title: PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63.
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.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: F
authors.initials: F
authors.lastname: Conforti
authors.forename: Ai Li
authors.initials: AL
authors.lastname: Yang
authors.forename: M Cristina
authors.initials: MC
authors.lastname: Piro
authors.forename: M
authors.initials: M
authors.lastname: Mellone
authors.forename: A
authors.initials: A
authors.lastname: Terrinoni
authors.forename: E
authors.initials: E
authors.lastname: Candi
authors.forename: P
authors.initials: P
authors.lastname: Tucci
authors.forename: G J
authors.initials: GJ
authors.lastname: Thomas
authors.forename: R A
authors.initials: RA
authors.lastname: Knight
authors.forename: G
authors.initials: G
authors.lastname: Melino
authors.forename: B S
authors.initials: BS
authors.lastname: Sayan
mesh_terms: D017398:Alternative Splicing; D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004848:Epithelium / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D008565:Membrane Proteins / Q000378:metabolism*; D059748:Proteolysis; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*
chemical_list: C493956:CDKN1A protein, human; C081876:CKAP4 protein, human; D002352:Carrier Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008565:Membrane Proteins; C571196:RNF144A protein, human; C508914:RNF144B protein, human; D044767:Ubiquitin-Protein Ligases