Differential control of TAp73 and ΔNp73 protein stability by the ring finger ubiquitin ligase PIR2

p73 is a p53-related transcription factor with fundamental rolesin development and tumor suppression. Transcription from twodifferent promoters on the p73 gene results in generation of transcriptionallyactive TAp73 isoforms and dominant negative ΔNp73isoforms with opposing pro- and anti-apoptotic functions. Therefore,the relative ratio of each isoform is an important determinantof the cell fate. Proteasomal degradation of p73 is mediated bypolyubiquitination-dependent and -independent processes bothof which appear, thus far, to lack selectivity for the TAp73 andΔNp73 isoforms. Here, we describe the characterization of anothertranscriptional target of TAp73; a ring finger domain ubiquitin ligasep73 Induced RING 2 protein (PIR2). Although PIR2 was initiallyidentified a p53-induced gene (p53RFP), low abundance of PIR2transcript in mouse embryonic fibroblasts of TAp73 KO mice comparedwith WT mice and comparison of PIR2 mRNA and proteinlevels following TAp73 or p53 overexpression substantiate TAp73isoforms as strong inducers of PIR2. Although PIR2 expression wasinduced by DNA damage, its expression did not alter apoptotic responseor cell cycle profile per se. However, coexpression of PIR2with TAp73 or ΔNp73 resulted in an increase of the TA/ΔNp73 ratio,due to preferential degradation of ΔNp73. Finally, PIR2 was able torelieve the inhibitory effect of ΔNp73 on TAp73 induced apoptosisfollowing DNA damage. These results suggest that PIR2, by beinginduced by TAp73 and degrading ΔNp73, differentially regulatesTAp73/ΔNp73 stability, and, hence, it may offer a therapeutic approachto enhance the chemosensitivity of tumor cells.