Abstract
The tumor suppressor p14(ARF) inhibits cell growth in response to oncogenic stress in a p53-dependent and independent manner. However, new physiologic roles for ARF activation have been proposed. We have previously demonstrated that ARF interacts with p63, influencing its transcriptional activity. p63 is a member of the p53 family involved in skin and limb development, as well as in the homeostasis of mature epidermis. Here, we show that, in human keratinocytes, as well as in tumor-derived cell lines, ARF targets DeltaNp63alpha, the most abundantly expressed p63 isoform, to proteasomal degradation by stimulating its sumoylation. Interestingly, we have observed an increase of ARF expression in differentiating keratinocytes, that is concomitant to the already described upregulation of SUMO2/3. Remarkably, we found that DeltaNp63alpha is preferentially sumoylated by SUMO2, instead of SUMO1, and p14(ARF) increases the efficiency of this 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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Cells, Cultured
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Cysteine Endopeptidases / drug effects
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Cysteine Endopeptidases / metabolism*
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Cysteine Proteinase Inhibitors / pharmacology
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Down-Regulation / drug effects
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Down-Regulation / physiology
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HeLa Cells
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Humans
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Keratinocytes / drug effects
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Keratinocytes / metabolism*
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Leupeptins / pharmacology
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Inhibitors
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Small Ubiquitin-Related Modifier Proteins / drug effects
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Small Ubiquitin-Related Modifier Proteins / metabolism*
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Trans-Activators / metabolism*
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Transcription Factors
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Tumor Suppressor Protein p14ARF / antagonists & inhibitors
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Tumor Suppressor Protein p14ARF / metabolism*
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Tumor Suppressor Protein p53 / metabolism*
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Tumor Suppressor Proteins / metabolism*
Substances
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Cysteine Proteinase Inhibitors
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Leupeptins
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Proteasome Inhibitors
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SUMO2 protein, human
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Small Ubiquitin-Related Modifier Proteins
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TP63 protein, human
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Protein p14ARF
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Tumor Suppressor Protein p53
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Tumor Suppressor Proteins
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Cysteine Endopeptidases
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SENP6 protein, human
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde