Regulation of p73 by Pirh2-AIP4 loop

Abstract

role in controlling the level and activity of a protein. The protein p73 has been identified as a homolog of the tumor suppressor protein p53 and is capable of inducing apoptosis or cell cycle arrest [1]. Nonetheless, p73 is rarely found to be mutated in human tumors, and p73deficient mice display no increase in tumor incidence. However, several studies have shown that p73 is missing or reduced in expression in certain human tumors (through loss of heterozygosity or allele silencing), thus implying that p73 has tumorsuppressive activities. Flores et al. have shown that p73 mice develop spontaneous tumors, that the loss of p73 can cooperate with p53 in tumor suppression, and that simultaneous mutation of both p73 and p53 leads to a more aggressive tumor phenotype, thus indicating that p73 plays an important role in tumor suppression in the mouse model [2]. This suggests that the regulation of p73 expression and stability are essential for maintaining normal cell growth. Several ubiquitin E3 ligases have been reported to regulate p73 stability; however, the mechanism of p73 regulation remains partially understood. Atrophin-1 interacting protein 4 (AIP4, also called Itch) contains an N-terminal C2 domain, protein interacting WW domains, and a Cterminal HECT ligase domain, which belongs to HECT (homologous to the E6-AP Carboxyl Terminus) domain proteins. It was reported that AIP4 serves as an E3 ligase for Notch, CXCR4, LMP2A, HEF1, Smad2, ErbB-4, p73, p63 [3]. AIP4 promotes the ubiquitination and degradation of p73 [4]. AIP4 inhibits p73 dependent transcriptional activity. Interestingly, AIP4 shows no E3 ligase activity towards p53 despite the homology between the two tumor suppressors [4]. Pirh2 is a RING finger ligase that binds to and promotes p53 degradation [5]. Furthermore, Pirh2 downregulates p53dependent transactivation and p53-mediated inhibition of cell growth, and like Mdm2, Pirh2 participates in an auto-regulatory feedback loop involving p53 [5]. Overexpression of Pirh2 in mouse tumors is accompanied by low p53 protein expression, but Mdm2 levels remain unchanged. E3 ligases often control the ubiquitination of multiple substrates; Pirh2 serves as an E3 ligase for AR, Tip60, hNTKL-BP1, p27, p73, p63, CHK2 [6]. It was reported that Pirh2 deficiency mice resulted in higher levels of p53 in several tissues in response to DNA damage and despite the presence of Editorial