The TP53 gene spans a region of 32,772 bp. The protypical TP53 gene is composed of 11 exons. Two novel alternatively spliced exons localized in intron 9 have been identified (exons 9β and 9γ).
To solve some confusing situation on TP53 nomenclature, an international consortium has joined forces with the Locus Reference Genomic (LRG) consortium to provide a stable reference sequence and a coordinate system for permanent and unambiguous reporting of disease-causing variants in genes related to any pathology. The TP53 nomenclature can be reached at http://ftp.ebi.ac.uk/pub/databases/lrgex/LRG_321.xml.

The transcription of the TP53 is highly complex and can vary between tissue and/or cellular context. Different p53 mRNA variants are expressed through the use of alternative splicing and an internal promoter in intron 4.

At least, 12 TP53 isoforms are expressed but the full-length protein (TP53 p1 or TP53α is always the major species detected in every tissue.
The p1 protein contains from N-term to C-term, two transactivationg domains (TAD1, 1-40 and TAD2, 41-61), a proline rich domain (63-97), a specific DNA binding domain (102-292), 3 nuclear localization signals (305-322), a tetramerization domain that includes a nuclear export signal (325-355) and a negative regulatory domain (360-393).
Shorter C-terminal TP53 isoforms do not contain either the tetramerization domain or the negative regulatory domain.
Shorter N-terminal TP53 isoforms do not contain TAD1 (Δ40 TP53 isoforms), TAD1, TAD2 and the proline rich domain (Δ133) or TAD1, TAD2, the proline rich domain and part of the DNA binding domain (Δ160)
TP53 is modified by numerous post-translational modifications phosphorylation, acetylation, ubiquitination, sumoylation, neddylation, methylation, ADP ribosylation, and glycosylation. Acetylation of multiple residues is essential for TP53 activation and DNA transcriptional activity.

The transcription factor TP53 is at the centre of a network that integrates and transmits multiple signals generated during various stress events to ensure cell and tissue homeostasis. This network also includes the two other members of the TP53 family, TP63 and TP73 as well as the two negative regulators, MDM2 and MDM4 (MDMX).
The p53 response can be conveniently divided into two sets of pathways acting upstream and downstream the core regulation of TP53.
The upstream pathways (stress signal detection and integration)
Multiple type of stress such as DNA damage, hypoxia, nucleotides pool depletion, viral infection, oncogene activation or oxidative stress can elicit a TP53 response. For each stress, a different panel of mediators is recruited.
In most cases, the goal of this step is the disruption of the TP53-MDM2 interaction leading to an accumulation and an activation of the TP53 protein. Subsequent post translational modifications (phosphorylation and acetylation principally) modulate TP53 activity depending of the type and the intensity of the damage and the cellular context.
For DNA damage, the ATM and CHEK2 kinase will phosphorylate TP53, MDM2 and MDM4 to release the negative regulation of the regulatory proteins.
For ribosomal stress, free ribosomal proteins will bind and sequester MDM2, relieving its inhibitory
For oncogene activation (hyperproliferative stress), the P16-ARF protein will sequester MDM2 in the nucleolus and relieve its inhibitory activity.
The core regulation of TP53
In normal tissues, TP53 protein levels are maintained at a very low level predominantly by the action of specific E3 ligases such as MDM2 and the ubiquitin proteosome pathway. Other E3 ligases such as Pirrh2, RFWD2 or TRIM24 target TP53 and able to regulate its stability.
TP53 translation is also highly regulated and enhanced after various types of stress. TP53 mRNA includes two Internal Ribosome Entry Sites (IRESs) elements. The first IRES is located in the 5UTR of the full-length isoform, the second is located into the protein-coding region and mediates the translation of a ΔN-p53 isoform.
The downstream pathways (effectors activation and TP53 response)
Several thousand genes have been shown to be activated by TP53 upon various types of stress. Different sets of genes are associated with a specific response. Initially, apoptosis, growth arrest and senescence have been considered to be the main response to TP53 activation. More recent studies have emphasized the importance of TP53 in other cellular responses such as DNA repair, metabolism and regulation of the Warburg effect, autophagy and regulation of stemm cell maintenance.
Although growth arrest, apoptosis and senescence were originally associated with the tumour suppressor activity of TP53, their importance has recently been challenged. Several mouse models defective for these three T53 activities lack any predisposition to develop neoplasia.
TP53 also has cytoplasmic transcription-independent functions (apoptosis and autophagy) via a direct interaction with pro- and anti-apoptotic factors in mitochondria.

Response	Gene
Apoptosis	APAF1 ; BAX - FAS - - MIR34A - PMAIP1 ; TP53AIP1 - PERP -PIDD1 - TP53I3 - BBC3 - SIVA1 ; TNFS10
Growth arrest	YWHAZ ; BTG2 ; CDKN1A - GADD45A ; MIR34A ; MIR34B / MIR34C ; Prl13; PTPRVP ; RPRM
Senescence	CDKN1A ; SERPINE1 ; PML l
DNA repair	Dbd2; ERCC5 ; FANCC ; GADD45A ; XRCC5 ; MGMT ; MLH1 ; MSH2 ; RRM2B ; PAPD7 ; XPC
Metabolism / Anti oxydant	ADORA2B ; ALDH4A1 ; PRKAB1 ; GAMT ; GLS2 ; SLC2A1 (-);SLC2A4  (-);GPX1 ; IGFBP3 ; LPIN1 ; PARK2 ; VCAN (-); PRKAB1 ; ten; SCO1 ; SESN1 ; SESN2 ; TIGAR ; TP53INP1 ; TSC2
Autophagy	ATG10 ; ATG2B ; ATG4A ; ATG4C ; ATG7 ; CTSD ; DDIT4 ; DRAM1 ; RBFOX3 ; LAPTM4A ; STK11 ; PIK3R3 ; PRKAG2 ; BBC3 ; ACD ; TSC2 ; ULK1 ; ULK2 ; UVRAG ; VAMP4 ; VMP1
Tumour micro environment	ADGRB1 ; CX3CL1 ; ICAM1 ; IRF9 ; ISG15 ; SERPINB5 ; CCL2 ; NCF2 ; SERPINE1 ; TLR1 - TLR10 ; PRSS55 ; ULBP1 ; ULBP2
Invasion metastasis	CDKN1A ; MIR34A ; MIR200C
Stem cell biology	CDKN1A ; ; MIR34A ; MIR34B / ; NOTCH1
TP53 regulation	CARD16 ; MDM2 , PIRH-2; TP63 , TP73
Unknown*	APOBEC3H; HRAS ; TNFAIP8 ; ZMAT3

This list is not exhaustive. Several TP53 responses overlap and include identical genes. Adapted from Bieging et al. with modifications.
* Genes induced by TP53 without any clear relation to a specific pathway

Widely expressed.

Nucleus

Germline TP53 mutations are associated with Li-Fraumeni (LFS) and Li-Fraumeni-like syndromes (LFL), characterized by a familial clustering of tumours, with a predominance of soft tissue and bone sarcomas, breast cancers, brain tumours, and adrenocortical carcinomas, diagnosed before the age of 45 years. TP53 germline mutations have also been observed in families at high risk of breast cancer, albeit at very low frequency.
A founder mutation TP53 (NG_017013.2:g.21852G>A, p.R337H) is detected in 0.3% of the general population in southern Brazil. This mutation is associated with an increased risk of childhood adrenal cortical carcinoma (ACC) but is also common in Brazilian LFS/LFL families.
The frequency of TP53 de novo germline mutation ranges between 7 and 20%.

Mutation of the TP53 gene can be found in 50% of human cancer. More than 80% of TP53 mutations are missense mutations that lead to the synthesis of a stable oncogenic protein that accumulates in the nucleus of tumour cells. The frequency of TP53 alterations range from less than 5% in cervical carcinoma to 90% in ovarian carcinoma or Small Cell Lung Cancer (SCLC) but these numbers must be taken with caution due to several factors such as the subtype of the cancer (lung or breast cancer), the stage of the tumour (prostate carcinoma or chronic lymphocytic leukaemia) and exogenous features such as viral or bacterial infection.
Two international consortiums have reported the sequencing of more than 10.000 tumour genomes and confirmed that the TP53 gene is the most frequently mutated gene in human cancer. TP53 mutations are strongly associated with tumours with high chromosomal instability.
Cancer specific driver genes can be noticed: APC in colorectal carcinoma (violet); VHL in kidney cancer (green) or PTEN and PIK3CA in endometrial carcinoma (green and red)
Molecular epidemiology studies demonstrate a link between exposure to various types of carcinogens, specific mutational events in the TP53 gene and the development of specific cancers.
Lung cancer
TP53 mutations in lung cancer are mostly GC to TA transversions, with a rate of transition mutations lower than in other cancers. There is a strong correlation between the frequency of these GC to TA transversions and lifetime cigarette smoking. This high frequency of GC to TA transversions has not been detected for other cancers such as colon, breast, ovary or brain cancer, which are not directly associated with smoking. This observation is compatible with the role of exogenous carcinogens such as benzo(a)pyrene in lung cancer. After metabolic activation, one of the derivative products of benzo(a)pyrene, the prime carcinogen in cigarette smoke, binds predominantly to guanine and gives rise to specific G-C to T-A transversions. Exposure of cells to benzo(a)pyrene lead to the formation of adducts at codon 157, 248 and 273 in the p53 gene. These positions are the major mutational hotspots in human lung cancer but not in other cancers. The p53 gene is one of the targets of carcinogens found in tobacco.
Liver cancer
There is a strong association between infection with hepatitis B virus and hepatocellular carcinoma. Aflatoxin B1 has been considered to be a significant etiological factor for liver cancer in Western Africa and Asia. Aflatoxins are compounds produced by fungal strains (such as Aspergillus flavus for aflatoxins B1) that are known food contaminants in these countries. Aflatoxins are highly carcinogenic in experimental animals, producing liver tumours in newborn mice, rats, fish, ducks and monkeys.
Worldwide epidemiological studies showed that a specific mutation at codon 249 (c.747G>T, p.R249S) is specifically found in liver cancer from countries in which food was contaminated by aflatoxin B1. In countries which do not consume contaminated food (including Europe and the USA), TP53 mutations are scattered along the central part of p53, as for the other types of cancer. In vitro and in vivo analysis showed a specific binding of aflatoxin B1 to codon 249 of the TP53 gene.
Bladder cancer
Aristolochic acid (AA), a common ingredient in many Chinese herbs, is a powerful nephrotoxin and human carcinogen associated with chronic kidney disease and upper urinary tract urothelial carcinomas including bladder cancer. AA exposure is also associated with Balkan endemic nephropathy (BEN) similarly characterized by kidney failure and a high frequency of transitional cancer of urothelial tracts including bladder, renal pelvis and ureters.
TP53 mutation from patients exposed to AA display a high frequency A:T-to-T:A transversions, a mutational signature associated with AA which forms a covalent adduct with adenine that leads to this transversion.
Skin cancer
Ultraviolet (UV) light induces specific DNA damage such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidine photoproducts (64PPs) at dipyrimidine sites, where two pyrimidine (Py) bases are juxtaposed in tandem in the nucleotide sequence of DNA. If left unrepaired, this lesion leads to specific types of mutation: base substitutions of cytosine (C) → thymine (T) at dipyrimidine sites and CC → TT tandem base substitutions. These two types of mutation are called UV signature and their detection suggests past exposure to UV. In skin cancer such as squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), the frequency of TP53 is high (70 to 80%) with more than 15% of tandem mutations (less than 1% for other cancer types).
Colorectal or brain cancer
The cytosine-guanine (CpG) dinucleotide is a hotspot for pathological mutations in the human genome. This hypermutability is due to its role as the major site of cytosine methylation with the attendant risk of spontaneous deamination of 5-methylcytosine (5mC) to yield C → T and G → A transitions. Most TP53 hotspots for mutations in colorectal or brain cancer are located at CpG sites with a mutation spectrum compatible with 5-methylcytosine deamination. These hotspot codons, CGN at positions 175, 248 or 273, encode arginine residues important for TP53 structure and/or activity. It is interesting to note that arginine can also be encoded by AGG and AGA that have the same frequency of usage in human but are not targeted by methylation. It has not yet been determined whether or not there is a specific selection to keep CGN in the TP53.