p53 Mutation and Mitotic Infidelity

Abstract

Chromosome instability (a high frequency of chromosomal loss and gain and genome doubling, often referred to as karyotypic instability) is one of the major characteristics of cancer cells. It facilitates carcinogenesis by increasing the chance of specific mutations responsible for malignant phenotypes. Chromosome instability in most cases reflects the occurrence of defective mitosis, including unequal distribution of chromosomes to daughter cells and failure to undergo cytokinesis, which leads to generation of aneuploid cells. Both in vivo and in vitro, chromosome instability has been shown to correlate with loss or mutation of the p53 tumor suppressor protein, the product of one of the most frequently mutated genes in cancer. The major function of p53 is to prevent cells from proceeding through the cell cycle when cells experience stress, insults, or errors that disturb the preprogrammed cell cycle progression. During the last several years, significant advances have been made in understanding how p53 is involved in the regulation of mitosis and how loss or mutation of p53 affects mitotic fidelity, which will be the subject of this review.