The p53 R181C mutation accumulates through impaired deacetylation by Sirt1 and facilitates tumor development.

Li-Fraumeni Syndrome (LFS) is linked to mutations in the p53 gene and is characterized by autosomal dominant early-onset familial cancer susceptibility. The p53R181C mutation is one of the earliest described mutations associated with early-onset familial hereditary breast cancer. Highly stable mutant p53 protein is often a prerequisite for tumor initiation and progression, but the pathways leading to p53R181C accumulation and carcinogenesis are not understood. Here, we found that p53 R181C mutation decreases the interaction of p53 with the Sirt1 deacetylase, resulting in increased p53 K382 acetylation and inhibition of MDM2-mediated ubiquitination and degradation of p53. Moreover, the R181C mutation leads to "loss-of-function" of transcriptional regulating tumor suppressor genes like p21, bax, and PUMA as well as "gain-of-function" of transcriptional regulating tumor promoting genes of PIK3CA, SHC1, SRC and PAK4. This dysregulation promotes genomic instability, enabling cancer cells to evade cell cycle control, senescence and apoptosis, thus facilitating tumor development. Our findings unraveled the mechanism by which the p53R181C mutant protein accumulates and facilitates tumor development.