-Inducing Ligand
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Receptors, Tumor Necrosis Factor / metabolism
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Stem Cells / metabolism*
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / metabolism*
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Ubiquitin-Protein Ligases
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Up-Regulation / drug effects
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Up-Regulation / genetics
Substances
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Apoptosis Regulatory Proteins
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Inhibitor of Apoptosis Proteins
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Membrane Glycoproteins
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Protein Synthesis Inhibitors
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RNA, Messenger
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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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Dactinomycin
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BIRC2 protein, human
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Ubiquitin-Protein Ligases
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CASP3 protein, human
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CASP8 protein, human
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Caspase 3
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Caspase 8
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Caspases