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

F. Conforti, Ai Li Yang, M. Cristina Piro, M. Mellone, A. Terrinoni, E. Candi, P. Tucci, G. J. Thomas, R. A. Knight, G. Melino, B. S. Sayan

Research output: Contribution to journalArticle

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 p21 WAF1/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 p21 WAF1/CIP1 and ΔNp63α.

Original languageEnglish
Pages (from-to)4758-4765
Number of pages8
JournalOncogene
Volume32
Issue number40
DOIs
Publication statusPublished - Oct 3 2013

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Keywords

  • p21WAF1
  • p63
  • PIR2
  • Rnf144B
  • skin
  • squamous cell carcinoma (SCC)

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Conforti, F., Li Yang, A., Cristina Piro, M., Mellone, M., Terrinoni, A., Candi, E., Tucci, P., Thomas, G. J., Knight, R. A., Melino, G., & Sayan, B. S. (2013). PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21 WAF1 and p63. Oncogene, 32(40), 4758-4765. https://doi.org/10.1038/onc.2012.497