Abstract
The low molecular weight compound PRIMA-1 and the structural analog PRIMA-1(MET), also named APR-246, reactivate mutant p53 through covalent binding to the core domain and induce apoptosis in tumor cells. Here, we asked whether PRIMA-1(MET)/APR-246 can rescue mutant forms of the p53 family members p63 and p73 that share high sequence homology with p53. We found that PRIMA-1(MET)/APR-246 can restore the pro-apoptotic function to mutant TAp63γ and TAp73β in tumor cells but has less effect on TAp73α. Moreover, PRIMA-1(MET)/APR-246-stimulated DNA binding of mutant TAp63γ and induced expression of the p53/p63/p73 downstream targets p21 and Noxa. The reactivation of mutant p53, p63 and p73 by PRIMA-1(MET)/APR-246 indicates a common mechanism, presumably involving homologous structural elements in the p53 family proteins. Our findings may open avenues for therapeutic intervention in human developmental disorders with mutations in p63.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology*
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Apoptosis / genetics*
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Aza Compounds / pharmacology*
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
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Cell Line, Tumor
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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DNA-Binding Proteins / genetics*
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Gene Expression / drug effects*
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Humans
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Mutation
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Nuclear Proteins / genetics*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Quinuclidines / pharmacology*
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Trans-Activators / genetics*
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Proteins / genetics*
Substances
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Antineoplastic Agents
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Aza Compounds
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Bridged Bicyclo Compounds, Heterocyclic
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Nuclear Proteins
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PMAIP1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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Quinuclidines
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TP63 protein, human
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TP73 protein, human
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Trans-Activators
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Transcription Factors
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Tumor Protein p73
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Tumor Suppressor Proteins
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2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
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eprenetapopt