p53 in Human Cancer — Somatic and Inherited Mutations and Mutation-independent Mechanisms

Abstract

The p53 tumor suppressor protein plays a central role in maintaining genomic integrity. It does so by occupying a nodal point in the DNA damage control pathway. When cells are subjected to ionizing radiation or other mutagenic events, p53 mediates cell cycle arrest, senescence or programmed cell death (apoptosis). Furthermore, some evidence suggests that p53 plays a role in the recognition and repair of damaged DNA. p53 is a tetrameric transcription factor but also has transcription-independent proapoptotic functions.

Conversely, disruption of the p53 response pathway strongly correlates with tumorigenesis. p53 is functionally inactivated by structural mutations, neutralization by viral products, cytoplasmic sequestration, and alterations in upstream regulators or downstream effectors in the vast majority of human cancers. p53-deficient mice have a highly penetrant tumor phenotype with over 90% tumor incidence within nine months. In some cancers direct physical evidence exists that identify the p53 gene as a target of known environmental carcinogens such as UV light and benzo[a]pyrene in cancers of the skin and lung. When p53 loss occurs, cells do not get repaired or eliminated but rather proceed to replicate damaged DNA, which results in more random mutations, gene amplifications, chromosomal rearrangements, and aneuploidy. In some experimental models, loss of p53 confers resistance to anticancer therapy due to loss of apoptotic competence. The translational potential of these discoveries are beginning to be tested in novel p53-based therapies.