Abstract
Studies from murine embryogenesis and cancer cells derived from human melanomas have identified a critical role for the transcription factor PAX3 in the suppression of p53 protein accumulation and p53-dependent apoptosis. Here we show, using a well-defined over-expression system, that PAX3 suppresses p53-dependent transcription from promoters of p53-responsive genes, notably BAX and HDM2-P2, and reduces p53 protein abundance by promoting its degradation. We define the functional domains of PAX3 required for this activity, and furthermore present evidence that PAX3-dependent inhibition of p53 is independent of binding of the N-terminal domain of p53 to HDM2, the primary negative regulator of cellular p53 activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Genes, Developmental*
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Humans
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Mice
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NIH 3T3 Cells
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PAX3 Transcription Factor
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Paired Box Transcription Factors / chemistry
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Paired Box Transcription Factors / metabolism*
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Protein Binding
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Protein Interaction Mapping
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-mdm2
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Transcription, Genetic
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Tumor Suppressor Protein p53 / antagonists & inhibitors
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Tumor Suppressor Protein p53 / metabolism*
Substances
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PAX3 Transcription Factor
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PAX3 protein, human
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Paired Box Transcription Factors
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2