P53 and Human Cancer: The First Ten Thousand Mutations

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Publisher Summary The p53 protein is a tight, hydrophobic central globule containing the DNA binding domain, flanked by accessible N- and C-terminal regions. This protein is expressed in all cell types but has a rapid turnover and is latent under normal conditions. p53 is mutated in most common human malignancies and behaves as a multifunctional transcription factor involved in the control of cell cycle, programmed cell death, senescence, differentiation and development, transcription, DNA replication, DNA repair, and maintenance of genomic stability. p53 is converted to an active form in response to a number of physical or chemical DNA-damaging agents such as X or gamma irradiation, UV rays, oxidizing agents, cytotoxic drugs, and cancer-causing chemicals. Induction of p53 implies nuclear retention, accumulation of the protein as a result of post-translational stabilization, and allosteric conversion to a form with high sequence-specific DNA-binding capacity. p53 is activated in response to DNA damage, thus acting as a “guardian of the genome” against genotoxic stress. The chapter describes a three-step model of pS3 activation by stress signals. The downstream pS3 signaling is mediated by transcriptional activation of specific genes and by complex formation between p53 and heterologous proteins. The mutations and variations in the p53 gene are due to p53 polymorphisms, somatic mutations, and germline mutations in p53. The chapter also accounts for p53 mutations in sporadic cancers focussing on host-environment interactions. The chapter concludes with the potential clinical applications of the detection of p53 mutations in human tissues.