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

Oncogene volume 32, pages 4758–4765 (2013)Cite this article

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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.

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Acknowledgements

This work has been supported by funding from the University of Southampton to BSS and by the Medical Research Council, UK; ‘Alleanza contro il Cancro’ (ACC12), MIUR/PRIN (RBIP06LCA9_0023), AIRC (2008-2010_33-08), Italian Human ProteomeNet RBRN07BMCT to GM.

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Authors and Affiliations

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

    F Conforti, M Mellone, G J Thomas & B S Sayan

  2. Medical Research Council, Toxicology Unit Leicester University, Leicester, UK

    Ai Li Yang, P Tucci, R A Knight & G Melino

  3. c/o Department of Experimental Medicine and Surgery, Biochemistry Laboratory, IDI-IRCCS, University of Rome "Tor Vergata", Rome, Italy

    M Cristina Piro, A Terrinoni, E Candi, P Tucci & G Melino

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  1. F Conforti
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Correspondence to B S Sayan.

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Conforti, F., Li Yang, A., Cristina Piro, M. et al. PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. Oncogene 32, 4758–4765 (2013). https://doi.org/10.1038/onc.2012.497

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