TP53

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.

TP53 Gene(Protein Coding) Tumor Protein P53

Antigen NY CO 13, Cellular tumor antigen p53, FLJ92943, LFS1, P53, Phosphoprotein p53, TP53, TRP53, tumor protein p53, Tumor suppressor p53

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. However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP. In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. 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 and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. 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. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2.

Autophagy
B cell lineage commitment
Bone marrow development
Cardiac septum morphogenesis
Cell aging
Cell cycle arrest
Cellular protein localization
Cellular response to actinomycin D
Cellular response to DNA damage stimulus
Cellular response to drug
Cellular response to gamma radiation
Cellular response to glucose starvation
Cellular response to hypoxia
Cellular response to ionizing radiation
Cellular response to UV
Cellular response to UV-C
Cerebellum development
Chromatin assembly
Circadian behavior
Cytokine-mediated signaling pathway
Determination of adult lifespan
DNA damage response, signal transduction by p53 class mediator
DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest
DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator
DNA strand renaturation
Double-strand break repair
Embryonic organ development
Entrainment of circadian clock by photoperiod
ER overload response
Gastrulation
Hematopoietic progenitor cell differentiation
Hematopoietic stem cell differentiation
Interferon-gamma-mediated signaling pathway
Intrinsic apoptotic signaling pathway
Intrinsic apoptotic signaling pathway by p53 class mediator
Intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
Intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress
Intrinsic apoptotic signaling pathway in response to hypoxia
In utero embryonic development
Mitochondrial DNA repair
Mitotic cell cycle arrest
Mitotic G1 DNA damage checkpoint
mRNA transcription
Multicellular organism growth
Necroptotic process
Negative regulation of apoptotic process
Negative regulation of cell growth
Negative regulation of cell population proliferation
Negative regulation of DNA replication
Negative regulation of fibroblast proliferation
Negative regulation of glucose catabolic process to lactate via pyruvate
Negative regulation of helicase activity
Negative regulation of mitophagy
Negative regulation of neuroblast proliferation
Negative regulation of pentose-phosphate shunt
Negative regulation of production of miRNAs involved in gene silencing by miRNA
Negative regulation of proteolysis
Negative regulation of reactive oxygen species metabolic process
Negative regulation of telomerase activity
Negative regulation of transcription, DNA-templated
Negative regulation of transcription by RNA polymerase II
Negative regulation of transforming growth factor beta receptor signaling pathway
Neuron apoptotic process
Nucleotide-excision repair
Oligodendrocyte apoptotic process
Oxidative stress-induced premature senescence
Positive regulation of apoptotic process
Positive regulation of cardiac muscle cell apoptotic process
Positive regulation of cell aging
Positive regulation of cell cycle arrest
Positive regulation of execution phase of apoptosis
Positive regulation of gene expression
Positive regulation of histone deacetylation
Positive regulation of intrinsic apoptotic signaling pathway
Positive regulation of mitochondrial membrane permeability
Positive regulation of neuron apoptotic process
Positive regulation of peptidyl-tyrosine phosphorylation
Positive regulation of pri-miRNA transcription by RNA polymerase II
Positive regulation of production of miRNAs involved in gene silencing by miRNA
Positive regulation of programmed necrotic cell death
Positive regulation of protein export from nucleus
Positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway
Positive regulation of reactive oxygen species metabolic process
Positive regulation of release of cytochrome c from mitochondria
Positive regulation of RNA polymerase II transcription preinitiation complex assembly
Positive regulation of thymocyte apoptotic process
Positive regulation of transcription, DNA-templated
Positive regulation of transcription by RNA polymerase II
Positive regulation of transcription from RNA polymerase II promoter in response to endoplasmic reticulum stress
Positive regulation of transcription from RNA polymerase II promoter in response to hypoxia
Positive regulation of transcription from RNA polymerase II promoter in response to stress
Protein-containing complex assembly
Protein deubiquitination
Protein import into nucleus
Protein localization
Protein stabilization
Protein tetramerization
Ras protein signal transduction
Regulation of apoptotic process
Regulation of cell cycle G2/M phase transition
Regulation of cellular senescence
Regulation of DNA damage response, signal transduction by p53 class mediator
Regulation of fibroblast apoptotic process
Regulation of intrinsic apoptotic signaling pathway by p53 class mediator
Regulation of mitochondrial membrane permeability involved in apoptotic process
Regulation of signal transduction by p53 class mediator
Regulation of tissue remodeling
Regulation of transcription, DNA-templated
Regulation of transcription by RNA polymerase II
Regulation of transcription from RNA polymerase II promoter in response to DNA damage
Regulation of transcription initiation from RNA polymerase II promoter
Release of cytochrome c from mitochondria
Replicative senescence
Response to antibiotic
Response to gamma radiation
Response to ischemia
Response to salt stress
Response to X-ray
rRNA transcription
Signal transduction by p53 class mediator
Somitogenesis
T cell differentiation in thymus
T cell lineage commitment
T cell proliferation involved in immune response
Transforming growth factor beta receptor signaling pathway
Tumor necrosis factor-mediated signaling pathway
Viral process

Endoplasmic reticulum; Nucleus; PML body; Mitochondrion matrix; Centrosome; Cytoplasm. 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.
Isoform 1: Nucleus; Cytoplasm. Predominantly nuclear but localizes to the cytoplasm when expressed with isoform 4.
Isoform 2: Nucleus; Cytoplasm. Localized mainly in the nucleus with minor staining in the cytoplasm.
Isoform 3: Nucleus; Cytoplasm. Localized in the nucleus in most cells but found in the cytoplasm in some cells.
Isoform 4: Nucleus; Cytoplasm. Predominantly nuclear but translocates to the cytoplasm following cell stress.
Isoform 7: Nucleus; Cytoplasm. Localized mainly in the nucleus with minor staining in the cytoplasm.
Isoform 8: Nucleus; Cytoplasm. Localized in both nucleus and cytoplasm in most cells. In some cells, forms foci in the nucleus that are different from nucleoli.
Isoform 9: Cytoplasm

Esophageal cancer (ESCR): A malignancy of the esophagus. The most common types are esophageal squamous cell carcinoma and adenocarcinoma. Cancer of the esophagus remains a devastating disease because it is usually not detected until it has progressed to an advanced incurable stage.
Li-Fraumeni syndrome (LFS): An autosomal dominant familial cancer syndrome that in its classic form is defined by the existence of a proband affected by a sarcoma before 45 years with a first degree relative affected by any tumor before 45 years and another first degree relative with any tumor before 45 years or a sarcoma at any age. Other clinical definitions for LFS have been proposed and called Li-Fraumeni like syndrome (LFL). In these families affected relatives develop a diverse set of malignancies at unusually early ages. 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. Less frequent tumors include choroid plexus carcinoma or papilloma before the age of 15, rhabdomyosarcoma before the age of 5, leukemia, Wilms tumor, malignant phyllodes tumor, colorectal and gastric cancers.
Squamous cell carcinoma of the head and neck (HNSCC): A non-melanoma skin cancer affecting the head and neck. The hallmark of cutaneous SCC is malignant transformation of normal epidermal keratinocytes.
Lung cancer (LNCR): A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis.
Papilloma of choroid plexus (CPP): A benign tumor of neuroectodermal origin that generally occurs in childhood, but has also been reported in adults. Although generally found within the ventricular system, choroid plexus papillomas can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. Patients present with signs and symptoms of increased intracranial pressure including headache, hydrocephalus, papilledema, nausea, vomiting, cranial nerve deficits, gait impairment, and seizures.
Adrenocortical carcinoma (ADCC): A malignant neoplasm of the adrenal cortex and a rare childhood tumor. It occurs with increased frequency in patients with Beckwith-Wiedemann syndrome and Li-Fraumeni syndrome.
Basal cell carcinoma 7 (BCC7): A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. It is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter.
Bone marrow failure syndrome 5 (BMFS5): A form of bone marrow failure syndrome, a heterogeneous group of life-threatening disorders characterized by hematopoietic defects in association with a range of variable extra hematopoietic features. BMFS5 is an autosomal dominant form characterized by infantile onset of severe red cell anemia requiring transfusion. Additional features include hypogammaglobulinemia, poor growth with microcephaly, developmental delay, and seizures.
Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation. Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity. Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370. Dimethylated at Lys-373 by EHMT1 and EHMT2. Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity. Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20. Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation. Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity.
Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.

Acetylated. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner.
Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated on Ser-15 upon ultraviolet irradiation; which is enhanced by interaction with BANP. 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. It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. 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. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin.
Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.
May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.
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-291 and Lys-292, which leads to proteasomal degradation. Deubiquitinated by USP10, leading to its stabilization. Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation. Ubiquitination by TOPORS induces degradation. Deubiquitination by USP7, leading to stabilization. Isoform 4 is monoubiquitinated in an MDM2-independent manner. Ubiquitinated by COP1, which leads to proteasomal degradation. Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2. Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation