p53 TUMOUR SUPPRESSOR
The p53 tumour suppressor gene is mutated in a large proportion of human tumours.
The p53 protein is a DNA-binding protein – a transcription factor that regulates many processes involved in the cellular response to DNA damage and potentially carcinogenic events. The p53 protein is activated by DNA damage caused, for example, by UV radiation, ionising radiation, and various chemicals. Activation of the p53 protein depends on specific proteolysis. In its activated form, it plays a critical role in temporarily halting the cell cycle, which allows DNA repair processes to act on the damage and restore the correct DNA sequence before replication takes place. If the amount of damage is very great, p53 causes the process of apoptosis to be initiated; mutations do not occur in dead cells.
Mutations in p53 are typically missense mutations that inactivate the protein and prevent the cytostatic and apoptotic responses. Mutations in one allele have no immediate effect, as the other allele produces active protein. A mutation in the second allele is necessary, and often this occurs through chromosome loss (loss of heterogeneity, LOH) rather than a second missense mutation. LOH is a characteristic feature of tumour cells, in which the genome is unstable, and aneuploidy is invariably present.
The Li-Fraumeni syndrome is a familial cancer-prone condition with a mutant form of one of the p53 alleles inherited through the germ-line. Thus only one somatic mutation in p53 is needed to produce a fully p53-deficient cell. The syndrome is characterised by early cancer – particularly brain tumours in children, and early onset breast cancer.