Abstract
The p53 tumor suppressor is activated in the cellular response to stress. Mdm2 inhibits p53-dependent transactivation and promotes degradation of p53 by the ubiquitin-proteosome pathway. The present studies demonstrate that p53 binds directly to the nuclear Lyn tyrosine kinase. Lyn increases p53 levels and stimulates p53-mediated transcription by a kinase-independent mechanism. The results also demonstrate that Lyn increases nuclear levels of ubiquitinated p53 by inhibiting export of p53 to the cytoplasm. In concert with these results, Lyn reverses Mdm2-mediated degradation of p53 and increases p53-dependent apoptosis. Our findings support a previously undefined role for nuclear Lyn in both activation and Mdm2-mediated regulation of p53.
MeSH terms
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Active Transport, Cell Nucleus
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Apoptosis / drug effects
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Cell Nucleus / metabolism*
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Cytoplasm / metabolism
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, Tumor Suppressor
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Glutathione Transferase / metabolism
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Humans
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Immunoblotting
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Luciferases / metabolism
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Microscopy, Confocal
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Nuclear Proteins*
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Plasmids
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Precipitin Tests
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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Recombinant Fusion Proteins / isolation & purification
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Recombinant Fusion Proteins / metabolism
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Transcriptional Activation
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Tumor Cells, Cultured / metabolism
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Tumor Cells, Cultured / pathology
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin / metabolism
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src-Family Kinases / metabolism*
Substances
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Nuclear Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Tumor Suppressor Protein p53
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Ubiquitin
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Luciferases
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2
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Glutathione Transferase
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lyn protein-tyrosine kinase
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src-Family Kinases