title: Differential control of TAp73 and DeltaNp73 protein stability by the ring finger ubiquitin ligase PIR2.
abstract: p73 is a p53-related transcription factor with fundamental roles in development and tumor suppression. Transcription from two different promoters on the p73 gene results in generation of transcriptionally active TAp73 isoforms and dominant negative DeltaNp73 isoforms with opposing pro- and anti-apoptotic functions. Therefore, the relative ratio of each isoform is an important determinant of the cell fate. Proteasomal degradation of p73 is mediated by polyubiquitination-dependent and -independent processes both of which appear, thus far, to lack selectivity for the TAp73 and DeltaNp73 isoforms. Here, we describe the characterization of another transcriptional target of TAp73; a ring finger domain ubiquitin ligase p73 Induced RING 2 protein (PIR2). Although PIR2 was initially identified a p53-induced gene (p53RFP), low abundance of PIR2 transcript in mouse embryonic fibroblasts of TAp73 KO mice compared with WT mice and comparison of PIR2 mRNA and protein levels following TAp73 or p53 overexpression substantiate TAp73 isoforms as strong inducers of PIR2. Although PIR2 expression was induced by DNA damage, its expression did not alter apoptotic response or cell cycle profile per se. However, coexpression of PIR2 with TAp73 or DeltaNp73 resulted in an increase of the TA/DeltaNp73 ratio, due to preferential degradation of DeltaNp73. Finally, PIR2 was able to relieve the inhibitory effect of DeltaNp73 on TAp73 induced apoptosis following DNA damage. These results suggest that PIR2, by being induced by TAp73 and degrading DeltaNp73, differentially regulates TAp73/DeltaNp73 stability, and, hence, it may offer a therapeutic approach to enhance the chemosensitivity of tumor cells.
authors.affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, United Kingdom.
authors.forename: Berna S
authors.initials: BS
authors.lastname: Sayan
authors.forename: Ai Li
authors.initials: AL
authors.lastname: Yang
authors.forename: Franco
authors.initials: F
authors.lastname: Conforti
authors.forename: Paola
authors.initials: P
authors.lastname: Tucci
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Piro
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Browne
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Agostini
authors.forename: Sergio
authors.initials: S
authors.lastname: Bernardini
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D000818:Animals; D017209:Apoptosis; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D054829:RING Finger Domains; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; C000606460:TP73 protein, human; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C000606369:delta Np73 protein, human; C508914:RNF144B protein, human; D044767:Ubiquitin-Protein Ligases