p53, also known astumor protein p53,TP53,cellular tumor antigen p53 (UniProt name), ortransformation-related protein 53 (TRP53) is a regulatorytranscription factor protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial invertebrates, where they preventcancer formation.[5] As such, p53 has been described as "the guardian of thegenome" because of its role in conserving stability by preventing genome mutation.[6] HenceTP53[note 1] is classified as atumor suppressor gene.[7][8][9][10][11]
TheTP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that theTP53 gene plays a crucial role in preventing cancer formation.[5]TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.[12] In addition to the full-length protein, the humanTP53 gene encodes at least 12 proteinisoforms.[13]
In humans, theTP53 gene is located on the short arm ofchromosome 17 (17p13.1).[7][8][9][10] The gene spans 20kb, with a non-codingexon 1 and a very long firstintron of 10 kb, overlapping theHp53int1 gene. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53.[14]TP53orthologs[15] have been identified in mostmammals for which complete genome data are available. Elephants, with 20 genes for TP53, rarely get cancer.[16]
A schematic of the known protein domains in p53 (NLS = Nuclear Localization Signal)Crystal structure of four p53 DNA-binding domains (as found in the bioactive homo-tetramer)
The full-length p53 protein (p53α) comprises seven distinctprotein domains:
An acidicN-terminustransactivation domain (TAD), including activation domains 1 and 2 (AD1: residues 1–42; AD2: residues 43–63), which regulate transcription of several pro-apoptotic genes.[17]
Aproline-rich domain (residues 64–92), involved in apoptotic function and nuclear export viaMAPK signaling.
A centralDNA-binding domain (DBD; residues 102–292), containing a zinc atom and multiplearginine residues, essential for sequence-specific DNA interaction and co-repressor binding such asLMO3.[18]
A homo-oligomerization domain (OD; residues 307–355), which mediates tetramerization—essential for p53 activityin vivo.
AC-terminal regulatory domain (residues 356–393), which modulates the DNA-binding activity of the central domain.[19]
Most cancer-associated mutations inTP53 occur in the DBD, impairing DNA binding and transcriptional activation. These are typicallyrecessive loss-of-function mutations. By contrast, mutations in the OD can exertdominant negative effects by forming inactive complexes withwild-type p53.
Although designated as a 53 kDa protein bySDS-PAGE, the actual molecular weight of p53α is 43.7 kDa. The discrepancy is due to its highproline content, which slows electrophoretic migration.[21]
p53 initially formsdimers cotranslationally during protein synthesis on ribosomes.[22] Each dimer consists of two p53 monomers joined through their oligomerization domains.[23]
The dimerization interface spans residues 325–356 and includes abeta-strand (residues 325–333), aalpha-helix (residues 335–356), and a sharp turn at the conserved hinge residue Gly334. This configuration links the beta-strand and alpha-helix to form a V-shaped monomer topology. The beta-strand contributes to the formation of an antiparallel intermolecularbeta-sheet between two p53 monomers, stabilized byhydrophobic interactions involving Phe328, Leu330, and Ile332. The alpha-helix forms an antiparallelcoiled-coil between the two monomers, with a packing angle of 156°. Helix–helix interactions are stabilized by hydrophobic contacts (e.g., Phe338, Phe341, Leu344) and electrostatic interactions, such as the Arg337–Asp352salt bridge.
Following dimer formation, p53 dimers associate posttranslationally to formtetramers (dimers of dimers).[22][24] The tetramerization domain (residues 325–356) plays a central role in stabilizing the tetrameric structure.[24]In the tetramer, the two primary dimers associate at an angle described as "roughly orthogonal," with a helix bundle packing angle (θ) of approximately 80°.
Tetramers represent the active form of p53 for DNA binding and transcriptional regulation.[25][23]
Like 95% of human genes,TP53 encodes multiple proteins, collectively known as thep53 isoforms.[5] These vary in size from 3.5 to 43.7 kDa. Since their initial discovery in 2005, 12 human p53 isoforms have been identified: p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, and ∆160p53γ. Isoform expression is tissue-dependent, and p53α is never expressed alone.[11]
The isoforms differ by the inclusion or exclusion of specific domains. Some, such as Δ133p53β/γ and Δ160p53α/β/γ, lack the transactivation or proline-rich domains and are deficient in apoptosis induction, illustrating the functional diversity ofTP53.[26][27]
Isoforms are generated through multiple mechanisms:
Alternative splicing of intron 9 creates the β and γ isoforms with altered C-termini.
An internal promoter in intron 4 produces the ∆133 and ∆160 isoforms, which lack part of the TAD and DBD.
Alternative translation initiation at codons 40 or 160 results in ∆40p53 and ∆160p53 isoforms, respectively.[11]
p53 functions as a transcription factor by binding DNA as a tetramer, a structure that is essential for its stability and effective DNA binding activity.[30] Once bound to DNA, p53 induces the transcription of numerous genes involved in DNA repair pathways. This includes components ofbase excision repair (BER) such as OGG1 and MUTYH,nucleotide excision repair (NER) factors like DDB2 and XPC,mismatch repair (MMR) genes such as MSH2 and MLH1, and elements ofhomologous recombination (HR) andnon-homologous end-joining (NHEJ) repair.[31][32] These transcriptional responses are crucial for theDNA damage response (DDR), allowing cells to efficiently repair damaged DNA and maintain genomic integrity. While p53's role is most clearly defined in transcriptional activation of repair genes, it also participates in non-transcriptional regulation of DNA repair processes, particularly in HR and NHEJ, by modulating protein interactions and chromatin accessibility.[31][33]
p53 binds specific elements in the promoter of target genes, includingCDKN1A, which encodesp21.[30][34] Upon activation by p53, p21 inhibitscyclin-dependent kinases, leading tocell cycle arrest and contributing totumor suppression.[30][35] However, p21 can also be induced independently of p53 during processes such as differentiation, development, and in response to serum stimulation.[34]
p21 (WAF1) binds tocyclin-CDK complexes (notablyCDK2,CDK1,CDK4, andCDK6), inhibiting their activity and blocking the G1/S transition.[36][37] This inhibition enforces a cell cycle pause that allows DNA repair to occur. In cells with functional p53, p21 is upregulated in response to DNA damage, ensuring this checkpoint control. In contrast, p53 mutations impair p21 induction and compromise this control.[30]
Inhuman embryonic stem cells (hESCs), although p21 mRNA is upregulated following DNA damage, the protein is not detectable. This reflects a nonfunctional p53-p21 axis at the G1/S checkpoint.[38] This discrepancy is largely due to post-transcriptional repression, particularly by the miR-302 family of microRNAs, which inhibit p21 translation.[39] Although p53 binds the CDKN1A promoter in hESCs, it does not regulate miR-302, which is constitutively expressed and suppresses p21 expression.[39][38]
The p53 pathway is interconnected with theRB1 pathway via p14^ARF, which links the regulation of these key tumor suppressors.[40]
Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life.[43]
In humanembryonic stem cells (hESCs)s, p53 is maintained at low inactive levels.[44] This is because activation of p53 leads to rapid differentiation of hESCs.[45] Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. Work in mouse embryonic stem cells has recently shown however that the expression of P53 does not necessarily lead to differentiation.[46] p53 also activatesmiR-34a andmiR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.[44]
In adult stem cells, p53 regulation is important for maintenance of stemness inadult stem cell niches. Mechanical signals such ashypoxia affect levels of p53 in these niche cells through thehypoxia inducible factors,HIF-1α andHIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it.[47] Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells.[48][49] Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect ofblastema formation in the legs of salamanders.[50] p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous.[51]
An overview of the molecular mechanism of action of p53 on the angiogenesis[52]
Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibitingangiogenesis.[52] As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators oftumor hypoxia that also affect angiogenesis, such as HIF1 and HIF2, (ii) inhibiting the production of angiogenic promoting factors, and (iii) directly increasing the production of angiogenesis inhibitors, such asarresten.[53][54]
p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stress, the p53-mdm2 complex dissociates. Activated p53 can inducecell cycle arrest for repair or initiate apoptosis. The mechanism behind this decision is not fully understood.
Under normal, unstressed conditions, p53 is maintained at low levels through continuous degradation mediated by theE3 ubiquitin ligaseMDM2 (HDM2 in humans).[57] MDM2 binds p53, exports it from the nucleus, and targets it forproteasomal degradation. Notably, p53 transcriptionally activatesMDM2, establishing a classicnegative feedback loop.
This feedback loop gives rise to damped oscillations in p53 levels, as demonstrated both experimentally[58] and inmathematical models.[59][60] These oscillations may determine cell fate decisions between survival and apoptosis.[61]
Activation involves two main steps: stabilization of the protein, leading to its accumulation in the nucleus, and a conformational change that allows DNA binding and transcriptional activation. This process is initiated by phosphorylation of the N-terminal transactivation domain by stress-responsivekinases.[citation needed]
Kinases that regulate p53 phosphorylation fall into two major categories. One group includes MAPK pathway members such as JNK1–3, ERK1/2, and p38 MAPK, which respond tooxidative stress, membrane damage, and heat shock. The second group comprises DNA damage response kinases, includingATM,ATR,CHK1,CHK2,DNA-PK, CAK, andTP53RK, which respond to genomic instability. Oncogene-induced activation of p53 occurs viap14ARF, which inhibits MDM2 and thereby stabilizes p53.[citation needed]
Severaldeubiquitinating enzymes (DUBs) modulate p53 stability by removing ubiquitin chains.USP7, also known as HAUSP, can deubiquitinate both p53 and MDM2. In unstressed cells, HAUSP preferentially stabilizes MDM2, and its depletion may paradoxically increase p53 levels.USP42 is another DUB that stabilizes p53 and enhances its ability to respond to stress.[64]USP10 operates primarily in the cytoplasm, where it counteracts MDM2 by directly deubiquitinating p53. After DNA damage, USP10 translocates to the nucleus and further stabilizes p53. It does not interact with MDM2.[65]
Phosphorylation of the N-terminus not only prevents MDM2 binding but also facilitates the recruitment of cofactors.Pin1 enhances conformational changes in p53, whilep300 andPCAF acetylate theC-terminus, exposing the DNA-binding domain and enhancing transcriptional activation. Conversely, deacetylases such asSirt1 andSirt7 remove these modifications, suppressing apoptosis and promoting cell survival.[66] Some oncogenes can also activate p53 indirectly by inhibiting MDM2.[67]
Both experimental evidence and mathematical modeling indicate that p53 levels oscillate over time in response to cellular signals. Theseoscillations become more pronounced in the presence ofDNA damage, such asdouble-stranded breaks or UV exposure. Modeling approaches also help illustrate how mutations in p53 isoforms affect oscillatory behavior, potentially informing tissue-specifictherapeutic development.[68][69][59]
p53 function is also influenced bychromatin environment. The corepressorTRIM24 restricts p53 binding to epigenetically repressed loci by recognizing methylated histones. This interaction enables p53 to interpret local chromatin context and regulate gene expression in a locus-specific manner.[70][citation needed]
Overview of signal transduction pathways involved inapoptosisAmicrograph showing cells with abnormal p53 expression (brown) in a brain tumor.p53 immunostain.
If theTP53 gene is damaged, its ability to suppress tumors is severely compromised. Individuals who inherit only one functional copy ofTP53 are predisposed to developing tumors in early adulthood, a condition known asLi–Fraumeni syndrome.[citation needed]
TheTP53 gene can also be altered bymutagens—such aschemicals,radiation, or certainviruses—thereby increasing the likelihood of uncontrolled cell division. More than 50 percent of humantumors harbor amutation ordeletion of theTP53 gene.[71] Loss of p53 function leads to genomic instability, frequently resulting in ananeuploidy phenotype.[72]
Certain pathogens can also disrupt p53 activity. For example,human papillomavirus (HPV) produces the viral proteinE6, which binds to and inactivates p53. In conjunction with the HPV proteinE7, which inactivates the cell cycle regulatorpRb, this promotes repeated cell division, clinically presenting aswarts. High-risk HPV types, particularly types 16 and 18, can drive the progression from benign warts to low- or high-gradecervical dysplasia, reversible precancerous lesions. Persistent cervical infection can lead to irreversible changes, includingcarcinoma in situ and invasive cervical cancer. These outcomes are primarily driven by viral integration into the host genome and the continued expression of the E6 and E7 oncoproteins.[73]
Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional effects.[69]
Pathogenic mechanisms associated with p53 mutations:[74] (A) Wild-type p53 forms homotetramers that activate gene expression. (B) Dominant-negative mutants form heterotetramers with wild-type p53, impairing transcription in heterozygous states (p53mut/+). (C) Loss-of-function arises from complete inactivation of wild-type alleles and inactivity of the mutant protein. (D) Gain-of-function mutations confer neomorphic activities, such as hijacking other transcription factors, promoting tumorigenesis. Abbreviation: WT, wild type.[74]
The large spectrum of cancer phenotypes due to mutations in theTP53 gene is also supported by the fact that differentisoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations inTP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recent studies show that p53 isoforms are differentially expressed in different human tissues, and theloss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provide cancerstem cellpotential in different tissues.[11][27][75][76] TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.[77]
A common humanpolymorphism inTP53 involves a substitution ofarginine forproline at codon 72 of exon 4. Numerous studies have explored the relationship between this variation and cancer susceptibility, yielding mixed results. For instance, a 2009 meta-analysis found no association between the codon 72 polymorphism and cervical cancer risk.[78]
Other studies have identified possible associations between the codon 72 polymorphism and various cancers. A 2011 study reported that the proline variant significantly increased pancreatic cancer risk in males.[79] Another study found that proline homozygosity was associated with decreased breast cancer risk in Arab women.[80] Additional research suggested thatTP53 codon 72 polymorphisms, in combination withMDM2 SNP309 andA2164G, may affect susceptibility and age of onset for non-oropharyngeal cancers in women.[81] A separate 2011 study linked the polymorphism to an increased risk of lung cancer in a Korean population.[82]
However, meta-analyses published in 2011 found no significant associations between the codon 72 variant and risks of either colorectal[83] or endometrial cancer.[84] A study of a Brazilian birth cohort found an association between the arginine variant and individuals without a family history of cancer.[85] Meanwhile, another study reported that individuals with the homozygous Pro/Pro genotype had a significantly increased risk of renal cell carcinoma.[86]
While increasing p53 levels might appear beneficial for treating cancer, sustained p53 activation can cause premature aging.[87] A more promising approach involves restoring normal,endogenous p53 function. In some tumor types, this leads to regression via apoptosis or normalization of cell growth.[88][89]
The small-molecule inhibitor MI-63 can bind toMDM2, blocking its interaction with p53 and reactivating p53 in cancers where its function is suppressed.[91]
This image shows different patterns of p53 expression in endometrial cancers on chromogenicimmunohistochemistry, whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation:[92]
Wild-type, upper left: Endometrial endometrioid carcinoma showing normal wild-type pattern of p53 expression with variable proportion of tumor cell nuclei staining with variable intensity. Note, this wild-type pattern should not be reported as "positive," because this is ambiguous reporting language.
Overexpression, upper right: Endometrial endometrioid carcinoma, grade 3, with overexpression, showing strong staining in virtually all tumor cell nuclei, much stronger compared with the internal control of fibroblasts in the center. Note, there is some cytoplasmic background indicating that this staining is quite strong but this should not be interpreted as abnormal cytoplasmic pattern.
Complete absence, lower left: Endometrial serous carcinoma showing complete absence of p53 expression with internal control showing moderate to strong but variable staining. Note, wild-type pattern in normal atrophic glands at 12 and 6 o'clock.
Both cytoplasmic and nuclear, lower right: Endometrial endometrioid carcinoma showing cytoplasmic p53 expression with internal control (stroma and normal endometrial glands) showing nuclear wild-type pattern. The cytoplasmic pattern is accompanied by nuclear staining of similar intensity.
Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[103] In a series of publications in 1991–92, Michael Kastan ofJohns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.[104]
In 1993, p53 was votedmolecule of the year byScience magazine.[105]
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"p53 Knowledgebase". Lane Group at the Institute of Molecular and Cell Biology (IMCB), Singapore. Archived fromthe original on 2006-01-03. Retrieved2008-04-06.
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