GenAge Human Genes Help Human Ageing Genomic Resources Citation

GenAge entry for TP53 (Homo sapiens)


Selected based on direct observations linking mammalian ageing to TP53


Gene name (HAGRID: 0006)

HGNC symbolTP53
AliasesP53; LFS1
Common nametumor protein p53

Potential relevance to the human ageing process

Main reason for selection

Entry selected based on evidence directly linking the gene product to ageing in a mammalian model organism

Description

TP53 is a tumour suppressor involved in cell cycle regulation, apoptosis, and DNA repair [0088]. Several lines of evidence from model organisms link TP53 to ageing. In flies, expression of a dominant-negative version of TP53 extends lifespan [1567]. Mice with an activated TP53 display signs of premature ageing starting at about 18 months of age [0011], as do mice heterozygous for TP53 and without BRCA1 [0037].

Human mutations in TP53 have been associated with cancer [0092]. People with a polymorphism that decreases the apoptotic potential of TP53 have increased survival despite a higher proportional mortality from cancer [1290]. The myriad of functions and interactions of TP53, as well as the findings from model organisms, make it a possible player in human ageing.

Cytogenetic information

Cytogenetic band17p13.1
Location7,512,463 bp to 7,531,642 bp
OrientationMinus strand
Display region using the UCSC Genome Browser

Protein information

FunctionDNA repair, apoptosis, stress response, cell cycle control
Cellular locationnucleus
Expressionubiquitous
Gene Ontology

GO:0002347; response to tumor cell; Process
GO:0006355; regulation of transcription, DNA-dependent; Process
GO:0006915; apoptosis; Process
GO:0018144; RNA-protein covalent cross-linking; Process
GO:0030308; negative regulation of cell growth; Process
GO:0044419; interspecies interaction between organisms; Process
GO:0045786; negative regulation of cell cycle; Process

GO:0003700; transcription factor activity; Function
GO:0008270; zinc ion binding; Function
GO:0046872; metal ion binding; Function

GO:0005634; nucleus; Cellular component
GO:0005737; cytoplasm; Cellular component
GO:0005783; endoplasmic reticulum; Cellular component

Protein-protein interactions

Interacting proteinsATM, ERCC2, WRN, PARP1, BRCA1, PIN1, PTEN, CREBBP, HIF1A, RPA1, BLM, S100B, HSP90AA1, EGR1, ABL1, BRCA2, TOP2A, TOP2B, TOP1, RAD51, UBE2I, TNF, ERCC6, STK11, EP300, PML, GSK3B, HTT, PRKCA, SSTR3, EEF2, ERCC3, HDAC1, MAPK8, YWHAZ, MAPK14, MED1, MAPK9, MAPK3, HMGB1, CCNA2, HMGB2, TFAP2A, TBP, APEX1, HBP1, PTGS2, HSPA9, SIN3A, CDC2, TFDP1, MDM2, POLA1, RELA, NR3C1, APTX, NFKBIA, ATR, CDC42.
Display interactions using the IGD

Retrieve sequences for TP53

PromoterPromoter
ORFORF
CDSCDS

Homologues in model organisms

P. troglodytesTP53 (tumor protein p53)
C. lupus familiarisTP53 (tumor protein p53)
B. taurusTP53 (tumor protein p53)
M. musculusTrp53 (transformation related protein 53)
R. norvegicusTp53 (tumor protein p53)
D. reriotp53 (tumor protein p53)
HomoloGene (460)

Selected references

[1903] Ryan and Scrable (2008), Mutant alleles of HD improve the life span of p53(-/-) mice, PubMed
[1900] Kanfi et al. (2008), Regulation of SIRT6 protein levels by nutrient availability, PubMed
[1902] Li and Ren (2007), Influence of cardiac-specific overexpression of insulin-like growth factor 1 on lifespan and aging-associated changes in cardiac intracellular Ca2+ homeostasis, protein damage and apoptotic protein expression, PubMed
[1915] Dai et al. (2007), Heat shock factor 1 is a powerful multifaceted modifier of carcinogenesis, PubMed
[1929] Wu et al. (2007), Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation, PubMed
[1917] Matheu et al. (2007), Delayed ageing through damage protection by the Arf/p53 pathway, PubMed
[1921] Kim et al. (2007), SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer's disease and amyotrophic lateral sclerosis, PubMed
[1840] Wang et al. (2007), Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes, PubMed
[1946] Suh et al. (2006), p63 protects the female germ line during meiotic arrest, PubMed
[1826] Eller et al. (2006), A role for WRN in telomere-based DNA damage responses, PubMed
[1828] de Oliveira (2006), Klotho RNAi induces premature senescence of human cells via a p53/p21 dependent pathway, PubMed
[1804] Wang et al. (2006), Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage, PubMed
[1777] Matoba et al. (2006), p53 regulates mitochondrial respiration, PubMed
[1838] Cao et al. (2006), ATM-Chk2-p53 activation prevents tumorigenesis at an expense of organ homeostasis upon Brca1 deficiency, PubMed
[1837] Nannenga et al. (2006), Augmented cancer resistance and DNA damage response phenotypes in PPM1D null mice, PubMed
[1594] Baker et al. (2006), Early aging-associated phenotypes in Bub3/Rae1 haploinsufficient mice, PubMed
[1601] Jeon et al. (2006), MCH-/- mice are resistant to aging-associated increases in body weight and insulin resistance, PubMed
[1586] Kamel et al. (2006), SirT1 fails to affect p53-mediated biological functions, PubMed
[1593] Bianchi et al. (2006), p53 and p66 proteins compete for hypoxia-inducible factor 1 alpha stabilization in young and old rat hearts exposed to intermittent hypoxia, PubMed
[1603] Mendrysa et al. (2006), Tumor suppression and normal aging in mice with constitutively high p53 activity, PubMed
[1536] Chung and Ng (2006), Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle, PubMed
[1604] Jacobs et al. (2005), p63 is an essential proapoptotic protein during neural development, PubMed
[1567] Bauer et al. (2005), Neuronal expression of p53 dominant-negative proteins in adult Drosophila melanogaster extends life span, PubMed
[1571] Strosznajder et al. (2005), Effect of aging and oxidative/genotoxic stress on poly(ADP-ribose) polymerase-1 activity in rat brain, PubMed
[1822] Sablina et al. (2005), The antioxidant function of the p53 tumor suppressor, PubMed
[1582] Chen et al. (2005), Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses, PubMed
[1491] Keyes et al. (2005), p63 deficiency activates a program of cellular senescence and leads to accelerated aging, PubMed
[1533] Chen et al. (2005), Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis, PubMed
[1472] Varela et al. (2005), Accelerated ageing in mice deficient in Zmpste24 protease is linked to p53 signalling activation, PubMed
[1575] Michishita et al. (2005), Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins, PubMed
[1480] Chua et al. (2005), Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress, PubMed
[1495] Attardi and Donehower (2005), Probing p53 biological functions through the use of genetically engineered mouse models, PubMed
[1506] Pandolfi et al. (2005), p66(shc) is highly expressed in fibroblasts from centenarians, PubMed
[1507] Gu et al. (2005), Roles of tumor suppressor and telomere maintenance genes in cancer and aging--an epidemiological study, PubMed
[1672] Fernandez-Fernandez et al. (2005), Proteins of the S100 family regulate the oligomerization of p53 tumor suppressor, PubMed
[1290] van Heemst et al. (2005), Variation in the human TP53 gene affects old age survival and cancer mortality, PubMed
[1569] Maehara et al. (2005), Reduction of total E2F/DP activity induces senescence-like cell cycle arrest in cancer cells lacking functional pRB and p53, PubMed
[1241] de Magalhaes et al. (2005), The influence of genes on the aging process of mice: a statistical assessment of the genetics of aging, PubMed
[0173] Nemoto et al. (2004), Nutrient availability regulates SIRT1 through a forkhead-dependent pathway, PubMed
[1738] Bond et al. (2004), A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans, PubMed
[1158] You et al. (2004), p53-dependent inhibition of FKHRL1 in response to DNA damage through protein kinase SGK1, PubMed
[1406] Qi et al. (2004), p19(ARF) directly and differentially controls the functions of c-Myc independently of p53, PubMed
[1119] Martin and Friedman (2004), Ticking fast or ticking slow, through shc must you go?, PubMed
[1107] Quarrie and Riabowol (2004), Murine models of life span extension, PubMed
[1117] Dumble et al. (2004), Insights into aging obtained from p53 mutant mouse models, PubMed
[1805] Yeung et al. (2004), Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase, PubMed
[1737] Kim et al. (2004), Expression of connective tissue growth factor, a biomarker in senescence of human diploid fibroblasts, is up-regulated by a transforming growth factor-beta-mediated signaling pathway, PubMed
[1077] Dorszewska and Adamczewska-Goncerzewicz (2004), Oxidative damage to DNA, p53 gene expression and p53 protein level in the process of aging in rat brain, PubMed
[1039] Orsini et al. (2004), The life span determinant p66Shc localizes to mitochondria where it associates with mtHsp70 and regulates trans-membrane potential, PubMed
[1823] Hussain et al. (2004), p53-induced up-regulation of MnSOD and GPx but not catalase increases oxidative stress and apoptosis, PubMed
[1099] Gueven et al. (2004), Aprataxin, a novel protein that protects against genotoxic stress, PubMed
[1063] Wang et al. (2004), Enhancement of Fas-mediated apoptosis in ageing human keratinocytes, PubMed
[1145] de Stanchina et al. (2004), PML is a direct p53 target that modulates p53 effector functions, PubMed
[1146] Maier et al. (2004), Modulation of mammalian life span by the short isoform of p53, PubMed
[1160] Torella et al. (2004), Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression, PubMed
[1660] Miyauchi et al. (2004), Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway, PubMed
[1006] Bassing and Alt (2004), H2AX may function as an anchor to hold broken chromosomal DNA ends in close proximity, PubMed
[0980] Cheng et al. (2003), Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice, PubMed
[1250] Lee et al. (2003), In vivo p53 function is indispensable for DNA damage-induced apoptotic signaling in Drosophila, PubMed
[0094] Stampfer et al. (2003), Loss of p53 function accelerates acquisition of telomerase activity in indefinite lifespan human mammary epithelial cell lines, PubMed
[1007] Celeste et al. (2003), H2AX haploinsufficiency modifies genomic stability and tumor susceptibility, PubMed
[1008] Bassing et al. (2003), Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors, PubMed
[1494] Collins and Sedivy (2003), Involvement of the INK4a/Arf gene locus in senescence, PubMed
[0089] Linke et al. (2003), p53 interacts with hRAD51 and hRAD54, and directly modulates homologous recombination, PubMed
[1042] O'Neill et al. (2003), p53 and a human premature ageing disorder, PubMed
[0161] Oren (2003), Decision making by p53: life, death and cancer, PubMed
[0165] Lagger et al. (2003), The tumor suppressor p53 and histone deacetylase 1 are antagonistic regulators of the cyclin-dependent kinase inhibitor p21/WAF1/CIP1 gene, PubMed
[0163] Krones-Herzig et al. (2003), Early growth response 1 protein, an upstream gatekeeper of the p53 tumor suppressor, controls replicative senescence, PubMed
[0093] Hwang et al. (2003), Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk, PubMed
[0037] Cao et al. (2003), Senescence, aging, and malignant transformation mediated by p53 in mice lacking the Brca1 full-length isoform, PubMed
[0889] Mendrysa et al. (2003), mdm2 is critical for inhibition of p53 during lymphopoiesis and the response to ionizing irradiation, PubMed
[1229] Bonafe et al. (2002), What studies on human longevity tell us about the risk for cancer in the oldest old: data and hypotheses on the genetics and immunology of centenarians, PubMed
[1933] Garcia-Cao et al. (2002), "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally, PubMed
[0424] Zacchi et al. (2002), The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults, PubMed
[0423] Zheng et al. (2002), The prolyl isomerase Pin1 is a regulator of p53 in genotoxic response, PubMed
[0034] Rouse and Jackson (2002), Interfaces between the detection, signaling, and repair of DNA damage, PubMed
[0036] Donehower (2002), Does p53 affect organismal aging?, PubMed
[0517] Bischof et al. (2002), Deconstructing PML-induced premature senescence, PubMed
[0992] Rubin (2002), The disparity between human cell senescence in vitro and lifelong replication in vivo, PubMed
[1811] Patturajan et al. (2002), DeltaNp63 induces beta-catenin nuclear accumulation and signaling, PubMed
[0008] Trinei et al. (2002), A p53-p66Shc signalling pathway controls intracellular redox status, levels of oxidation-damaged DNA and oxidative stress-induced apoptosis, PubMed
[1397] Schmitt et al. (2002), A senescence program controlled by p53 and p16-INK4a contributes to the outcome of cancer therapy, PubMed
[0734] Langley et al. (2002), Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence, PubMed
[0339] Ferbeyre et al. (2002), Oncogenic ras and p53 cooperate to induce cellular senescence, PubMed
[1004] Celeste et al. (2002), Genomic instability in mice lacking histone H2AX, PubMed
[0011] Tyner et al. (2002), p53 mutant mice that display early ageing-associated phenotypes, PubMed
[0735] Vaziri et al. (2001), hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase, PubMed
[1070] Luo et al. (2001), Negative control of p53 by Sir2alpha promotes cell survival under stress, PubMed
[0509] Karuman et al. (2001), The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death, PubMed
[0440] Shen and Loeb (2001), Unwinding the molecular basis of the Werner syndrome, PubMed
[1038] Maya et al. (2001), ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage, PubMed
[1779] Lebel et al. (2001), Tumorigenic effect of nonfunctional p53 or p21 in mice mutant in the Werner syndrome helicase, PubMed
[0652] Mohaghegh and Hickson (2001), DNA helicase deficiencies associated with cancer predisposition and premature ageing disorders, PubMed
[1673] Das et al. (2001), Ionizing radiation down-regulates p53 protein in primary Egr-1(-/-) mouse embryonic fibroblast cells causing enhanced resistance to apoptosis, PubMed
[0738] Luo et al. (2000), Deacetylation of p53 modulates its effect on cell growth and apoptosis, PubMed
[0148] Blander et al. (2000), The Werner syndrome protein contributes to induction of p53 by DNA damage, PubMed
[0091] Gonzalez-Suarez et al. (2000), Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis, PubMed
[0519] Ferbeyre et al. (2000), PML is induced by oncogenic ras and promotes premature senescence, PubMed
[0340] Pearson et al. (2000), PML regulates p53 acetylation and premature senescence induced by oncogenic Ras, PubMed
[0543] Goukassian et al. (2000), Mechanisms and implications of the age-associated decrease in DNA repair capacity, PubMed
[0906] Kaula et al. (2000), Inactivation of p53 and life span extension of human diploid fibroblasts by mot-2, PubMed
[0471] Whang et al. (2000), c-Abl is required for development and optimal cell proliferation in the context of p53 deficiency, PubMed
[0595] Lim et al. (2000), Analysis of ku80-mutant mice and cells with deficient levels of p53, PubMed
[0198] Difilippantonio et al. (2000), DNA repair protein Ku80 suppresses chromosomal aberrations and malignant transformation, PubMed
[1704] Lombard et al. (2000), Mutations in the WRN gene in mice accelerate mortality in a p53-null background, PubMed
[1863] Hirao et al. (2000), DNA damage-induced activation of p53 by the checkpoint kinase Chk2, PubMed
[1679] Brown and Baltimore (2000), ATR disruption leads to chromosomal fragmentation and early embryonic lethality, PubMed
[0133] Bulavin et al. (1999), Phosphorylation of human p53 by p38 kinase coordinates N-terminal phosphorylation and apoptosis in response to UV radiation, PubMed
[0160] Sionov and Haupt (1999), The cellular response to p53: the decision between life and death, PubMed
[0553] Jimenez et al. (1999), DNA-dependent protein kinase is not required for the p53-dependent response to DNA damage, PubMed
[0169] Spillare et al. (1999), p53-mediated apoptosis is attenuated in Werner syndrome cells, PubMed
[1487] Mills et al. (1999), p63 is a p53 homologue required for limb and epidermal morphogenesis, PubMed
[0078] Karlseder et al. (1999), p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2, PubMed
[0121] Dumont et al. (1999), Hydrogen peroxide-induced apoptosis is CD95-independent, requires the release of mitochondria-derived reactive oxygen species and the activation of NF-kappaB, PubMed
[0033] Canman et al. (1998), Activation of the ATM kinase by ionizing radiation and phosphorylation of p53, PubMed
[0032] Banin et al. (1998), Enhanced phosphorylation of p53 by ATM in response to DNA damage, PubMed
[0556] Woo et al. (1998), DNA-dependent protein kinase acts upstream of p53 in response to DNA damage, PubMed
[0396] Fearon (1997), Human cancer syndromes: clues to the origin and nature of cancer, PubMed
[0373] Vaziri et al. (1997), ATM-dependent telomere loss in aging human diploid fibroblasts and DNA damage lead to the post-translational activation of p53 protein involving poly(ADP-ribose) polymerase, PubMed
[0087] Sugrue et al. (1997), Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53, PubMed
[0092] Varley et al. (1997), Li-Fraumeni syndrome--a molecular and clinical review, PubMed
[0477] Ludwig et al. (1997), Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos, PubMed
[0857] Jayaraman et al. (1997), Identification of redox/repair protein Ref-1 as a potent activator of p53, PubMed
[0088] Ko and Prives (1996), p53: puzzle and paradigm, PubMed
[0120] Wu and Lozano (1994), NF-kappa B activation of p53. A potential mechanism for suppressing cell growth in response to stress, PubMed
[0090] Di Leonardo et al. (1994), DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts, PubMed
[0976] McWhir et al. (1993), Mice with DNA repair gene (ERCC-1) deficiency have elevated levels of p53, liver nuclear abnormalities and die before weaning, PubMed
[0979] Donehower et al. (1992), Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours, PubMed
[0890] Momand et al. (1992), The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation, PubMed
[0118] Irving et al. (1992), An altered repertoire of fos/jun (AP-1) at the onset of replicative senescence, PubMed

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External links

EPDHS_TP53
ORF AccessionNM_000546
CDS AccessionNP_000537
OMIM191170
HPRD01859
EnsemblTP53
Swiss-ProtP53_HUMAN
GeneCardsTP53
Entrez Gene7157
UniGene654481
GenAtlasTP53
InternetSearch Google


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