Pirh2 (p53-induced RING-H2) is an E3 ubiquitin ligase that can target p53 for degradation and thereby repress a diverse group of biological activities regulated by p53. Notably, Pirh2, rather than MDM2, is the primary degrader of active p53 under conditions of DNA damage. Moreover, Pirh2 is highly expressed in multiple cancer cell lines regardless of p53 status. Recent research has shown that Pirh2 is involved in many signalling pathways related to the genesis and evolution of cancer. This review aims to summarize a comprehensive picture of the role of Pirh2 in cellular processes and its significance to tumorigenesis. Furthermore, this review focuses on its potential role as a cancer therapeutic target. (Cancer Sci 2011; 102: 909-917) T he tumor suppressor p53, known as ''the guardian of the genome'', plays a key role in eliciting cellular responses to many signals of cell stress. Upon activation, p53 can affect cellular functions including transcription, DNA synthesis and repair, cell cycle arrest, senescence and apoptosis. Recent studies have demonstrated that p53 also influences metabolism and angiogenesis, regulates cell motility and immune responses and mediates cell-cell communication.(1) By promoting cell cycle arrest, apoptosis, senescence and DNA repair, p53 helps prevent cancer development. (2,3) The importance of p53 in tumor suppression is highlighted by the abundant, inactivating, somatic p53 mutations that are found in more than 50% of human cancer cells.(4) p53 is subjected to a variety of post-translational modifications, including phosphorylation, acetylation, ubiquitylation and methylation. (5,6) Ubiquitylation is an important mechanism for controlling p53 activity. (7) Pirh2, first identified as an androgen receptor N-terminalinteracting protein (ARNIP) (8) and also known as ring finger and CHY zinc finger domain-containing 1 (Rchy1), is a member of the RING finger family of E3 ubiquitin ligases, which can facilitate protein degradation via the ubiquitin-proteasome pathway.(9) The RING domain of Pirh2 contains a RING-H2 (Cys 3 His 2 Cys 3 ) motif, which is critical for maintaining the functions of several important E3 ubiquitin ligases including c-Cbl, anaphase-promoting complex (APC) and SCF complexes. (10)(11)(12) The N-terminal lobe of the Pirh2 N-terminal domain is a member of the CHY zinc finger family (Fig. 1).(13) Currently, the best understood function of Pirh2 is its role in the Pirh2-p53 feedback loop that is independent of MDM2. Pirh2 is transcriptionally activated by p53, and Pirh2, in turn, inhibits p53 activity in several ways. Notably, Pirh2 has been shown to degrade active p53 under conditions of DNA damage when MDM2 dissociates from and fails to degrade p53. (14) In addition, the disruption of Pirh2 homeostasis is closely related to the formation of various human tumors (Table 1). (15)(16)(17)(18)(19)(20)(21)(22) Rchy1 is one of the key genes related to the locoregional recurrence control of breast cancer, (23,24) and Pirh2 was elevated in approximately 93% of all murine l...