Schwab (ed.), Encyclopedia of Cancer, Springer-Verlag Berlin Heidelberg 2015
The TP53 tumor suppressor gene is located on chromosome 17p13.1 and encodes a ubiquitous phosphoprotein of molecular mass 51,000–53,000, essentially expressed in the nucleus. This gene is frequently inactivated by somatic mutation or by loss of alleles in many common human cancers. More than 25,000 such mutations have been described so far. Inherited, heterozygous mutations have been identified in about 400 families with Li-Fraumeni syndrome and Li-Fraumeni-like syndromes (LFS and LFL), characterized by the early occurrence of cancers at multiple organ sites. TP53 belongs to a p53 family that also includes TP73 (1p36) and P63 (3p28). In contrast with TP53, these two genes have a restricted, tissue-specific, and developmental expression pattern and are not frequently mutated in cancer.
The p53 protein is a latent transcription factor that is activated in response to multiple forms of physical and chemical stress to exert diverse, complementary effects in the regulation of cell proliferation, genetic integrity, and survival. These effects include:
- Induction of apoptosis
- Control of cell division through regulation of cell cycle progression in G1 and G2, centrosome duplication, and mitosis
- Modulation of DNA replication and repair of DNA
The main function of the p53 protein is to act as an “emergency brake” to prevent the proliferation of cells with damaged genetic material, caused by exposure to genotoxic agents (Fig. 1). In a broader context, the protein acts as an integrator of multiple exogenous and intracellular signals to regulate cell proliferation during replicative senescence, differentiation, and development. Inactivation of TP53 in mice resulted in accelerated development of multiple tumors, while a fraction of p53-deficient embryos displayed a lethal defect in neural tubule closure, resulting in exencephaly.
Fig. 1. The p53 pathway. The p53 protein is induced in response to various forms of stress and mediates a set of coordinated, antiproliferative responses including cell cycle arrest, control of replication, transcription, repair, and apoptosis. Blue: factors that bind to p53 and that are regulated by protein interactions. Red: factors that are regulated by p53 at the transcriptional level