MitoSciences: p53, Cellular tumor antigen (TP53)

UniProt Number:	P04637
Alternate Names:	Cellular tumor antigen p53, Antigen NY-CO-13, Phosphoprotein p53, Tumor suppressor p53, TP53
Structure and Function:	p53 (TP53 gene) acts as a tumor suppressor in many tumor types and induces growth arrest or apoptosis depending on the physiological circumstances and cell type. p53 is involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. p53 mediated apoptosis induction seems to be by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. p53 is also implicated in Notch signaling cross-over. Acetylation of the C-terminal end of p53 exposes the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis. Phosphorylation of the N-terminal end of p53, and conformational changes to p53, disrupt Mdm2-binding leading to p53 accumulation. Phosphorylation on Ser residues mediates transcriptional activation. The most important modification for the induction of apoptosis is the phosphorylation at Ser-46. P53 is phosphorylated on Ser-46 by HIPK2 upon UV irradiation. The Phosphorylation on Ser-46 is required for acetylation by CREBBP. P53 is phosphorylated on Ser-392 following UV but not gamma irradiation. P53 is phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1. P53 is stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. P53 is phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage.
Disease Associations:	The p53 protein is found in increased amounts in a wide variety of transformed cells. p53 is mutated or inactivated in about 60% of cancers. Four types of cancers account for 80% of tumors occurring in TP53 germline mutation carriers: breast cancers, soft tissue and bone sarcomas, brain tumors (astrocytomas) and adrenocortical carcinomas.