PIG3 (p53 inducible gene 3)

The product of p53-inducible gene 3 (PIG3) is a cytoplasmic protein, which is induced by exposure to genotoxic agents before the onset of apoptosis during p53-mediated growth arrest. The induction of PIG3 is p53-dependent and occurs with delayed kinetics as compared with other p53 downstream targets, such as p21 and MDM2. When cells lines are treated with adriamyein, a DNA-damaging and apoptotic-inducing agent known to increas endogenous p53 levels, PIG3, like p21, was found to be strongly induced in the cell lines with wild-type p53 genes, but not in the cell with mutant p53. This observation supports the p53-dependence of PIG3 induction. When p53-mediated growth arrest is reversed, elevated levels of PIG3 are maintained even in cells that resumed cycling in the absence of ectopic p53 expression, suggesting that PIG3 is a long-lived reporter, which may be useful for detecting transient activation of p53.The proline-rich region of p53 is required for PIG3 activation. p53 protein lacking this region (p53delta62-91) can still induce many p53-responsive genes but not PIG3. This p53 mutant induces growth arrest but not apoptosis. Some tumor-derived p53-mutants, especially M246I, retained the ability to activate transcription of MDM2 but specifically fail to induce the PIG3 promoter, thus resembling p53delta62-91. Further, p53delta62-91 and p53M246I are defective for induction of apoptosis. PIG3 shares significant homology to TED2, a plant NADPH oxidoreductase. Interestingly, TED2 is one of the few genes implicated in the apoptotic process necessary for the fomation of plant meristems. The closest relative of PIG3 in mammals is an NADPH-quinone oxidoreductase that is a potent generator of ROS. Reactive oxygen species are powerful inducers of apoptosis. Expression profiles (SAGE_based) of p53-induced genes suggested that p53 might induce apoptosis by stimulating the production of ROS. Wild-type p53 is a tumor supressor gene which can activate or repress transcription, as well as induce apoptosis. The proteins encoded by these genes then collectively increase the content of ROS, which in turn damage mitochondria. Leakage of calcium and proteinaceous components from damged mitochondria then stimulate the caspases that are ubiquitously activated during the apoptotic process.