AI Article Synopsis
- p53 is a crucial transcription factor involved in preventing cancer, with its inactivation found in almost all tumors, primarily due to mutations in the TP53 gene.
- The TP53 gene exhibits a unique and diverse mutational spectrum compared to other cancer-related proteins, influenced by various factors that increase its susceptibility to mutations.
- The evolutionary history of TP53 has made it a vulnerable tumor suppressor, resulting in a loss of function that significantly undermines its role in combating cancer, often leading to dominant-negative effects from certain mutations.
Article Abstract
The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.
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| http://dx.doi.org/10.1038/s41418-024-01391-6 | DOI Listing |
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