Tp53

Domain

The [KR]-[STA]-K motif is specifically recognized by the SETD7 methyltransferase.

Function

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. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (By similarity). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (By similarity). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression (By similarity). Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis, but seems to have to effect on cell-cycle regulation. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).

Involvement in disease

p53 is found in increased amounts in a wide variety of transformed cells. p53 is frequently mutated or inactivated in many types of cancer.

Post-translational modifications

Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylation at Ser-12 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-21 by VRK1. Phosphorylated on Ser-23 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-23 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Probably phosphorylated on by CDK7 in a CAK complex in response to DNA damage. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-18 leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes (By similarity). Phosphorylated on Ser-389 following UV but not gamma irradiation. Phosphorylated by HIPK1. Phosphorylation at Ser-18 is required for interaction with DDX3X and gamma-tubulin (By similarity).

Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner (By similarity). Acetylated. Its deacetylation by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence.

Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation. Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome. Ubiquitinated by MKRN1 at Lys-288 and Lys-289, which leads to proteasomal degradation. Deubiquitinated by USP10, leading to stabilize it. Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation. Ubiquitination by TOPORS induces degradation. Deubiquitination by USP7, leading to stabilize it. Ubiquitinated by COP1, which leads to proteasomal degradation (By similarity). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (PubMed:24240685).

Monomethylated at Lys-369 by SETD7, leading to stabilization and increased transcriptional activation. Monomethylated at Lys-367 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity. Lys-369 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-367. Dimethylated at Lys-370 by EHMT1 and EHMT2. Monomethylated at Lys-379 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity. Demethylation of dimethylated Lys-367 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (By similarity). Monomethylated at Arg-330 and dimethylated at Arg-332 and Arg-334 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (By similarity). Polyubiquitinated by MUL1 at Lys-27 which leads to proteasomal degradation (By similarity).

Sumoylated with SUMO1. Sumoylated at Lys-383 by UBC9 (By similarity).

Sequence similarities

Belongs to the p53 family.

Cellular localization

• Cytoplasm
• Nucleus
• Nucleus
• PML body
• Endoplasmic reticulum
• Mitochondrion matrix
• Cytoplasm
• Cytoskeleton
• Microtubule organizing center
• Centrosome
• Interaction with BANP promotes nuclear localization. Recruited into PML bodies together with CHEK2. Translocates to mitochondria upon oxidative stress. Translocates to mitochondria in response to mitomycin C treatment (By similarity).

Alternative names

• Cellular tumor antigen p53
• Tumor suppressor p53
• P53
• Tp53
• Trp53

Database links

• entrezGene:22059
• swissprot:P02340

Target type

Proteins

Primary research area

Oncology

Other research areas

• Epigenetics

Molecular weight

43458Da