Pirh2, a p53-Induced Ubiquitin-Protein Ligase, Promotes p53 Degradation

Abstract

The p53 tumor suppressor exerts anti-proliferative effects in response to various types of stress including DNA damage and abnormal proliferative signals. Tight regulation of p53 is essential for maintaining normal cell growth and this occurs primarily through posttranslational modifications of p53. Here, we describe Pirh2, a gene regulated by p53 that encodes a RING-H2 domain-containing protein with intrinsic ubiquitin-protein ligase activity. Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of Mdm2. Expression of Pirh2 decreases the level of p53 protein and abrogation of endogenous Pirh2 expression increases the level of p53. Furthermore, Pirh2 represses p53 functions including p53-dependent transactivation and growth inhibition. We propose that Pirh2 is involved in the negative regulation of p53 function through physical interaction and ubiquitin-mediated proteolysis. Hence, Pirh2, like Mdm2, participates in an autoregulatory feedback loop that controls p53 function.

Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4

“…A number of other p53 ubiquitin ligases, such as Pirh2, Cop-1, Yin Yang1 and ARF/BP1, have indeed been discovered and shown to function in a Mdm2-independent manner. [22][23][24][25] Together these data challenge the conventional view that Mdm2 is essential for p53 turnover in vivo. A clear answer to this key issue could have come from studies of the mdm2-deletion mutants.…”

The P53 pathway: what questions remain to be explored?

“…Recently, two other ubiquitin ligases were shown to act upon the p53 protein, COP-1 and PIRH-2. 19,20 Why is this redundancy employed? What are the roles of these enzymes for the many diverse stress inputs, in different tissue or cell types or at the different times in development of an organism?…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…Pirh2 is a gene regulated by p53 that encodes a RING-H2 domain-containing protein with intrinsic ubiquitin-protein ligase activity. Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of MDM2 (Leng et al, 2003). Tip60 induces p53 acetylation specifically at Lys120 (K120), within the DNA-binding domain, that is crucial for p53-dependent apoptosis but is dispensable for its mediated growth arrest (Tang et al, 2006).…”