ABL1, AKT1, AKT2, AKT3, ATM, ATR, BAI1, BAX, BCL2, BRCA1, CASP1, CASP10, CASP2, CASP3, CASP4, CASP5, CASP6, CASP7, CASP8, CASP9, CCND1, CCNE1, CDK2, CDK4, CDKN1A, CHEK1, CHEK2, CSNK1D, DDR1, E2F1, E2F2, E2F3, E2F4, E2F5, E2F6, EP300, FAS, FOS, GADD45A, GADD45B, GADD45G, GSK3B, HDAC1, HDAC10, HDAC11, HDAC2, HDAC3, HDAC4..., HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HIF1A, HIPK2, KAT2B, MAPK10, MAPK11, MAPK12, MAPK13, MAPK14, MAPK8, MAPK9, MDM2, PIAS1, PRKDC, PSMA2, PSMA3, PSMA6, PSMB2, PSMB4, PSMB5, PSMC2, PSMC3, PSMC4, PSMC5, PSMD4, PTEN, RB1, SFN, SIRT1, SIRT2, SIRT3, SIRT4, SIRT5, SIRT6, THBS1, TNFRSF10B, TP53, UBB, UBC, UBD
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p53 is a tumor suppressor protein that regulates the expression of a wide variety of genes involved in apoptosis, growth arrest, inhibition of cell cycle progression, differentiation and accelerated DNA repair or senescence in response to genotoxic or cel ...lular stress. As a transcription factor, p53 is composed of an N-terminal Activation Domain, a central specific DNA Binding Domain, and a C-terminal Tetramerization Domain, followed by a Regulatory Domain rich in basic Amino acids. Having a short half-life, p53 is normally maintained at low levels in unstressed mammalian cells by continuous ubiquitylation and subsequent degradation by the 26S Proteasome. Nonphosphorylated p53 is ubiquitylated by the MDM2 (Mouse Double Minute-2) ubiquitin ligase. MDM2 binding inactivates p53 by two mechanisms. First, MDM2 binds to the transactivation domain of p53, precluding interaction with the transcriptional machinery. Second, this binding mediates the covalent attachment of ubiquitin to p53. Ubiquitylated p53 is then degraded by the Proteosome. Thus MDM2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. When the cell is confronted with stress like DNA damage, hypoxia, cytokines, metabolic changes, viral infection, or oncogenes, however, p53 ubiquitylation is suppressed and p53 accumulates in the nucleus, where it is activated and stabilized by undergoing multiple covalent modifications including Phosphorylation and Acetylation.
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