P53 (Protein 53 kDa)

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P53 (Protein 53 kDa)

TP53 (tumor protein p53 (Li-Fraumeni syndrome))

Identity

Other names TP53 (Tumour Protein 53)

Hugo TP53

Location 17p13

DNA/RNA

Description The gene encompasses 20 kb of DNA; 11 exons (the first is non-coding).

Transcription 3.0 kb mRNA; 1179 bp open reading frame.

Protein

Description 393 amino acids; 53 kDa protein; numerous post translational modifications: phosphorylation, acetylation, ubiquitination, sumoylation, neddylation. Contains from N-term to C-term, a transactivation domain ((1-42), a Proline rich domain (63-97), a specific DNA binding domain (102-292), 3 nuclear localization signals (305-322), a tetramerization domain that include a nuclear export signal (325-355) and a negative regulatory domain (360-393).

Expression Widely expressed

Localisation Nucleus

Function Tumour suppressor gene. P53 is a transcription factor present at minute level in any normal cells. Upon various types of stress (DNA damage, hypoxia, nucleotide pool depletion, viral infection, oncogene activation), postranslational modification lead to p53 stabilisation and activation. Although the number of genes activated by p53 is rather large, the outcome of p53 activation is either cell cycle arrest in G1 (by p21 ), in G2 (by 14-3-3 s) or apoptosis (by BAX, PUMA or NOXA). The cell growth arrest activity of p53 allows the activation of the DNA repair system of the cell.

Homology The five domains are highly-conserved regions between species (from human to fly). Two new genes homologous to p53 have been discovered, p73 localized at 1p36 and p63 localized at 3q27.

Mutations

Germinal In Li-Fraumeni syndrome, a dominantly inherited disease in which affected individuals are predisposed to develop sarcomas, osteosarcomas, leukemias and breast cancers at unusually early ages. Inherited TP53 mutations are associated with Li-Fraumeni and Li-Fraumeni-like syndromes, characterized by a familial clustering of tumors, with a predominance of soft tissue and bone sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas, diagnosed before the age of 45 years.

Somatic P53 is mutated in about 50% of human cancers, and the non-mutated allele is generally lost. The frequency and the type of mutation may vary from one tumour type to another. Somatic TP53 mutations are frequent in most human cancers, ranging from 5% to 80% depending on the type, stage and etiology of tumors. Most mutations are missense (75%) and other include non-sense (7.5%), deletions, insertions or splicing mutations (17.5%). There are some hot-spots for mutations at CpG dinucleotides at codon positions 175, 248, 273 and 282. TP53 gene mutation is a marker of bad prognosis in a number of cancers, such as breast cancer. Specific mutation spectra are observed in lung, liver and skin cancer that are related to specific carcinogen exposure (tobacco smoke, aflatoxin and UV respectively).

Implicated in

Entity Li-Fraumeni syndrome (LFS)

Disease Autosomal dominant condition, cancer prone disease, Li-Fraumeni syndrome (LFS) is defined by the existence of a proband with early onset sarcoma and a first degree relative with cancer before 45 years, plus another first/second degree relative with cancer at before 45 years or sarcoma at any age. Clinical definitions for Li-Fraumeni like syndromes (LFL) have also been proposed by Eeles and Birch. Germline mutation of TP53 is found in about 70% of LFS and 50% of LFL cases. In a few cases of LFS/LFL families free of TP53 mutations, germline mutations in genes connected to the p53 pathway have been found: CHK2, PTEN, CDKN2A.

Prognosis Most common cancer in Li-Fraumeni children (before the age of 10 years) are: soft tissues sarcoma, brain tumors and adrenocortical carcinomas; osteosarcoma predominate in adolescents; afterwards, female breast cancer, soft tissue sarcomas and brain tumors prevail, and other less frequent cancers such as leukaemias or colon carcinomas are also observed. Multiple primary cancers are quite characteristic of Li- Fraumeni syndrome but may also be representative of Bloom's syndrome. Cancers in this disease, as in other cancer-prone diseases, often occur early in life: 50% of patients aged 30 years have had a cancer (i.e. penetrance is 50%, according to this disease definition), and penetrance is 90% at age 60 years.

Oncogenesis (known) germinal mutations are variable, but are mostly missense mutations located in exons 4 to 10. In tumours occurring in these patients, the other (wild-type) allele is often lost, in accordance with the two-hit model for neoplasia.

Entity Haematological malignancies

Oncogenesis TP53 gene alterations have been found in:
- 20 - 30% of blast crisis CML (mostly in the myeloid type), often associated with i(17q).
- 5% of MDS cases and 15% of ANLL often with a visible del(17p).
- 2% of ALL (but with high variations according to the ALL type, reaching 50% of L3 ALL (and Burkitt lymphomas).
- 15% of CLL (and 40% in the aggressive CLL transformation into the Richter's syndrome) and 30% of adult T-cell leukaemia (only found in the aggressive form).
- 5-10% of multiple myelomas.
- 60-80% of Hodgkin disease.
- 30% of high grade B-cell NHL (rare in low grade NHL), and 50% of HIV-related NHL.
TP53 gene alterations in haematological malignancies are associated with a poor prognosis.

Entity Skin cancers

Disease Skin cancers include basal cell carcinomas, squamous cell cercinomas, and melanomas.

Prognosis Highly different according to the pathological group.

Oncogenesis TP53 is mutated in 40% of basal cell carcinomas and squamous cell carcinomas while mutations are infrequent in malignant melanoma. The pattern of TP53 mutation in skin cancer is highly related to UV exposure with a high frequency of CC->TT and C->T transitions and specific hotspots at codons 196 and 278.

Entity Melanoma

Disease Melanoma is a malignant tumor of melanocytes. Epidemiologic evidence suggests that exposure to ultraviolet (UV) radiation and the sensitivity of an individual's skin to UV radiation are risk factors for skin cancer including melanoma.

Oncogenesis TP53 gene mutations are rare in melanoma. They often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. It may contribute to the low frequency of TP53 mutations observed in this highly chemoresistant tumour type.

Entity Breast cancer

Oncogenesis TP53 is mutated in 25% of breast cancers with hotspots at codons 175, 220, 245, 248, 273. Geographical variations in mutation patterns have been observed. The prevalence of mutations is higher in large size, high grade and estrogen receptor negative tumors. It is also higher in BRCA1-related tumors. TP53 mutation is a factor of poor prognosis independently of tumor stage and hormone receptor content. It is associated with poor response to doxorubicin therapy.

Entity Head and neck squamous cell carcinoma

Disease Head and neck cancer is an important health problem around the world accounting for approximately 500 000 new cases each year. The carcinogenesis of head and neck results from a dysregulation of cellular proliferation, differentiation and cell death. The major etiologic agents are tobacco and alcohol consumption and for some cases human papilloma virus (HPV) infection.

Oncogenesis TP53 mutation can be found in about 40-60% of HNSCC cancers and is thought to be an early event as it is often detected in precancerous lesions. TP53 mutation is associated with poor prognosis in HNSCC.

Entity Lung cancers

Disease Lung cancers are neuroendocrine lung tumours (small cell lung carcinomas, carcinoids, large cell neuroendocrine carcinomas) or non neuroendocrine lung tumours (squamous carcinomas, adenocarcinomas, large cell carcinomas).

Oncogenesis Is multistep, through C-MYC or N-MYC activation, H-RAS1 or K-RAS2 mutation, P53, RB1, and P16 inactivation, loss of heterozygosity (LOH) at 3p, 13q, 17p. TP53 is mutated in 40% of lung cancers with frequent G->T transversions at codons 157, 158, 245, 248, 249 and 273. These mutations are linked to exposure to tobacco smoke. TP53 gene mutations may be associated with bad prognosis.

Entity Oesophagus cancers

Disease Two main forms: squamous cell carcinoma and adenocarcinoma

Oncogenesis TP53 is mutated in 45% of oesophageal cancers with hotspots at codons 175, 176, 248, 273, 282. It is thought to be an early event as it is often detected in precancerous lesions.

Entity Liver cancer

Cytogenetics Losses of 1p, 4q, 5p, 5q, 8q, 13q, 16p, 16q, and 17p in 20 to 50% of cases.

Oncogenesis Specific mutation at codon 249 related to aflatoxin B1 dietary exposure in exposed area (China, Africa); low frequency of mutation in developed countries.

Entity Gastric cancer

Disease Risk factors for gastric cancer include: Helicobacter pylori gastric infection, advanced age, male gender, diet including dry salted foods, atrophic gastritis, pernicious anemia, cigarette smoking, Menetrier's disease , and familial polyposis. Adenocarcinoma histology accounts for 90% to 95% of all gastric malignancies. The prognosis of patients with gastric cancer is related to tumor extent and includes both nodal involvement and direct tumor extension beyond the gastric wall. Tumor grade may also provide some prognostic information.

Oncogenesis TP53 mutations are found in about 30% of gastric cancer with a spectrum similar to the one of colorectal cancer. The prognostic value of these mutations is unknown.

Entity Colorectal cancers

Disease There are two types of colorectal cancers, according to the ploidy:
- The diploid form, RER+ (Replication Error+), sporadic, without loss of heterozygosity (LOH), with few mutations of p53 and APC, and right-sided.
-The polyploid form, RER-, with LOH (5q, 17p, 18q), mutations in p53, and more often left-sided, they have a worse prognosis.

Prognosis Survival, although improving, is not much more than 50% after 5 years.

Cytogenetics Diploid tumours without frequent allelic losses; aneuploid tumours with numerous allelic losses; LOH on chromosomes 17 and 18 in more than 75% of cases; other chromosome arms losses in about 50% of cases.

Oncogenesis A number of genes are known to be implicated in tumour progression in colorectal cancers : APC, P53, KRAS2, mismatch repair genes (MMR genes). TP53 is mutated in 45% of colorectal cancer cases with a majority of C->T transitions at CpG sites and hotspots at codons 175, 245, 248, 273 and 282. TP53 mutation may be associated with poor prognosis in patient treated with chemotherapy.

Entity Bladder cancer

Prognosis Highly variable, according to the stage and the grade.

Cytogenetics -9, -11 or del(11p), del(17p) and LOH at 17p, del(13q), frequent other LOH, aneuploidy, polyploidy, complex karyotypes.

Oncogenesis Multi-step and largely unknown process; loss of 9q and P53 mutations would be early events; RB1, and P16 inactivation, EGFR overexpression, LOH at 3p, 8p, 11p, 13q, 17p, 18q. TP53 is mutated in 30% of bladder cancers with a majority of G->A transitions at non-CpG sites and 2 hotspots at codons 280 and 285.

Entity Cervical cancer

Disease Risk factors for cervical cancer include predominantly infection with certain human papillomaviruses such as HPV16 and HPV18. Carcinoma of the uterine cervix is one of the most common neoplasias among women worldwide.

Oncogenesis The frequency of TP53 mutation in cervical cancer is very low. The p53 pathway is inactivated by the E6 protein that binds and inactivates the p53 protein. Rare TP53 mutations have been detected in HPV negative cancer.

Entity Ovary carcinoma

Disease Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies. The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease.

Oncogenesis TP53 mutation is present in 20% in early stage to 80% in late stage ovarian cancers. The prognostic value of TP53 gene mutation is still a matter of debate, although positive IHC staining for p53 protein seems to be associated with poor prognosis.

Entity Prostate cancer

Oncogenesis TP53 mutations are found in less than 20% of prostate cancers with a main hotspot at codon 273. Little is known about the role and prognostic value of these mutations.

Entity Glioblastoma

Disease Glioblastoma is the most malignant astrocytic tumor and is preferentially located in the cerebral hemisphere. It may develop from a less malignant precursor lesion such as diffuse astrocytoma or anaplastic astrocytoma, or may develop de novo (secondary glioblastoma and primary glioblastoma respectively). Secondary glioblastoma are more frequent in younger patients and have a better prognosis.

Oncogenesis TP53 mutation is an early and frequent (over 60%) event in secondary glioblastomas while it is rare in primary glioblastomas (inferior to 10%) with hotspots at codons 175, 248 and 273. TP53 mutation is associated with good prognosis as it is more frequent in secondary glioblastomas which occur in young patients and are of better prognosis.

To be noted

Germinal mutations of P53 have also been found in families where the criteria for LFS or LFL were not reached.

External links

	Nomenclature
Hugo	TP53
GDB	TP53
Entrez_Gene	TP53 7157 tumor protein p53
	Cards
Atlas	P53ID88
GeneCards	TP53
Ensembl	TP53 [Search_View] ENSG00000141510 [Gene_View]
Genatlas	TP53
GeneLynx	TP53
eGenome	TP53
euGene	7157
	Genomic and cartography
GoldenPath	TP53 - 17p13 chr17:7512445-7531642 - 17p13.1 [Description] (hg18-Mar_2006)
Ensembl	TP53 - 17p13.1 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	TP53
	Gene and transcription
Genbank	AB082923 [ ENTREZ ]
Genbank	AF052180 [ ENTREZ ]
Genbank	AF307851 [ ENTREZ ]
Genbank	AK223026 [ ENTREZ ]
Genbank	AK225838 [ ENTREZ ]
RefSeq	NM_000546 [ SRS ] NM_000546 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ] AC_000060 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ] NC_000017 [ ENTREZ ]
RefSeq	NT_010718 [ SRS ] NT_010718 [ ENTREZ ]
RefSeq	NW_926584 [ SRS ] NW_926584 [ ENTREZ ]
AceView	TP53 AceView - NCBI
Unigene	Hs.654481 [ SRS ] Hs.654481 [ NCBI ] HS654481 [ spliceNest ]
Fast-db	3234 (alternative variants)
	Protein : pattern, domain, 3D structure
	Protein Interaction databases
	Polymorphism : SNP, mutations, diseases
OMIM	114480;114500;114550;151623;161550;191170;202300;260350 [ map ]
GENECLINICS	114480;114500;114550;151623;161550;191170;202300;260350
SNP	TP53 [dbSNP-NCBI]
SNP	NM_000546 [SNP-NCI]
SNP	TP53 [GeneSNPs - Utah] TP53] [HGBASE - SRS]
HAPMAP	TP53 [HAPMAP]
COSMIC	TP53 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	TP53
	General knowledge
Family Browser	TP53 [UCSC Family Browser]
SOURCE	NM_000546
SMD	Hs.654481
SAGE	Hs.654481
GO	DNA strand annealing activity [Amigo] DNA strand annealing activity
GO	response to tumor cell [Amigo] response to tumor cell
GO	chromatin binding [Amigo] chromatin binding
GO	transcription factor activity [Amigo] transcription factor activity
GO	transcription factor activity [Amigo] transcription factor activity
GO	nuclease activity [Amigo] nuclease activity
GO	copper ion binding [Amigo] copper ion binding
GO	protein binding [Amigo] protein binding
GO	ATP binding [Amigo] ATP binding
GO	insoluble fraction [Amigo] insoluble fraction
GO	nucleus [Amigo] nucleus
GO	nucleus [Amigo] nucleus
GO	nucleoplasm [Amigo] nucleoplasm
GO	nucleolus [Amigo] nucleolus
GO	cytoplasm [Amigo] cytoplasm
GO	cytoplasm [Amigo] cytoplasm
GO	mitochondrion [Amigo] mitochondrion
GO	endoplasmic reticulum [Amigo] endoplasmic reticulum
GO	base-excision repair [Amigo] base-excision repair
GO	nucleotide-excision repair [Amigo] nucleotide-excision repair
GO	regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA-dependent
GO	regulation of transcription, DNA-dependent [Amigo] regulation of transcription, DNA-dependent
GO	protein complex assembly [Amigo] protein complex assembly
GO	apoptosis [Amigo] apoptosis
GO	response to DNA damage stimulus [Amigo] response to DNA damage stimulus
GO	ER overload response [Amigo] ER overload response
GO	cell cycle [Amigo] cell cycle
GO	cell cycle arrest [Amigo] cell cycle arrest
GO	multicellular organismal development [Amigo] multicellular organismal development
GO	cell aging [Amigo] cell aging
GO	protein localization [Amigo] protein localization
GO	zinc ion binding [Amigo] zinc ion binding
GO	zinc ion binding [Amigo] zinc ion binding
GO	cell proliferation [Amigo] cell proliferation
GO	induction of apoptosis by intracellular signals [Amigo] induction of apoptosis by intracellular signals
GO	caspase activation via cytochrome c [Amigo] caspase activation via cytochrome c
GO	nuclear matrix [Amigo] nuclear matrix
GO	RNA-protein covalent cross-linking [Amigo] RNA-protein covalent cross-linking
GO	enzyme binding [Amigo] enzyme binding
GO	cell differentiation [Amigo] cell differentiation
GO	negative regulation of cell growth [Amigo] negative regulation of cell growth
GO	cellular response to glucose starvation [Amigo] cellular response to glucose starvation
GO	DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis [Amigo] DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis
GO	regulation of apoptosis [Amigo] regulation of apoptosis
GO	negative regulation of cell cycle [Amigo] negative regulation of cell cycle
GO	positive regulation of transcription from RNA polymerase II promoter [Amigo] positive regulation of transcription from RNA polymerase II promoter
GO	metal ion binding [Amigo] metal ion binding
GO	regulation of mitochondrial membrane permeability [Amigo] regulation of mitochondrial membrane permeability
GO	protein heterodimerization activity [Amigo] protein heterodimerization activity
GO	protein N-terminus binding [Amigo] protein N-terminus binding
GO	negative regulation of helicase activity [Amigo] negative regulation of helicase activity
GO	protein tetramerization [Amigo] protein tetramerization
BIOCARTA	Estrogen-responsive protein Efp controls cell cycle and breast tumors growth [Genes]
BIOCARTA	Tumor Suppressor Arf Inhibits Ribosomal Biogenesis [Genes]
BIOCARTA	ATM Signaling Pathway [Genes]
BIOCARTA	Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]
BIOCARTA	BTG family proteins and cell cycle regulation [Genes]
BIOCARTA	Apoptotic Signaling in Response to DNA Damage [Genes]
BIOCARTA	CTCF: First Multivalent Nuclear Factor [Genes]
BIOCARTA	Cell Cycle: G1/S Check Point [Genes]
BIOCARTA	Cell Cycle: G2/M Checkpoint [Genes]
BIOCARTA	p53 Signaling Pathway [Genes]
BIOCARTA	Hypoxia and p53 in the Cardiovascular system [Genes]
BIOCARTA	Regulation of cell cycle progression by Plk3 [Genes]
BIOCARTA	Regulation of transcriptional activity by PML [Genes]
BIOCARTA	RB Tumor Suppressor/Checkpoint Signaling in response to DNA damage [Genes]
BIOCARTA	Double Stranded RNA Induced Gene Expression [Genes]
BIOCARTA	Telomeres, Telomerase, Cellular Aging, and Immortality [Genes]
BIOCARTA	Overview of telomerase protein component gene hTert Transcriptional Regulation [Genes]
BIOCARTA	Chaperones modulate interferon Signaling Pathway [Genes]
KEGG	MAPK signaling pathway
KEGG	Cell cycle
KEGG	Apoptosis
KEGG	Wnt signaling pathway
KEGG	Amyotrophic lateral sclerosis (ALS)
KEGG	Huntington's disease
KEGG	Colorectal cancer
PubGene	TP53
TreeFam	TP53
CTD	7157 [Comparative ToxicoGenomics Database]
	Other databases
Other database	IARC TP53 Mutation Database
Other database	P53 Knowledge Database
Other database	http://p53.free.fr/Database/p53_database.html
Other database	Database of germline p53 mutations
	Probes
Probe	TP53 Related clones (RZPD - Berlin)
	PubMed
PubMed	499 Pubmed reference(s) in LocusLink

Bibliography

Li-Fraumeni syndrome--a molecular and clinical review.

Varley JM, Evans DG, Birch JM

British journal of cancer. 1997 ; 76 (1) : 1-14.

PMID 9218725

Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress.

Ljungman M

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PMID 10935507

Surfing the p53 network.

Vogelstein B, Lane D, Levine AJ

Nature. 2000 ; 408 (6810) : 307-310.

PMID 11099028

p53: death star.

Vousden KH

Cell. 2000 ; 103 (5) : 691-694.

PMID 11114324

P63 and P73: P53 mimics, menaces and more.

Yang A, McKeon F

Nature reviews. Molecular cell biology. 2000 ; 1 (3) : 199-207.

PMID 11252895

Assessing TP53 status in human tumours to evaluate clinical outcome.

Soussi T, B��roud C

Nature reviews. Cancer. 2001 ; 1 (3) : 233-240.

PMID 11902578

The evolution of diverse biological responses to DNA damage: insights from yeast and p53.

Wahl GM, Carr AM

Nature cell biology. 2001 ; 3 (12) : E277-E286.

PMID 11781586

p73: Friend or foe in tumorigenesis.

Melino G, De Laurenzi V, Vousden KH

Nature reviews. Cancer. 2002 ; 2 (8) : 605-615.

PMID 12154353

Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype.

Olivier M, Goldgar DE, Sodha N, Ohgaki H, Kleihues P, Hainaut P, Eeles RA

Cancer research. 2003 ; 63 (20) : 6643-6650.

PMID 14583457

Focus on the p53 gene and cancer: advances in TP53 mutation research.

Soussi T

Human mutation. 2003 ; 21 (3) : 173-175.

PMID 12619102

25 Years of p53 Research

Pierre Hainaut and Klas G Wiman

Eds..

The p53 pathway: positive and negative feedback loops.

Harris SL, Levine AJ

Oncogene. 2005 ; 24 (17) : 2899-2908.

PMID 15838523

Transcription-independent pro-apoptotic functions of p53.

Moll UM, Wolff S, Speidel D, Deppert W

Current opinion in cell biology. 2005 ; 17 (6) : 631-636.

PMID 16226451

p53 aerobics: the major tumor suppressor fuels your workout.

Kruse JP, Gu W

Cell metabolism. 2006 ; 4 (1) : 1-3.

PMID 16814724

p53: more research and more questions.

Braithwaite AW, Prives CL

Cell death and differentiation. 2006 ; 13 (6) : 877-880.

PMID 16708075

TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes.

Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M

Oncogene. 2007 ; 26 (15) : 2157-2165.

PMID 17401424

Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.

Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M

Human mutation. 2007 ; 28 (6) : 622-629.

PMID 17311302

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Search in all EBI NCBI

Contributor(s)

Written 07-1998 Richard Hamelin, Jean-Loup Huret

INSERM U434, Laboratoire de Genetique des Tumeurs, CEPH, Paris (RH), and Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers (JLH), France.

Updated 12-2001 Thierry Soussi

INSERM U434, Laboratoire de Genetique des Tumeurs, CEPH, Paris (RH), and Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers (JLH), France.

Updated 10-2002 Thierry Soussi

Laboratoire de Genotoxicologie des tumeurs, Institut Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75005 Paris, France.

Updated 04-2007 Magali Olivier

Laboratoire de Genotoxicologie des tumeurs, Institut Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75005 Paris, France.

Updated

Molecular Carcinogenesis and Biomarkers Group, International Agency for Research on Cancer (IARC/CIRC), 150 Cours Albert Thomas, F-69372 Lyon CEDEX 08, France

Citation

This paper should be referenced as such :
Hamelin R, Huret JL . P53 (Protein 53 kDa); TP53 (tumor protein p53 (Li-Fraumeni syndrome)). Atlas Genet Cytogenet Oncol Haematol. July 1998 .
URL : http://AtlasGeneticsOncology.org/Genes/P53ID88.html

Hamelin R, Huret JL . P53 (Protein 53 kDa); TP53 (tumor protein p53 (Li-Fraumeni syndrome)). Atlas Genet Cytogenet Oncol Haematol. December 2001 .
URL : http://AtlasGeneticsOncology.org/Genes/P53ID88.html

Soussi T . P53 (Protein 53 kDa); TP53 (tumor protein p53 (Li-Fraumeni syndrome)). Atlas Genet Cytogenet Oncol Haematol. October 2002 .
URL : http://AtlasGeneticsOncology.org/Genes/P53ID88.html

Soussi T . P53 (Protein 53 kDa); TP53 (tumor protein p53 (Li-Fraumeni syndrome)). Atlas Genet Cytogenet Oncol Haematol. April 2007 .
URL : http://AtlasGeneticsOncology.org/Genes/P53ID88.html

Olivier M . P53 (Protein 53 kDa); TP53 (tumor protein p53 (Li-Fraumeni syndrome)). Atlas Genet Cytogenet Oncol Haematol. .
URL : http://AtlasGeneticsOncology.org/Genes/P53ID88.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Wed Jul 2 08:25:47 2008

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j.l.huret@chu-poitiers.fr.

Other names	TP53 (Tumour Protein 53)
Hugo	TP53
Location	17p13

Description	The gene encompasses 20 kb of DNA; 11 exons (the first is non-coding).
Transcription	3.0 kb mRNA; 1179 bp open reading frame.

Description	393 amino acids; 53 kDa protein; numerous post translational modifications: phosphorylation, acetylation, ubiquitination, sumoylation, neddylation. Contains from N-term to C-term, a transactivation domain ((1-42), a Proline rich domain (63-97), a specific DNA binding domain (102-292), 3 nuclear localization signals (305-322), a tetramerization domain that include a nuclear export signal (325-355) and a negative regulatory domain (360-393).
Expression	Widely expressed
Localisation	Nucleus
Function	Tumour suppressor gene. P53 is a transcription factor present at minute level in any normal cells. Upon various types of stress (DNA damage, hypoxia, nucleotide pool depletion, viral infection, oncogene activation), postranslational modification lead to p53 stabilisation and activation. Although the number of genes activated by p53 is rather large, the outcome of p53 activation is either cell cycle arrest in G1 (by p21 ), in G2 (by 14-3-3 s) or apoptosis (by BAX, PUMA or NOXA). The cell growth arrest activity of p53 allows the activation of the DNA repair system of the cell.
Homology	The five domains are highly-conserved regions between species (from human to fly). Two new genes homologous to p53 have been discovered, p73 localized at 1p36 and p63 localized at 3q27.

Entity	Li-Fraumeni syndrome (LFS)
Disease	Autosomal dominant condition, cancer prone disease, Li-Fraumeni syndrome (LFS) is defined by the existence of a proband with early onset sarcoma and a first degree relative with cancer before 45 years, plus another first/second degree relative with cancer at before 45 years or sarcoma at any age. Clinical definitions for Li-Fraumeni like syndromes (LFL) have also been proposed by Eeles and Birch. Germline mutation of TP53 is found in about 70% of LFS and 50% of LFL cases. In a few cases of LFS/LFL families free of TP53 mutations, germline mutations in genes connected to the p53 pathway have been found: CHK2, PTEN, CDKN2A.
Prognosis	Most common cancer in Li-Fraumeni children (before the age of 10 years) are: soft tissues sarcoma, brain tumors and adrenocortical carcinomas; osteosarcoma predominate in adolescents; afterwards, female breast cancer, soft tissue sarcomas and brain tumors prevail, and other less frequent cancers such as leukaemias or colon carcinomas are also observed. Multiple primary cancers are quite characteristic of Li- Fraumeni syndrome but may also be representative of Bloom's syndrome. Cancers in this disease, as in other cancer-prone diseases, often occur early in life: 50% of patients aged 30 years have had a cancer (i.e. penetrance is 50%, according to this disease definition), and penetrance is 90% at age 60 years.
Oncogenesis	(known) germinal mutations are variable, but are mostly missense mutations located in exons 4 to 10. In tumours occurring in these patients, the other (wild-type) allele is often lost, in accordance with the two-hit model for neoplasia.

Entity	Haematological malignancies
Oncogenesis	TP53 gene alterations have been found in: - 20 - 30% of blast crisis CML (mostly in the myeloid type), often associated with i(17q). - 5% of MDS cases and 15% of ANLL often with a visible del(17p). - 2% of ALL (but with high variations according to the ALL type, reaching 50% of L3 ALL (and Burkitt lymphomas). - 15% of CLL (and 40% in the aggressive CLL transformation into the Richter's syndrome) and 30% of adult T-cell leukaemia (only found in the aggressive form). - 5-10% of multiple myelomas. - 60-80% of Hodgkin disease. - 30% of high grade B-cell NHL (rare in low grade NHL), and 50% of HIV-related NHL. TP53 gene alterations in haematological malignancies are associated with a poor prognosis.

Entity	Skin cancers
Disease	Skin cancers include basal cell carcinomas, squamous cell cercinomas, and melanomas.
Prognosis	Highly different according to the pathological group.
Oncogenesis	TP53 is mutated in 40% of basal cell carcinomas and squamous cell carcinomas while mutations are infrequent in malignant melanoma. The pattern of TP53 mutation in skin cancer is highly related to UV exposure with a high frequency of CC->TT and C->T transitions and specific hotspots at codons 196 and 278.

Entity	Melanoma
Disease	Melanoma is a malignant tumor of melanocytes. Epidemiologic evidence suggests that exposure to ultraviolet (UV) radiation and the sensitivity of an individual's skin to UV radiation are risk factors for skin cancer including melanoma.
Oncogenesis	TP53 gene mutations are rare in melanoma. They often lose Apaf-1, a cell-death effector that acts with cytochrome c and caspase-9 to mediate p53-dependent apoptosis. It may contribute to the low frequency of TP53 mutations observed in this highly chemoresistant tumour type.

Entity	Breast cancer
Oncogenesis	TP53 is mutated in 25% of breast cancers with hotspots at codons 175, 220, 245, 248, 273. Geographical variations in mutation patterns have been observed. The prevalence of mutations is higher in large size, high grade and estrogen receptor negative tumors. It is also higher in BRCA1-related tumors. TP53 mutation is a factor of poor prognosis independently of tumor stage and hormone receptor content. It is associated with poor response to doxorubicin therapy.

Entity	Head and neck squamous cell carcinoma
Disease	Head and neck cancer is an important health problem around the world accounting for approximately 500 000 new cases each year. The carcinogenesis of head and neck results from a dysregulation of cellular proliferation, differentiation and cell death. The major etiologic agents are tobacco and alcohol consumption and for some cases human papilloma virus (HPV) infection.
Oncogenesis	TP53 mutation can be found in about 40-60% of HNSCC cancers and is thought to be an early event as it is often detected in precancerous lesions. TP53 mutation is associated with poor prognosis in HNSCC.

Entity	Lung cancers
Disease	Lung cancers are neuroendocrine lung tumours (small cell lung carcinomas, carcinoids, large cell neuroendocrine carcinomas) or non neuroendocrine lung tumours (squamous carcinomas, adenocarcinomas, large cell carcinomas).
Oncogenesis	Is multistep, through C-MYC or N-MYC activation, H-RAS1 or K-RAS2 mutation, P53, RB1, and P16 inactivation, loss of heterozygosity (LOH) at 3p, 13q, 17p. TP53 is mutated in 40% of lung cancers with frequent G->T transversions at codons 157, 158, 245, 248, 249 and 273. These mutations are linked to exposure to tobacco smoke. TP53 gene mutations may be associated with bad prognosis.

Entity	Oesophagus cancers
Disease	Two main forms: squamous cell carcinoma and adenocarcinoma
Oncogenesis	TP53 is mutated in 45% of oesophageal cancers with hotspots at codons 175, 176, 248, 273, 282. It is thought to be an early event as it is often detected in precancerous lesions.

Entity	Liver cancer
Cytogenetics	Losses of 1p, 4q, 5p, 5q, 8q, 13q, 16p, 16q, and 17p in 20 to 50% of cases.
Oncogenesis	Specific mutation at codon 249 related to aflatoxin B1 dietary exposure in exposed area (China, Africa); low frequency of mutation in developed countries.

Entity	Gastric cancer
Disease	Risk factors for gastric cancer include: Helicobacter pylori gastric infection, advanced age, male gender, diet including dry salted foods, atrophic gastritis, pernicious anemia, cigarette smoking, Menetrier's disease , and familial polyposis. Adenocarcinoma histology accounts for 90% to 95% of all gastric malignancies. The prognosis of patients with gastric cancer is related to tumor extent and includes both nodal involvement and direct tumor extension beyond the gastric wall. Tumor grade may also provide some prognostic information.
Oncogenesis	TP53 mutations are found in about 30% of gastric cancer with a spectrum similar to the one of colorectal cancer. The prognostic value of these mutations is unknown.

Entity	Colorectal cancers
Disease	There are two types of colorectal cancers, according to the ploidy: - The diploid form, RER+ (Replication Error+), sporadic, without loss of heterozygosity (LOH), with few mutations of p53 and APC, and right-sided. -The polyploid form, RER-, with LOH (5q, 17p, 18q), mutations in p53, and more often left-sided, they have a worse prognosis.
Prognosis	Survival, although improving, is not much more than 50% after 5 years.
Cytogenetics	Diploid tumours without frequent allelic losses; aneuploid tumours with numerous allelic losses; LOH on chromosomes 17 and 18 in more than 75% of cases; other chromosome arms losses in about 50% of cases.
Oncogenesis	A number of genes are known to be implicated in tumour progression in colorectal cancers : APC, P53, KRAS2, mismatch repair genes (MMR genes). TP53 is mutated in 45% of colorectal cancer cases with a majority of C->T transitions at CpG sites and hotspots at codons 175, 245, 248, 273 and 282. TP53 mutation may be associated with poor prognosis in patient treated with chemotherapy.

Entity	Bladder cancer
Prognosis	Highly variable, according to the stage and the grade.
Cytogenetics	-9, -11 or del(11p), del(17p) and LOH at 17p, del(13q), frequent other LOH, aneuploidy, polyploidy, complex karyotypes.
Oncogenesis	Multi-step and largely unknown process; loss of 9q and P53 mutations would be early events; RB1, and P16 inactivation, EGFR overexpression, LOH at 3p, 8p, 11p, 13q, 17p, 18q. TP53 is mutated in 30% of bladder cancers with a majority of G->A transitions at non-CpG sites and 2 hotspots at codons 280 and 285.

Entity	Cervical cancer
Disease	Risk factors for cervical cancer include predominantly infection with certain human papillomaviruses such as HPV16 and HPV18. Carcinoma of the uterine cervix is one of the most common neoplasias among women worldwide.
Oncogenesis	The frequency of TP53 mutation in cervical cancer is very low. The p53 pathway is inactivated by the E6 protein that binds and inactivates the p53 protein. Rare TP53 mutations have been detected in HPV negative cancer.

Entity	Ovary carcinoma
Disease	Epithelial carcinoma of the ovary is one of the most common gynecologic malignancies. The most important risk factor for ovarian cancer is a family history of a first-degree relative (mother, daughter, or sister) with the disease.
Oncogenesis	TP53 mutation is present in 20% in early stage to 80% in late stage ovarian cancers. The prognostic value of TP53 gene mutation is still a matter of debate, although positive IHC staining for p53 protein seems to be associated with poor prognosis.

Entity	Prostate cancer
Oncogenesis	TP53 mutations are found in less than 20% of prostate cancers with a main hotspot at codon 273. Little is known about the role and prognostic value of these mutations.

Entity	Glioblastoma
Disease	Glioblastoma is the most malignant astrocytic tumor and is preferentially located in the cerebral hemisphere. It may develop from a less malignant precursor lesion such as diffuse astrocytoma or anaplastic astrocytoma, or may develop de novo (secondary glioblastoma and primary glioblastoma respectively). Secondary glioblastoma are more frequent in younger patients and have a better prognosis.
Oncogenesis	TP53 mutation is an early and frequent (over 60%) event in secondary glioblastomas while it is rare in primary glioblastomas (inferior to 10%) with hotspots at codons 175, 248 and 273. TP53 mutation is associated with good prognosis as it is more frequent in secondary glioblastomas which occur in young patients and are of better prognosis.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Written	07-1998	Richard Hamelin, Jean-Loup Huret
		INSERM U434, Laboratoire de Genetique des Tumeurs, CEPH, Paris (RH), and Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers (JLH), France.
Updated	12-2001	Thierry Soussi
		INSERM U434, Laboratoire de Genetique des Tumeurs, CEPH, Paris (RH), and Genetics, Dept Medical Information, University of Poitiers; CHU Poitiers Hospital, F-86021 Poitiers (JLH), France.
Updated	10-2002	Thierry Soussi
		Laboratoire de Genotoxicologie des tumeurs, Institut Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75005 Paris, France.
Updated	04-2007	Magali Olivier
		Laboratoire de Genotoxicologie des tumeurs, Institut Curie, Universite Pierre et Marie Curie, 26 rue d'Ulm, 75005 Paris, France.
Updated
		Molecular Carcinogenesis and Biomarkers Group, International Agency for Research on Cancer (IARC/CIRC), 150 Cours Albert Thomas, F-69372 Lyon CEDEX 08, France