Tumor development is thought to be the result of several oncogenic events.One long-standing hope in cancer research is that a common biochemical pathway for control of cell growth is perturbed in various cancers.Inactivation of the p53 tumor suppressor gene is the most commonly identified genetic event in cancer, occurring in more than 50% of all human tumors, implying that loss of this gene represents a fundamentally important step in the pathogenesis of cancer.The pathway involving p53 may provide a common basis for understanding, treating, and preventing cancer.Using the method of differential display, two novel p53 regulated genes were recently identified.One encodes a death domain-containing protein called Pidd (Lin et al, Nature Genetics, 2000) and the other encodes a RING-H2 containing protein called Pirh2 (Leng et al., Cell, 2003).Over the past years, we have shown that Pirh2 expression is induced by DNA damage in a p53-dependent manner.Furthermore, we have demonstrated that Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of Mdm2.Expression of Pirh2 in human cells decreases the level of p53 protein and antisense oligonucleotide-mediated abrogation of endogenous Pirh2 expression increases the level of p53.Furthermore, Pirh2 represses p53 functions including p53-dependent transactivation and growth inhibition.Our results show that the DNA binding domain of p53 (82-292aa) is required for binding Pirh2, which is distinguished from the Mdm2.Interestingly, the amino acids 82-292 of p53 are frequently mutanted in human tumors.Inhibiting the p53-Pirh2 interaction is a promising approach for activating p53.Inhibiting the p53-Pirh2 interaction with synthetic molecules should lead to p53-mediated cell-cycle arrest or apoptosis in p53-positive stressed cells.Therefore, the design of compounds that prevent the interaction between p53 and Pirh2 is an attractive strategy for activating p53 tumour-suppressor activity in cancer.This approach should provide a highly selective means of activating p53.