Tumor protein p53 (zinc-deficient mutant)

Zinc-deficient mutant tumor protein p53 refers to a class of oncogenic variants of the p53 protein that are inactivated due to the loss of a critical structural zinc ion in the DNA-binding domain (DBD) (Blanden et al., 2015, Drug Discov Today; Yu et al., 2014, Oncotarget). The p53 protein is a zinc-dependent transcription factor that requires a single zinc ion for proper folding and sequence-specific DNA binding; without it, the protein adopts a misfolded, inactive apo conformation that lacks tumor-suppressive activity (Loh, 2020, NIH; elifesciences.org, 2020). This target is highly relevant in oncology as TP53 is the most frequently mutated gene in human cancers, and specific zinc-binding mutations like R175H contribute to a significant portion of these cases (Biorxiv, 2020; NIH, 2018). Therapeutic strategies focus on zinc metallochaperones (ZMCs), which act as ionophores to shuttle zinc into cells and buffer intracellular concentrations to levels that allow the mutant protein to bind zinc and refold into a functional holo state (Clin Cancer Res, 2018; MDPI, 2018). Once restored, the protein can reactivate its tumor-suppressive program, inducing apoptosis and cell cycle arrest specifically in cancer cells harboring these mutations (NIH, 2018; MDPI, 2024). However, therapeutic challenges include potential toxicity from off-target metal chelation and the generation of reactive oxygen species (ROS) (AACR, 2018).

Other names

Apo-mutant p53Zinc-binding deficient p53p53 R175Hp53 R172HZinc-deficient p53mutp53

Zinc metallochaperones (ZMCs) function as zinc ionophores that increase and buffer intracellular free zinc concentrations to a level that allows the low-affinity mutant p53 to bind zinc and refold into a wild-type-like functional conformation, thereby restoring its tumor-suppressive transcriptional activity.