PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21 WAF1 and p63

Conforti, F; Yang, AL; Piro, MC; Mellone, M; Terrinoni, A; Candi, E; Tucci, P; Thomas, GJ; Knight, RA; Melino, G; Sayan, BS

Abstract

ΔNp63 is a transcription factor that is critical for the development of stratified epithelia and is overexpressed or amplified in >80% of squamous cell carcinomas (SCCs). We identified the RING finger E3 ubiquitin ligase PIR2/Rnf144b as a direct transcriptional target of ΔNp63α and showed that its expression parallels that of ΔNp63α in keratinocytes, SCC cell lines and SCCs. We used primary keratinocytes as a model system to investigate the function of PIR2/Rnf144b in stratified epithelia. Depletion of PIR2/Rnf144b severely impaired keratinocyte proliferation and differentiation, associated with accumulation of p21WAF1/CIP1; a known target of PIR2/Rnf144b. More importantly, we found that PIR2/Rnf144b binds and mediates proteasomal degradation of ΔNp63α, generating a hitherto unknown auto-regulatory feedback loop. These findings substantiate PIR2/Rnf144b as a potentially critical component of epithelial homeostasis, acting downstream of ΔNp63α to regulate cellular levels of p21WAF1/CIP1 and ΔNp63α.

• Journal Article Type: Article
• Online Publication Date: Nov 5, 2012
• Publication Date: Nov 5, 2012
• Deposit Date: Feb 8, 2023
• Journal: Oncogene
• Print ISSN: 0950-9232
• Electronic ISSN: 1476-5594
• Publisher: Nature Publishing Group
• Volume: 32
• DOI: https://doi.org/10.1038/onc.2012.497
• Publisher URL: https://doi.org/10.1038/onc.2012.497