This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277).
Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. 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. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Implicated in Notch signaling cross-over. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis.
p53 is the most commonly mutated gene in human cancer identified to date. Expression of p53 leads to inhibition of cell growth by preventing progression of cells from G1 to S phase of the cell cycle. Most importantly, p53 functions to cause arrest of cells in the G1 phase of the cell cycle following any exposure of cells to DNA-damaging agents. The MDM2 (murine double minute-2) protein was initially identified as an oncogene in a murine transformation system. MDM2 functions to bind p53 and block p53-mediated transactivation of cotransfected reporter constructs. The MDM2 gene is amplified in a high percentage of human sarcomas that retain wildtype p53 and tumor cells that overexpress MDM2 can tolerate high levels of p53 expression. Another p53 target protein is the p53-inducible RING finger protein (p53RFP), an auto-ubiquitinylated protein acting as an E3 ubiquitin ligase. p53RFP, also designated IBRDC2 in mouse and rat, receives ubiquitin from specific E2 ubiquitin-conjugating enzymes and transfers it to substrates that promote their degradation by the proteasome. p53RFP may mediate re-entry into the cell cycle.
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