Figure 4.

Functional consequences of p53 mutations. p53 mutations can lead to a loss-of-function of wild-type p53 activity abrogating the ability of mutant p53 to transactivate canonical p53 target genes. p53 mutants co-occurring with wild-type p53 can diminish canonical p53 target gene expression via exerting a dominant-negative effect over wild-type p53 by forming hetero-oligomers and preventing binding of wild-type p53 to its response elements. Mutant p53 proteins can also obtain gain-of-function activities by acquiring novel, non-canonical pro-tumorigenic functions through different molecular mechanisms. (I) The binding of mutant p53 to novel, non-canonical binding sites leads to the transactivation of non-canonical genes. (II) Protein–protein interactions (e.g., with other transcription factors or chromatin remodeling complexes) also induce the expression of non-canonical genes. (III) Sequestration of other transcription factors via protein–protein interactions with mutant p53 disrupts target gene expression of those transcription factors. RE, response element; TF, transcription factor.