Pir2/rnf144b regulates epithelial homeostasis by mediating degradation of p21and p63

Conforti, F., Yang, A.L., Piro, M.C., Mellone, Max, Terrinoni, A., Candi, E., Tucci, P., Thomas, G., Knight, R.A., Melino, G. and Sayan, B. (2012) Pir2/rnf144b regulates epithelial homeostasis by mediating degradation of p21and p63. Oncogene, 32, 4758-4765. (doi:10.1038/onc.2012.497). (PMID:23128396)

Abstract

?Np63 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 ?Np63? and showed that its expression parallels that of ?Np63? 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 ?Np63?, generating a hitherto unknown auto-regulatory feedback loop. These findings substantiate PIR2/Rnf144b as a potentially critical component of epithelial homeostasis, acting downstream of ?Np63? to regulate cellular levels of p21WAF1/CIP1 and ?Np63?

This record has no associated files available for download.

Contributors

Download statistics