Pirh2 is a newly identified E3 ubiquitin ligase known to inhibit tumor suppressor p53 function via ubiquitination and proteasomal degradation. We have identified two novel Pirh2 splice variants that encode different Pirh2 isoforms and named these Pirh2B and Pirh2C. Accordingly, the full-length protein is now classified as isoform Pirh2A. The central region of Pirh2 harbors a RING finger domain that is critical for its ubiquitin ligase function. The Pirh2B isoform lacks amino acids 171-179, whereas Pirh2C is missing C-terminal amino acids 180-261, which for each isoform results in a RING domain deletion and the abrogation of ubiquitin ligase activity. Our findings further indicate that the Pirh2B isoform but not the Pirh2C isoform is capable of binding to Pirh2A, suggesting that the C-terminal region absent in Pirh2C is critical for Pirh2-Pirh2 interactions. Similar to Pirh2A, both Pirh2B and Pirh2C interact with p53; however, interactions between p53 and Pirh2B appear stronger than those between p53 and Pirh2C. Interestingly, although both Pirh2B and Pirh2C are not able to promote in vitro p53 ubiquitination, both are capable of negatively regulating p53 protein stability and promoting the intracellular ubiquitination of p53. Furthermore, like Pirh2A, both isoforms are able to inhibit p53 transcriptional activity. We have also for the first time demonstrated that Pirh2A as well as the novel isoforms also interact directly with MDM2 within a region encompassing MDM2 acidic and zinc finger domains. It is therefore possible that Pirh2A and the novel Pirh2 isoforms identified in this study may also modulate p53 function by engaging MDM2.
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