| http://identifiers.org/unip... | rdf:type | biopax3:ProteinReference | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:comment | 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. 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. COFACTOR: Binds 1 zinc ion per subunit. SUBUNIT: Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Binds DNA as a homotetramer. Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. In vitro, the interaction of TP53 with cancer- associated/HPV (E6) viral proteins leads to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with human cytomegalovirus/HHV-5 protein UL123. SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Nucleus, PML body. Endoplasmic reticulum. Note=Interaction with BANP promotes nuclear localization. Recruited into PML bodies together with CHEK2. SUBCELLULAR LOCATION: Isoform 1: Nucleus. Cytoplasm. Note=Predominantly nuclear but localizes to the cytoplasm when expressed with isoform 4. SUBCELLULAR LOCATION: Isoform 2: Nucleus. Cytoplasm. Note=Localized mainly in the nucleus with minor staining in the cytoplasm. SUBCELLULAR LOCATION: Isoform 3: Nucleus. Cytoplasm. Note=Localized in the nucleus in most cells but found in the cytoplasm in some cells. SUBCELLULAR LOCATION: Isoform 4: Nucleus. Cytoplasm. Note=Predominantly nuclear but translocates to the cytoplasm following cell stress. SUBCELLULAR LOCATION: Isoform 7: Nucleus. Cytoplasm. Note=Localized mainly in the nucleus with minor staining in the cytoplasm. SUBCELLULAR LOCATION: Isoform 8: Nucleus. Cytoplasm. Note=Localized in both nucleus and cytoplasm in most cells. In some cells, forms foci in the nucleus that are different from nucleoli. SUBCELLULAR LOCATION: Isoform 9: Cytoplasm. ALTERNATIVE PRODUCTS: Event=Alternative promoter usage, Alternative splicing; Named isoforms=9; Name=1; Synonyms=p53, p53alpha; IsoId=P04637-1; Sequence=Displayed; Name=2; Synonyms=I9RET, p53beta; IsoId=P04637-2; Sequence=VSP_006535, VSP_006536; Note=Expressed in quiescent lymphocytes. Seems to be non-functional. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=3; Synonyms=p53gamma; IsoId=P04637-3; Sequence=VSP_040560, VSP_040561; Note=Expressed in quiescent lymphocytes. Seems to be non-functional. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay; Name=4; Synonyms=Del40-p53, Del40-p53alpha, p47; IsoId=P04637-4; Sequence=VSP_040832; Name=5; Synonyms=Del40-p53beta; IsoId=P04637-5; Sequence=VSP_040832, VSP_006535, VSP_006536; Name=6; Synonyms=Del40-p53gamma; IsoId=P04637-6; Sequence=VSP_040832, VSP_040560, VSP_040561; Name=7; Synonyms=Del133-p53, Del133-p53alpha; IsoId=P04637-7; Sequence=VSP_040833; Note=Produced by alternative promoter usage; Name=8; Synonyms=Del133-p53beta; IsoId=P04637-8; Sequence=VSP_040833, VSP_006535, VSP_006536; Note=Produced by alternative promoter usage and alternative splicing; Name=9; Synonyms=Del133-p53gamma; IsoId=P04637-9; Sequence=VSP_040833, VSP_040560, VSP_040561; Note=Produced by alternative promoter usage and alternative splicing; TISSUE SPECIFICITY: Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine. INDUCTION: Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress. DOMAIN: The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors. PTM: 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. PTM: 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 upon DNA damage, probably by ATM or ATR. Phosphorylated on Ser-15 upon ultraviolet irradiation; which is enhanced by interaction with BANP. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was intially 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 (PubMed:21317932). 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 at Ser-315 and Ser-392 by CDK2 in response to DNA- damage. PTM: Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A. PTM: May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line. PTM: 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, 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. PTM: 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 SETD8, promoting interaction with L3MBTL1 and leading to repress transcriptional activity. Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation. PTM: Sumoylated by SUMO1. DISEASE: Note=TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma. DISEASE: Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:133239]. DISEASE: Defects in TP53 are a cause of Li-Fraumeni syndrome (LFS) [MIM:151623]. LFS is 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 (PubMed:8118819 and PubMed:8718514) 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. DISEASE: Defects in TP53 are involved in head and neck squamous cell carcinomas (HNSCC) [MIM:275355]; also known as squamous cell carcinoma of the head and neck. DISEASE: Defects in TP53 are a cause of lung cancer (LNCR) [MIM:211980]. LNCR is 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. DISEASE: Defects in TP53 are a cause of choroid plexus papilloma (CPLPA) [MIM:260500]. Choroid plexus papilloma is a slow-growing benign tumor of the choroid plexus that often invades the leptomeninges. In children it is usually in a lateral ventricle but in adults it is more often in the fourth ventricle. Hydrocephalus is common, either from obstruction or from tumor secretion of cerebrospinal fluid. If it undergoes malignant transformation it is called a choroid plexus carcinoma. Primary choroid plexus tumors are rare and usually occur in early childhood. DISEASE: Defects in TP53 are a cause of adrenocortical carcinoma (ADCC) [MIM:202300]. ADCC is a rare childhood tumor of the adrenal cortex. It occurs with increased frequency in patients with the Beckwith-Wiedemann syndrome and is a component tumor in Li- Fraumeni syndrome. SIMILARITY: Belongs to the p53 family. WEB RESOURCE: Name=IARC TP53 mutation database; Note=Somatic and germline TP53 mutations in human cancers; URL="http://www-p53.iarc.fr/"; WEB RESOURCE: Name=p53 web site at the Institut Curie; URL="http://p53.free.fr/"; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/P53ID88.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TP53"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/tp53/"; WEB RESOURCE: Name=SHMPD; Note=The Singapore human mutation and polymorphism database; URL="http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=TP53"; WEB RESOURCE: Name=Wikipedia; Note=P53 entry; URL="http://en.wikipedia.org/wiki/P53"; GENE SYNONYMS:TP53 P53. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License. | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:comment | SEQUENCE 393 AA; 43653 MW; AD5C149FD8106131 CRC64; | lld:biopax3 |
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| http://identifiers.org/unip... | biopax3:displayName | P53_HUMAN | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:name | TP53 | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:name | Tumor suppressor p53 | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:name | Phosphoprotein p53 | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:name | Antigen NY-CO-13 | lld:biopax3 |
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| http://identifiers.org/unip... | biopax3:sequence | MEEPQSDPSVEPPLSQETFSDLWKLLPENNVLSPLPSQAMDDLMLSPDDIEQWFTEDPGPDEAPRMPEAAPPVAPAPAAPTPAAPAPAPSWPLSSSVPSQKTYQGSYGFRLGFLHSGTAKSVTCTYSPALNKMFCQLAKTCPVQLWVDSTPPPGTRVRAMAIYKQSQHMTEVVRRCPHHERCSDSDGLAPPQHLIRVEGNLRVEYLDDRNTFRHSVVVPYEPPEVGSDCTTIHYNYMCNSSCMGGMNRRPILTIITLEDSSGNLLGRNSFEVRVCACPGRDRRTEEENLRKKGEPHHELPPGSTKRALPNNTSSSPQPKKKPLDGEYFTLQIRGRERFEMFRELNEALELKDAQAGKEPGGSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD | lld:biopax3 |
| http://identifiers.org/unip... | biopax3:standardName | Cellular tumor antigen p53 | lld:biopax3 |
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| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.reactome.org/bio... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://pid.nci.nih.gov/biop... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.phosphosite.org/... | biopax3:entityReference | http://identifiers.org/unip... | lld:biopax3 |
| http://www.pantherdb.org/pa... | biopax3:memberEntityReferen... | http://identifiers.org/unip... | lld:biopax3 |
| http://www.pantherdb.org/pa... | biopax3:memberEntityReferen... | http://identifiers.org/unip... | lld:biopax3 |
| http://www.pantherdb.org/pa... | biopax3:memberEntityReferen... | http://identifiers.org/unip... | lld:biopax3 |
| http://www.pantherdb.org/pa... | biopax3:memberEntityReferen... | http://identifiers.org/unip... | lld:biopax3 |
| http://www.pantherdb.org/pa... | biopax3:memberEntityReferen... | http://identifiers.org/unip... | lld:biopax3 |
