Abstract
We here show a new relationship between the human p14ARF oncosuppressor and the MDM2 oncoprotein. MDM2 overexpression in various cancer cell lines causes p14ARF reduction inducing its degradation through the proteasome. The effect does not require the ubiquitin ligase activity of MDM2 and preferentially occurs in the cytoplasm. Interestingly, treatment with inhibitors of the PKC (Protein Kinase C) pathway and use of p14ARF phosphorylation mutants indicate that ARF phosphorylation could play a role in MDM2 mediated ARF degradation reinforcing our previous observations that ARF phosphorylation influences its stability and biological activity. Our study uncovers a new potentially important mechanism through which ARF and MDM2 can counterbalance each other during the tumorigenic process.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Line, Tumor
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism
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Cytoplasm
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Enzyme Activation
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Gene Expression
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Gene Silencing
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Humans
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Neoplasms / metabolism
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Proteasome Endopeptidase Complex / metabolism
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Protein Binding
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Protein Interaction Domains and Motifs
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Protein Kinase C / metabolism
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Protein Transport
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Proteolysis
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / metabolism*
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Tumor Suppressor Protein p14ARF / metabolism*
Substances
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Tumor Suppressor Protein p14ARF
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Proto-Oncogene Proteins c-mdm2
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Protein Kinase C
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Proteasome Endopeptidase Complex
Grants and funding
This work was supported by grants from Legge Regionale (Regione Campania) no 5/2007 to AP and GLM and Progetto “Campania Research in Experimental Medicine” (CREME). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.