Mutant p53 rescue and modulation of p53 redox state

Abstract

The p53 tumor suppressor is a key regulator of cell growth and survival upon various forms of cellular stress. p53 is a redox-regulated transcription factor that binds specifically to DNA and activates transcription of target genes. The core domain of p53 holds a zinc atom that protects p53 from oxidation and is critical for DNA binding. A large fraction of human tumors carry p53 mutation, allowing evasion of apoptosis and tumor progression. Restoration of wild type p53 expression triggers rapid elimination of tumors in vivo. This makes mutant p53 an attractive target for novel cancer therapy. Small molecules have been identified that reactivate mutant p53 and induce apoptosis in tumor cells. Interestingly, several of these compounds share the ability to target thiols and affect the redox state of p53, indicating that this is critical for mutant p53 rescue. The identification of a common chemical activity among mutant p53-targeting compounds will facilitate the design of even more potent and selective mutant p53-targeting drugs for improved cancer therapy in the future.