p53 reactivation

Lack of p53 expression or expression of mutant p53 is common in human cancers and is associated with increased tumor growth and resistance to therapies. Significant efforts toward pharmaceutical reactivation of defective p53 by small molecules are therefore underway, targeting the different means that inactivate p53. Indeed, reactivated p53 can lead to tumor destruction. A recent paper in Cancer Cell by Yu et al. describes reactivation of mutant p53 (mtp53) by thiosemicarbazone compounds. These compounds induce wildtype (wt)p53 conformation, in particular for the p53H175 mutant, and this restores p53-dependent apoptosis and inhibition of xenograft tumor growth. In this paper, the authors emphasize that the mechanism of p53H175 reactivation depends on the zinc ion chelating properties of the thiosemicarbazone compounds that allow the p53H175 mutant to change conformation into a wild-type folding. p53 is a zinc-containing transcription factor that includes one zinc ion as an important cofactor, which is coordinated to the side chains of three Cys and one His residue in the DNA binding domain (DBD, residues 94–312). Zinc stabilizes the second and third loops of the DBD and is needed for wtp53 function. Many tumor-associated p53 mutations, classified as contact (e.g., R273H and R273C) or structural mutations (e.g., R175H, V143A, Y220C, G245S, R249S, F270L, R282W), may change the DBD conformation resulting in diminished DNA binding. Interestingly, mutant p53 proteins are prone to the loss of the DBD-bound Zn that promotes protein unfolding and aggregation. Similarly, mutations of the coordinating p53 reactivation The link to zinc