Abstract
Although genetic studies have demonstrated that MDMX is essential to maintain p53 activity at low levels in non-stressed cells, it is unknown whether MDMX regulates p53 activation by DNA damage. We show here that DNA damage-induced p53 induction is associated with rapid down-regulation of the MDMX protein. Significantly, interference with MDMX down-regulation results in the suppression of p53 activation by genotoxic stress. We also demonstrate that DNA damage-induced MDMX reduction is mediated by MDM2, which targets MDMX for proteasomal degradation by a distinct mechanism that permits preferential MDMX degradation and therefore ensures optimal p53 activation.
Publication types
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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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Blotting, Western
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Cell Cycle
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Cell Line, Tumor
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Cysteine Endopeptidases / metabolism
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DNA Damage*
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Down-Regulation
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Humans
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Microscopy, Fluorescence
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Multienzyme Complexes / metabolism
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Nuclear Proteins*
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Plasmids / metabolism
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Precipitin Tests
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Proteasome Endopeptidase Complex
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Retroviridae / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Time Factors
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Transfection
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin / metabolism
Substances
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Multienzyme Complexes
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Nuclear Proteins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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Ubiquitin
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex