Abstract
Prion protein (PrP) prevents Bcl-2-associated protein X (Bax)-mediated cell death, but the step at which PrP inhibits is not known. We first show that PrP is very specific for Bax and cannot prevent Bak (Bcl-2 antagonist killer 1)-, tBid-, staurosporine- or thapsigargin-mediated cell death. As Bax activation involves Bax conformational change, mitochondrial translocation, cytochrome c release and caspase activation, we investigated which of these events was inhibited by PrP. PrP inhibits Bax conformational change, cytochrome c release and cell death in human primary neurons and MCF-7 cells. Serum deprivation-induced Bax conformational change is more rapid in PrP-null cells. PrP does not prevent active caspase-mediated cell death. PrP does not colocalize with Bax in normal or apoptotic primary neurons and cannot prevent Bax-mediated cytochrome c release in a mitochondrial cell-free system. We conclude that PrP protects against Bax-mediated cell death by preventing the Bax proapoptotic conformational change that occurs initially in Bax activation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Apoptosis* / drug effects
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BH3 Interacting Domain Death Agonist Protein
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Carrier Proteins / metabolism
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Caspase 6
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Cell Line, Tumor
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Cysteine Endopeptidases / metabolism
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Cytochromes c / metabolism
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Enzyme Inhibitors / pharmacology
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Female
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Humans
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Membrane Proteins / metabolism
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Mitochondria / metabolism
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Neurons / drug effects
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Neurons / metabolism*
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PrPC Proteins / metabolism*
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Protein Structure, Quaternary
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / chemistry*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Thapsigargin / pharmacology
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
Substances
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BAK1 protein, human
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BAX protein, human
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BH3 Interacting Domain Death Agonist Protein
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BID protein, human
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Carrier Proteins
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Enzyme Inhibitors
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Membrane Proteins
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PrPC Proteins
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Proto-Oncogene Proteins c-bcl-2
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bcl-2 Homologous Antagonist-Killer Protein
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bcl-2-Associated X Protein
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Thapsigargin
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Cytochromes c
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CASP6 protein, human
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Caspase 6
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Cysteine Endopeptidases