Oncogenic mutations of the p53 tumor suppressor: The demons of the guardian of the genome

The p53 guardian of the genome is inactivated in the majority of cancers, m ostly through missense mutations that cause single residue changes in the D NA binding core domain of the protein. Not only do such mutations result in the abrogation of wild-type p53 activity, but the expressed p53 mutant pro teins also tend to gain oncogenic functions, such as interference with wild -type p53-independent apoptosis, Because p53 mutants are highly expressed i n cancer cells and not in normal cells, their reactivation to wild-type p53 function may eliminate the cancer by apoptosis or another p53-dependent me chanism. Several studies that embarked on this quest for reactivation have succeeded in restoring wildtype p53 activity to several p53 mutants, Howeve r, mutants with more extensive structural changes in the DNA binding core d omain may be refractory to reactivation to the wild-type p53 phenotype, The refore, understanding the structure and functions of oncogenic p53 mutants may lead to more potent reactivation modalities or to the ability to elimin ate mutant p53 gain of function.