The p53 Tumour Suppressor Protein

Abstract

Cancer is a genetic disease dependent upon the accumulation of mutations within the genes that control cellular proliferation. Mutations may arise, either as a consequence of errors made during DNA replication, or after exposure to physical or chemical mutagens. DNA damaging agents, such as the oxygen free radicals produced by the mitochondria during respiration, are continually generated as a result of normal cellular activity (Kaufmann and Paules, 1996). Disruption of the genes responsible for cell growth regulation, programmed cell death (apoptosis), differentiation and motility may contribute to tumour formation, either promoting unrestrained cell division or allowing inappropriate cell survival. The earliest studies revealed that tumours contain gain-of-function mutations within genes that normally signal cell division under specific growth conditions. The products of these genes are often components of the signal transduction pathways that are either overexpressed or expressed as overactive mutant proteins (Cantley et al., 1991). The constitutive activation of these pathways favours proliferation under conditions that would otherwise be growth prohibitive. However, it is clear that a single oncogenic mutation is insufficient to induce the formation of a tumour. The creation of artificial tumour cell lines by exogenous expression of oncogenes has demonstrated that at least four growth regulatory pathways must be disrupted to enable tumourigenic conversion of primary cells (Hahn et al., 1999). The requirement for additional mutations is explained, at least in part, by the existence of cell cycle checkpoints that have evolved to protect multicellular organisms against tumourigenesis. It is now clear that these checkpoints are governed by a second class of genes, the tumour suppressor genes, which repress cellular proliferation and which are frequently mutated in tumours. In normal tissues, the growth restraint exerted by the tumour suppressor gene products