Figure 2. Regulation of p53.

The expression and activity of p53 are controlled by multilayered regulation at the DNA, RNA, and protein levels. At the DNA level, SNPs (e.g. P72R) and mutations (e.g. R273H) may occur in the p53 gene. p53 possesses two promoters, which can be methylated and silenced. The transcription of p53 gene is activated or suppressed by various TFs (e.g. HOXA5). At the RNA level, the cellular localization, stability, and translation of p53 mRNA are modulated by RNA-binding proteins (e.g. TIA1) and ncRNAs (e.g. miR-380–5p). p53 pre-mRNA and mRNA can undergo alternative splicing and alternative translation, respectively. At the protein level, p53 folding, stability, cellular localization, DNA binding, transactivation ability, and target selection are primarily mediated by post-translational modifications (e.g. ubiquitination, phosphorylation, and acetylation) and cofactors (e.g. MDM2, MDMX, and CBP). Diverse stress signals (e.g. DNA damage) can activate p53, and its activity as a TF is highly dynamic. p53 also exhibits TF-independent function in cytoplasm (e.g. promoting apoptosis via interacting with Bcl-XL). P1 and P2, promoter 1 and 2; SNP, single nucleotide polymorphism; E3, E3 ubiquitin ligase; TF, transcription factor; Me, methylation; Ub, ubiquitination; P, phosphorylation; Ac, acetylation.