Downregulation of ΔNp63α in keratinocytes by p14ARF-mediated SUMO-conjugation and degradation

• DOI: 10.4161/cc.8.21.9954
• Publication Date: 2011-01-20T16:26:04Z
• Authors: Maria Vivo; Antonella Di Cost...; Paola Fortugno; Alessandra Pollice; Viola Calabrò; Girolama La Mantia
• Keywords: Keratinocytes; Proteasome Endopeptidase Complex; Keratinocyte differentiation; p14ARF; p63; Protein degradation; Sumoylation; Leupeptins; Down-Regulation; p14ARF; Protein degradation; Cysteine Proteinase Inhibitors; 03 medical and health sciences; Cell Line, Tumor; Tumor Suppressor Protein p14ARF; Humans; Cells, Cultured; p63; 0303 health sciences; Keratinocyte differentiation; Tumor Suppressor Proteins; Sumoylation; Cysteine Endopeptidases; Small Ubiquitin-Related Modifier Proteins; Trans-Activators; Tumor Suppressor Protein p53; Proteasome Inhibitors; HeLa Cells; Transcription Factors

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.