The tango of ROS and p53 in tissue stem cells

The p53 protein is a master regulator of cellular response to many types of stress, including oxidative stress. Depending upon the cellular context and the extent to which p53 is activated, this protein is capable of initiating programs that can eventually lead to inhibition of cell proliferation, induction of cell differentiation, modulation of metabolism, and induction of apoptosis or cellular senescence [ 1 ]. The functional versatility and complexity of p53 are mediated by the hundreds of p53 transcriptional targets. Reactive oxygen species (ROS) are essential signaling molecules in many biological processes, wherein their level is tightly regulated. Excess ROS may cause apoptosis, premature senescence or unscheduled differentiation of stem cells. Various studies showed that, under physiological conditions or when exposed to transient and mild oxidative stress, p53 possesses antioxidant function and contributes to the maintenance of low level of ROS [ 2 ]. The list of p53 target genes that encode proteins with antioxidant function has been growing over the years and now includes GPX1 , SOD2 , TIGAR , SESN1 , SESN2 , GLS2 and SLC2A9 . However, the antioxidant function of p53 is only context-dependent. When under persistent and severe stress, p53 becomes hyperactivated and turns into a strong promoter of oxidative stress instead. This pro-oxidative activity of p53 is believed to be driven by its transcriptional activation of genes encoding pro-oxidative proteins such as TP53I3 (PIG3) and excessive ROS level often lead to apoptosis or cellular senescence [ 3 , 4 , 5 ]. Because p53 can be further activated or maintained at high levels by persistent high level of ROS, the p53 and ROS eventually form a positive feedback loop, resulting in a vicious cycle and further exacerbating oxidative stress [ 5 , 6 ]. While the antioxidant function of p53 is mainly attained via upregulating the classical antioxidant enzymes, the mechanisms by which p53 elevates ROS are less understood. Nevertheless, p21, a classical p53 target, has been shown to have pro-oxidant function [ 5 ]. A recent study by Kang et al showed that p53 and PIG3 can each interact with and inhibit catalase when p53 is hyperactivated, leading to high ROS level and apoptosis [ 7 ]. Interestingly, the study also showed that p53R2, another p53 target gene, actually contributes to the maintenance of increased catalase activity under physiological conditions. How p53 is shifted in its function from being an antioxidant to a pro-oxidant under different stress levels remains to be elucidated.