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. 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.

p53 Related Areas

Cancer>>Cancer Biomarkers>>p53/TP53

Signal Transduction>>Transcription Factor & Regulator>>p53/TP53

p53 Related Pathways

• EGFR Signaling Pathway

p53 Alternative Names

p53, TP53, FLJ92943, LFS1, P53, TRP53 [Homo sapiens]
p53, Trp53, RP23-56I20.1, Tp53, bbl, bfy, bhy, p44 [Mus musculus]

Summaries for p53

Entrez Gene summary for p53:

 

OMIM - description for p53:

The transcription factor p53 responds to diverse cellular stresses to regulate target genes that induce cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In addition, p53 appears to induce apoptosis through nontranscriptional cytoplasmic processes. In unstressed cells, p53 is kept inactive essentially through the actions of the ubiquitin ligase MDM2 (164785), which inhibits p53 transcriptional activity and ubiquitinates p53 to promote its degradation. Numerous posttranslational modifications modulate p53 activity, most notably phosphorylation and acetylation. Several less abundant p53 isoforms also modulate p53 activity. Activity of p53 is ubiquitously lost in human cancer either by mutation of the p53 gene itself or by loss of cell signaling upstream or downstream of p53

Wikipedia summary for p53:

p53 (also known as protein 53 or tumor protein 53), is a tumor suppressor protein that in humans is encoded by the TP53 gene.[2][3][4][5] p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.[6] The name p53 is in reference to its apparent molecular mass: It runs as a 53-kilodalton (kDa) protein on SDS-PAGE. But, based on calculations from its amino acid residues, p53's mass is actually only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slows its migration on SDS-PAGE, thus making it appear heavier than it actually is.[7] This effect is observed with p53 from a variety of species, including humans, rodents, frogs, and fish.

Human p53 Protein General Information

 

• Protein names: Recommended name: Cellular tumor antigen p53
  Short name: p53
• Sequence length: 393 AA
• Sequence similarities: Belongs to the p53 family.
• Post-translational modification: 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. 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 (Ref.110). 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.
• Subunit structure: 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 P53DINP1. 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 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 ubiquination 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.
• Subcellular location: Cytoplasm. Nucleus. Nucleus › PML body. Endoplasmic reticulum. Note: Interaction with BANP promotes nuclear localization. Recruited into PML bodies together with CHEK2.
• 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.
• Involvement in 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. Defects in TP53 are a cause of esophageal cancer (ESCR) [MIM:133239]. 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 (Ref.155 and Ref.158) 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.

General information above from UniProt

Function for p53 Protein

UniProtKB:

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.

Genatlas:

• p53 required for G1 growth arrest by WAF1 (CDKN1A) following DNA damage or induction of apoptosis
• p53 regulating by its C terminus a G2 checkpoint through cyclin B1
• transcriptional activator through acetylation of transactivation site by CREBBP
• p53 binding MDM2 resulting in transcriptional silencing and ubiquitin/proteasome dependent degradation of p53
• p53 putative teratologic suppressor gene and modulator of TFIIH (GTF2H), associated in nucleotide excision repair
• p53 playing a transcriptional role only in irradiated S phase cells (delta p53)
• p53 maintaining the ATR-intra-S phase checkpoint to promote coordination repair and replication (delta p53)
• p53 contributes to transcription or replication regulatory mechanisms of mitochondria and also boosts mitochondrial genomic stability via stimulation of base excision repair (Pubmed 20466735)
• key role of TP53-dependent apoptosis in depleting adult stem cells after the accumulation of DNA damage, which leads to a decrease in tissue regeneration (Pubmed 20818388)
• p53 has a pivotal role in the suppression of NOTCH-associated tumorigenesis in the mammary gland (Pubmed 21402876)

Homology for human p53

• homolog to rattus Tp53 (78,35 pc)

Phenotype Information for p53

• Gene/Locus: TP53, P53, LFS1
• Phenotype: Adrenal cortical carcinoma
  Choroid plexus papilloma
  Colorectal cancer
  Hepatocellular carcinoma
  Nasopharyngeal carcinoma
  Osteosarcoma
  Pancreatic cancer

Phenotype Information for p53 from OMIM (Online Mendelian Inheritance in Man)

Drugs for p53

Target	Drug Name	Disease	Drug Status
p53	Curaxin CBLC102 DCL000015	Prostate Cancer	Kidney Cancer Phase II

Drugs for p53 from TTD (Therapeutic Targets Database)