Abstract
Following DNA damage, p53 translocates to the cytoplasm and mitochondria, where it triggers transcription-independent apoptosis by binding to Bcl-2 family proteins. However, little is known about how this exonuclear function of p53 is regulated. Here, we identify and characterize a p53-interacting protein called Hades, an E3 ligase that interacts with p53 in the mitochondria. Hades reduces p53 stability via a mechanism that requires its RING-finger domain with ubiquitin ligase activity. Hades polyubiquitinates p53 in vitro independent of Mdm2 and targets a critical lysine residue in p53 (lysine 24) distinct from those targeted by Mdm2. Hades inhibits a p53-dependent mitochondrial cell death pathway by inhibiting p53 and Bcl-2 interactions. These findings show that Hades-mediated p53 ubiquitination is a novel mechanism for negatively regulating the exonuclear function of p53.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line
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Cell Nucleus / metabolism
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Cell Proliferation
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Green Fluorescent Proteins / metabolism
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Humans
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Leupeptins / pharmacology
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Mitochondria / metabolism
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Polyubiquitin / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Protein Binding
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Protein Stability
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Proteolysis
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RING Finger Domains
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Recombinant Fusion Proteins / metabolism
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Transcription Factors / metabolism*
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Protein p53 / physiology
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Ubiquitin-Protein Ligases / metabolism*
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Ubiquitination
Substances
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Leupeptins
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Proteasome Inhibitors
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Recombinant Fusion Proteins
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TP53 protein, human
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Transcription Factors
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Tumor Suppressor Protein p53
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Polyubiquitin
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Green Fluorescent Proteins
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MUL1 protein, human
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Ubiquitin-Protein Ligases
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde