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Oncogene. 2013 Oct;32(40):4758-65. doi: 10.1038/onc.2012.497. Epub 2012 Nov 5.

PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63.

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1
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.

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.

PMID:
23128396
DOI:
10.1038/onc.2012.497
[Indexed for MEDLINE]
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