Mammalian aging is associated with elevated levels of oxidative damage of DNA, proteins, and lipids as a result of unbalanced prooxidant and antioxidant activities. Accumulating evidence indicates that oxidative stress is a major physiological inducer of aging. p53, the guardian of the genome that is important for cellular responses to oxidative stresses, might be a key coordinator of oxidative stress and aging. In response to low levels of oxidative stresses, p53 exhibits antioxidant activities to eliminate oxidative stress and ensure cell survival; in response to high levels of oxidative stresses, p53 exhibits prooxidative activities that further increase the levels of stresses, leading to cell death. p53 accomplishes these context-dependent roles by regulating the expression of a panel of genes involved in cellular responses to oxidative stresses and by modulating other pathways important for oxidative stress responses. The mechanism that switches p53 function from antioxidant to prooxidant remains unclear, but could account for the findings that increased p53 activities have been linked to both accelerated aging and increased life span in mice. Therefore, a balance of p53 antioxidant and prooxidant activities in response to oxidative stresses could be important for longevity by suppressing the accumulation of oxidative stresses and DNA damage. Antioxid. Redox Signal. 15, 1669–1678.

TP53 is the most frequently mutated tumor suppressor gene in human cancer. The majority of mutations of p53 are missense mutations, leading to the expression of the full length p53 mutant proteins. Mutant p53 (Mutp53) proteins not only lose wild-type p53-dependent tumor suppressive functions, but also frequently acquire oncogenic gain-of-functions (GOF) that promote tumorigenesis. In this review, we summarize the recent advances in our understanding of the oncogenic GOF of mutp53 and the potential therapies targeting mutp53 in human cancers. In particular, we discuss the promising drugs that are currently under clinical trials as well as the emerging therapeutic strategies, including CRISPR/Cas9 based genome edition of mutant TP53 allele, small peptide mediated restoration of wild-type p53 function, and immunotherapies that directly eliminate mutp53 expressing tumor cells.

P53‐mediated transcription activity is essential for cell cycle arrest, but its importance for apoptosis remains controversial. To address this question, we employed homologous recombination and LoxP/Cre‐mediated deletion to produce mutant murine embryonic stem (ES) cells that express p53 with Gln and Ser in place of Leu25 and Trp26, respectively. p53^Gln25Ser26 was stable but did not accumulate after DNA damage; the expression of p21/Waf1 and PERP was not induced, and p53‐dependent repression of MAP4 expression was abolished. Therefore, p53^Gln25Ser26 is completely deficient in transcriptional activation and repression activities. After DNA damage by UV radiation, p53^Gln25Ser26 was phosphorylated at Ser18 but was not acetylated at C‐terminal sites, and its DNA binding activity did not increase, further supporting a role for p53 acetylation in the activation of sequence‐specific DNA binding activity. Most importantly, p53^Gln25Ser26 mouse thymocytes and ES cells, like p53^−/− cells, did not undergo DNA damage‐induced apoptosis. We conclude that the transcriptional activities of p53 are required for p53‐dependent apoptosis.