Relevance of p53 Protein and itsMutations for Novel Strategies in Cancer Therapy

Overview

Mutational inactivation of the p53 gene products is one of the most common genetic events that occur in humancancer confirming the central role of p53 as a tumour suppressor. The wild type p53 protein acts as a powerfultranscription factor binding as many as 300 different promoter sequences in the genome. As a transcription factor,p53 can broadly alter patterns of specific gene expression leading to cell-cycle arrest and/or apoptosis. Thetranscriptional activity of the p53 protein is precisely regulated and its basal activity is enhanced in cells exposed toa wide variety of stress signals. This stress regulated transactivation function of p53 is driven by its sequence-specificDNA-binding domain and is co-ordinated by specific protein-protein interactions that can be modulated by covalentand non-covalent modifications. The mutant forms of p53 protein are defective in sequence specific DNA-bindingbecause the missense mutation affects one or all of the assembly pathways. Analysis of p53 mutant has shown thatdifferent conformational classes of mutants exist and the reactivation of each class requires a different strategydepending on the mechanism of p53 protein misfolding. Potential reactivation of both wild type and mutant p53protein in vivo raises our hopes of developing anti-cancer drugs useful in combination with sophisticated diagnosticsfor the treatment of cancer.

Key words:
tumour suppressor, p53, mutation, cancer, cell cycle, apoptosis.