SNPing away at mutant p53 activities.

A delicate balance in the levels of proteins that regulate the p53 tumor suppressor pathway exists such that subtle changes alter p53 tumor suppressor activity and cancer risk. Many single-nucleotide polymorphisms (SNPs) in the p53 pathway alter p53 transcriptional activity and are associated with cancer risk. In addition, some SNPs influence the gain-of-function (GOF) activities of mutant p53 through unknown mechanisms. In this issue of Genes & Development , Basu and colleagues (pp. 230-243) provide direct evidence that the presence of an R72 polymorphism enhances the GOF invasive and metastatic properties of mutant p53 by regulating interactions with PGC-1α, an important regulator of mitochondrial biogenesis and oxidative phosphorylation. The study culminates with evidence that R72 is associated with worse outcomes in human breast cancer.