p53: Recent Facts and New Questions

Activation of TP53 can stimulate diverse cellular responses. In unstressed cells, the TP53 protein is bound and ubiquitinated by its negative regulator, the E3 ubiquitin ligase MDM2 (called HDM2 in humans). This targets the TP53 protein for ubiquitin-dependent proteasomal degradation. When cells are exposed to stress, such as DNA damage, MDM2 is phosphorylated and is then no longer able to ubiquitinate TP53, allowing for TP53 stabilisation and functional activation. Of note, TP53 can be phosphorylated at the N-terminus, and this also interferes with MDM2 binding and its ability to ubiquitinate TP53, and thereby prime it for proteasomal degradation. Once activated, TP53 can transcriptionally induce ~500 direct target genes, with some of them known to be critical for the induction of diverse cellular responses, including apoptotic cell death via induction of PUMA and NOXA, as well as genes involved in cell cycle arrest and cell senescence, (e.g., p21), DNA repair (e.g., MLH1, MSH2) and metabolism (e.g., TIGAR), to implement tumour suppression.

The attributes proposed for mutant TP53 to drive tumour development and possible approaches to target them. Model depicting the three attributes by which mutant TP53 is thought to promote tumour development: loss-of-function (LOF), dominant negative effects (DNE) over wt TP53 and neomorphic gain-of-function (GOF) effects.