TP53

About TP53

TP53 on chromosome 17p13.1 encodes p53, the protein often called the guardian of the genome. It is the most frequently mutated gene in human cancer, altered in roughly half of all tumors. p53 is a transcription factor that responds to DNA damage, oncogene activation, and other stresses by inducing cell cycle arrest through p21, DNA repair, senescence, or apoptosis through targets such as BAX and PUMA. MDM2 is the key negative regulator, targeting p53 for proteasomal degradation, and MDM2 amplification is an alternative way tumors disable the pathway. Most TP53 mutations are missense changes in the DNA binding domain that cause loss of transactivation and sometimes dominant negative or gain of function effects. Germline TP53 variants cause Li Fraumeni syndrome, an autosomal dominant condition with a very high lifetime risk of multiple cancers, often beginning in childhood or young adulthood, including sarcomas, breast cancer, brain tumors, adrenocortical carcinoma, and leukemia. p53 was discovered in 1979, and tumors with mutant p53 are often more aggressive and resistant to therapy.