Biology:P53

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p53, also known as tumor protein p53, TP53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription 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 in vertebrates, where they prevent cancer formation.[1] As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation.[2] Hence TP53[note 1] is classified as a tumor suppressor gene.[3][4][5][6][7]

The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation.[1] TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.[8] In addition to the full-length protein, the human TP53 gene encodes at least 12 protein isoforms.[9]

Gene

In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1).[3][4][5][6] The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb, overlapping the Hp53int1 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.[10] TP53 orthologs[11] have been identified in most mammals for which complete genome data are available. Elephants, with 20 genes for TP53, rarely get cancer.[12]

Structure

File:P53 Schematic.tif

Crystal structure of four p53 DNA-binding domains (as found in the bioactive homo-tetramer)

The full-length p53 protein (p53α) comprises seven distinct protein domains:

  1. An acidic N-terminus transactivation domain (TAD), including activation domains 1 and 2 (AD1: residues 1–42; AD2: residues 43–63), which regulate transcription of several pro-apoptotic genes.[13]
  2. A proline-rich domain (residues 64–92), involved in apoptotic function and nuclear export via MAPK signaling.
  3. A central DNA-binding domain (DBD; residues 102–292), containing a zinc atom and multiple arginine residues, essential for sequence-specific DNA interaction and co-repressor binding such as LMO3.[14]
  4. A nuclear localization sequence (NLS; residues 316–325), required for nuclear import.
  5. A homo-oligomerization domain (OD; residues 307–355), which mediates tetramerization—essential for p53 activity in vivo.
  6. A C-terminal regulatory domain (residues 356–393), which modulates the DNA-binding activity of the central domain.[15]

Most cancer-associated mutations in TP53 occur in the DBD, impairing DNA binding and transcriptional activation. These are typically recessive loss-of-function mutations. By contrast, mutations in the OD can exert dominant negative effects by forming inactive complexes with wild-type p53.

Wild-type p53 is a labile protein containing both folded and intrinsically disordered regions that act synergistically.[16]

Although designated as a 53 kDa protein by SDS-PAGE, the actual molecular weight of p53α is 43.7 kDa. The discrepancy is due to its high proline content, which slows electrophoretic migration.[17]

Tetramerization

p53 initially forms dimers cotranslationally during protein synthesis on ribosomes.[18] Each dimer consists of two p53 monomers joined through their oligomerization domains.[19]

The dimerization interface spans residues 325–356 and includes a beta-strand (residues 325–333), a alpha-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 intermolecular beta-sheet between two p53 monomers, stabilized by hydrophobic interactions involving Phe328, Leu330, and Ile332. The alpha-helix forms an antiparallel coiled-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–Asp352 salt bridge.

Following dimer formation, p53 dimers associate posttranslationally to form tetramers (dimers of dimers).[18][20] The tetramerization domain (residues 325–356) plays a central role in stabilizing the tetrameric structure.[20] 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.[21][19]

Isoforms

Like 95% of human genes, TP53 encodes multiple proteins, collectively known as the p53 isoforms.[1] 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.[7]

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 of TP53.[22][23]

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.[7]

Function

DNA damage and repair

Activation of p53 in response to stress signals initiates its transcriptional activity, leading to the activation of cellular protective pathways[24]

p53 regulates cell cycle progression, apoptosis, and genomic stability through multiple mechanisms:

  • Activates DNA repair proteins in response to DNA damage,[24] suggesting a potential role in aging.[25]
  • Arrests the cell cycle at the G1/S checkpoint upon DNA damage, allowing time for repair before progression.
  • Initiates apoptosis if the damage is beyond repair.
  • Essential for the senescence response triggered by short telomeres.

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.[26] Once bound to DNA, p53 induces the transcription of numerous genes involved in DNA repair pathways. This includes components of base 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 of homologous recombination (HR) and non-homologous end-joining (NHEJ) repair.[27][28] These transcriptional responses are crucial for the DNA 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.[27][29]

p53 binds specific elements in the promoter of target genes, including CDKN1A, which encodes p21.[26][30] Upon activation by p53, p21 inhibits cyclin-dependent kinases, leading to cell cycle arrest and contributing to tumor suppression.[26][31] However, p21 can also be induced independently of p53 during processes such as differentiation, development, and in response to serum stimulation.[30]

p21 (WAF1) binds to cyclin-CDK complexes (notably CDK2, CDK1, CDK4, and CDK6), inhibiting their activity and blocking the G1/S transition.[32][33] 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.[26]

In human 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.[34] This discrepancy is largely due to post-transcriptional repression, particularly by the miR-302 family of microRNAs, which inhibit p21 translation.[35] Although p53 binds the CDKN1A promoter in hESCs, it does not regulate miR-302, which is constitutively expressed and suppresses p21 expression.[35][34]

The p53 pathway is interconnected with the RB1 pathway via p14^ARF, which links the regulation of these key tumor suppressors.[36]

p53 expression can be induced by UV radiation, which also causes DNA damage. In this context, p53 activation can initiate processes that lead to melanin production and tanning.[37][38]

Stem cells

Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life.[39]

In human embryonic stem cells (hESCs)s, p53 is maintained at low inactive levels.[40] This is because activation of p53 leads to rapid differentiation of hESCs.[41] 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.[42] p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.[40]

In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches. Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it.[43] 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.[44][45] 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 of blastema formation in the legs of salamanders.[46] 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.[47]

Other

An overview of the molecular mechanism of action of p53 on the angiogenesis[48]

Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting angiogenesis.[48] As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators of tumor 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 as arresten.[49][50]

p53 by regulating Leukemia Inhibitory Factor has been shown to facilitate implantation in the mouse and possibly human reproduction.[51]

The immune response to infection also involves p53 and NF-κB. Checkpoint control of the cell cycle and of apoptosis by p53 is inhibited by some infections such as Mycoplasma bacteria,[52] raising the specter of oncogenic infection.

Regulation

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 induce cell cycle arrest for repair or initiate apoptosis. The mechanism behind this decision is not fully understood.

Basal regulation

Under normal, unstressed conditions, p53 is maintained at low levels through continuous degradation mediated by the E3 ubiquitin ligase MDM2 (HDM2 in humans).[53] MDM2 binds p53, exports it from the nucleus, and targets it for proteasomal degradation. Notably, p53 transcriptionally activates MDM2, establishing a classic negative feedback loop.

This feedback loop gives rise to damped oscillations in p53 levels, as demonstrated both experimentally[54] and in mathematical models.[55][56] These oscillations may determine cell fate decisions between survival and apoptosis.[57]

Activation by cellular stress

p53 is activated in response to a range of cellular stressors, including DNA damage (from ultraviolet or ionizing radiation, or oxidative chemicals),[58] osmotic shock, ribonucleotide depletion, oncogene activation, and viral pneumonia.[59]


Stress-responsive kinases

Deubiquitination

Several deubiquitinating 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.[60] 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.[61]

Post-translational modifications and cofactors

Phosphorylation of the N-terminus not only prevents MDM2 binding but also facilitates the recruitment of cofactors. Pin1 enhances conformational changes in p53, while p300 and PCAF acetylate the C-terminus, exposing the DNA-binding domain and enhancing transcriptional activation. Conversely, deacetylases such as Sirt1 and Sirt7 remove these modifications, suppressing apoptosis and promoting cell survival.[62] Some oncogenes can also activate p53 indirectly by inhibiting MDM2.[63]

Dynamics

Both experimental evidence and mathematical modeling indicate that p53 levels oscillate over time in response to cellular signals. These oscillations become more pronounced in the presence of DNA damage, such as double-stranded breaks or UV exposure. Modeling approaches also help illustrate how mutations in p53 isoforms affect oscillatory behavior, potentially informing tissue-specific therapeutic development.[64][65][55]

Epigenetics

p53 function is also influenced by chromatin environment. The corepressor TRIM24 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.[66]

Role in disease

Overview of signal transduction pathways involved in apoptosis
A micrograph showing cells with abnormal p53 expression (brown) in a brain tumor. p53 immunostain.

The TP53 gene can also be altered by mutagens—such as chemicals, radiation, or certain viruses—thereby increasing the likelihood of uncontrolled cell division. More than 50 percent of human tumors harbor a mutation or deletion of the TP53 gene.[67] Loss of p53 function leads to genomic instability, frequently resulting in an aneuploidy phenotype.[68]

Certain pathogens can also disrupt p53 activity. For example, human papillomavirus (HPV) produces the viral protein E6, which binds to and inactivates p53. In conjunction with the HPV protein E7, which inactivates the cell cycle regulator pRb, this promotes repeated cell division, clinically presenting as warts. High-risk HPV types, particularly types 16 and 18, can drive the progression from benign warts to low- or high-grade cervical dysplasia, reversible precancerous lesions. Persistent cervical infection can lead to irreversible changes, including carcinoma 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.[69]

Mutations

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.[65]

Pathogenic mechanisms associated with p53 mutations:[70] (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.[70]

The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 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 the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provide cancer stem cell potential in different tissues.[7][23][71][72] TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.[73]

A common human polymorphism in TP53 involves a substitution of arginine for proline 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.[74]

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.[75] Another study found that proline homozygosity was associated with decreased breast cancer risk in Arab women.[76] Additional research suggested that TP53 codon 72 polymorphisms, in combination with MDM2 SNP309 and A2164G, may affect susceptibility and age of onset for non-oropharyngeal cancers in women.[77] A separate 2011 study linked the polymorphism to an increased risk of lung cancer in a Korean population.[78]

However, meta-analyses published in 2011 found no significant associations between the codon 72 variant and risks of either colorectal[79] or endometrial cancer.[80] A study of a Brazilian birth cohort found an association between the arginine variant and individuals without a family history of cancer.[81] Meanwhile, another study reported that individuals with the homozygous Pro/Pro genotype had a significantly increased risk of renal cell carcinoma.[82]

Therapeutic reactivation and gene therapy

While increasing p53 levels might appear beneficial for treating cancer, sustained p53 activation can cause premature aging.[83] 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.[84][85]

The first commercial gene therapy, Gendicine, was approved in China in 2003 for head and neck squamous cell carcinoma. It delivers a functional copy of the TP53 gene using a modified adenovirus.[86]

The small-molecule inhibitor MI-63 can bind to MDM2, blocking its interaction with p53 and reactivating p53 in cancers where its function is suppressed.[87]

Diagnostic and prognostic significance

This image shows different patterns of p53 expression in endometrial cancers on chromogenic immunohistochemistry, whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation:[88]

  • 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.
Immunohistochemistry for p53 can help distinguish a papillary urothelial neoplasm of low malignant potential (PUNLMP) from a low grade urothelial carcinoma. Overexpression is seen in 75% of low-grade urothelial carcinomas and only 10% of PUNLMP.[89][90]

Discovery

p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK), Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The name p53 is in fact a misnomer, as it describes the apparent molecular mass measured when it was first discovered, though it was later realised this was an overestimate: the correct molecular mass is only 43.7 kDa.[91]

The TP53 gene from the mouse was first cloned by Peter Chumakov of The Academy of Sciences of the USSR in 1982,[92] and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).[93][94] The human TP53 gene was cloned in 1984[3] and the full length clone in 1985.[95]

It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University.[96][97] p53 went on to be identified as a transcription factor by Guillermina Lozano working at MD Anderson Cancer Center.[98]

Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[99] In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage.[100]

In 1993, p53 was voted molecule of the year by Science magazine.[101]

Interactions

p53 has been shown to interact with:

See also

  • Eprenetapopt, a reactivator of some mutant forms of p53
  • Pifithrin, an inhibitor of p53

Notes

  1. ↑ italics are used to denote the TP53 gene name and distinguish it from the protein it encodes

References

  1. ↑ 1.0 1.1 1.2 "Uncovering the role of p53 splice variants in human malignancy: a clinical perspective". OncoTargets and Therapy 7: 57–68. December 2013. doi:10.2147/OTT.S53876. PMID 24379683. 
  2. ↑ "The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure". Cancers 10 (5): 135. May 2018. doi:10.3390/cancers10050135. PMID 29734785. 
  3. ↑ 3.0 3.1 3.2 "Isolation and characterization of a human p53 cDNA clone: expression of the human p53 gene". The EMBO Journal 3 (13): 3257–62. December 1984. doi:10.1002/j.1460-2075.1984.tb02287.x. PMID 6396087. 
  4. ↑ 4.0 4.1 "Localization of gene for human p53 tumour antigen to band 17p13". Nature 320 (6057): 84–5. 1986. doi:10.1038/320084a0. PMID 3456488. Bibcode: 1986Natur.320...84I. 
  5. ↑ 5.0 5.1 "Identification of p53 as a sequence-specific DNA-binding protein". Science 252 (5013): 1708–11. June 1991. doi:10.1126/science.2047879. PMID 2047879. Bibcode: 1991Sci...252.1708K. 
  6. ↑ 6.0 6.1 "The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13)". Proceedings of the National Academy of Sciences of the United States of America 83 (1): 130–4. January 1986. doi:10.1073/pnas.83.1.130. PMID 3001719. Bibcode: 1986PNAS...83..130M. 
  7. ↑ 7.0 7.1 7.2 7.3 "p53 isoforms can regulate p53 transcriptional activity". Genes & Development 19 (18): 2122–37. September 2005. doi:10.1101/gad.1339905. PMID 16131611. 
  8. ↑ The p53 family. Cold Spring Harbor Perspectives in Biology. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press. 2010. ISBN 978-0-87969-830-0. 
  9. ↑ "p53 Isoforms: An Intracellular Microprocessor?". Genes Cancer 2 (4): 453–65. April 2011. doi:10.1177/1947601911408893. PMID 21779513. 
  10. ↑ "Twenty years of p53 research: structural and functional aspects of the p53 protein". Oncogene 18 (53): 7621–36. December 1999. doi:10.1038/sj.onc.1203285. PMID 10618702. 
  11. ↑ "OrthoMaM phylogenetic marker: TP53 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000141510_TP53.xml. 
  12. ↑ "TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants". eLife 5. September 2016. doi:10.7554/eLife.11994. PMID 27642012. 
  13. ↑ "The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression". The EMBO Journal 17 (16): 4668–79. August 1998. doi:10.1093/emboj/17.16.4668. PMID 9707426. 
  14. ↑ 14.0 14.1 "LMO3 interacts with p53 and inhibits its transcriptional activity". Biochemical and Biophysical Research Communications 392 (3): 252–7. February 2010. doi:10.1016/j.bbrc.2009.12.010. PMID 19995558. Bibcode: 2010BBRC..392..252L. 
  15. ↑ "The C terminus of p53 family proteins is a cell fate determinant". Molecular and Cellular Biology 25 (5): 2014–30. March 2005. doi:10.1128/MCB.25.5.2014-2030.2005. PMID 15713654. 
  16. ↑ "p53 contains large unstructured regions in its native state". Journal of Molecular Biology 322 (5): 917–27. October 2002. doi:10.1016/S0022-2836(02)00848-3. PMID 12367518. 
  17. ↑ "Cell-free translations of proline-rich protein mRNAs". The Journal of Biological Chemistry 257 (18): 11176–80. September 1982. doi:10.1016/S0021-9258(18)33948-6. PMID 7107651. 
  18. ↑ 18.0 18.1 "Biogenesis of p53 involves cotranslational dimerization of monomers and posttranslational dimerization of dimers. Implications on the dominant negative effect". The Journal of Biological Chemistry 277 (15): 12937–12945. April 2002. doi:10.1074/jbc.M108815200. PMID 11805092. 
  19. ↑ 19.0 19.1 "TIMELESS-dependent positive and negative autoregulation in the Drosophila circadian clock". The EMBO Journal 18 (3): 675–686. February 1999. doi:10.1093/emboj/18.3.675. PMID 9927427. 
  20. ↑ 20.0 20.1 "Ultraslow oligomerization equilibria of p53 and its implications". Proceedings of the National Academy of Sciences of the United States of America 106 (34): 14327–14332. August 2009. doi:10.1073/pnas.0907840106. PMID 19667193. Bibcode: 2009PNAS..10614327N. 
  21. ↑ "Structure of the p53 core domain dimer bound to DNA". The Journal of Biological Chemistry 281 (29): 20494–20502. July 2006. doi:10.1074/jbc.M603634200. PMID 16717092. 
  22. ↑ "Definition of the p53 functional domains necessary for inducing apoptosis". The Journal of Biological Chemistry 275 (51): 39927–34. December 2000. doi:10.1074/jbc.M005676200. PMID 10982799. 
  23. ↑ 23.0 23.1 "p53 Isoforms: An Intracellular Microprocessor?". Genes & Cancer 2 (4): 453–65. April 2011. doi:10.1177/1947601911408893. PMID 21779513. 
  24. ↑ 24.0 24.1 "Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control?". Cell Death and Differentiation 32 (1): 1–8. January 2025. doi:10.1038/s41418-024-01259-9. PMID 38379088.  This article incorporates text from this source, which is available under the CC BY 4.0 license.
  25. ↑ Developmental Biology, 10th ed.. Sunderland, MA USA: Sinauer Associates, Inc. Publishers. p. 588. 
  26. ↑ 26.0 26.1 26.2 26.3 "Cell cycle regulation: p53-p21-RB signaling". Cell Death and Differentiation 29 (5): 946–960. May 2022. doi:10.1038/s41418-022-00988-z. PMID 35361964. 
  27. ↑ 27.0 27.1 "p53 in the DNA-Damage-Repair Process". Cold Spring Harbor Perspectives in Medicine 6 (5). May 2016. doi:10.1101/cshperspect.a026070. PMID 27048304. 
  28. ↑ "p53 and regulation of DNA damage recognition during nucleotide excision repair". DNA Repair 2 (9): 947–54. September 2003. doi:10.1016/s1568-7864(03)00087-9. PMID 12967652. 
  29. ↑ "p53 in recombination and repair". Cell Death and Differentiation 13 (6): 1003–16. June 2006. doi:10.1038/sj.cdd.4401903. PMID 16543940. 
  30. ↑ 30.0 30.1 "Examination of the expanding pathways for the regulation of p21 expression and activity". Cellular Signalling 22 (7): 1003–12. July 2010. doi:10.1016/j.cellsig.2010.01.013. PMID 20100570. 
  31. ↑ "Mechanisms of transcriptional regulation by p53". Cell Death and Differentiation 25 (1): 133–143. January 2018. doi:10.1038/cdd.2017.174. PMID 29125602. 
  32. ↑ "The Role of the Cyclin Dependent Kinase Inhibitor p21cip1/waf1 in Targeting Cancer: Molecular Mechanisms and Novel Therapeutics". Cancers 11 (10): 1475. September 2019. doi:10.3390/cancers11101475. PMID 31575057. 
  33. ↑ "Multiple functions of p21 in cell cycle, apoptosis and transcriptional regulation after DNA damage". DNA Repair 42: 63–71. June 2016. doi:10.1016/j.dnarep.2016.04.008. PMID 27156098. 
  34. ↑ 34.0 34.1 "An Updated View of the Roles of p53 in Embryonic Stem Cells". Stem Cells 40 (10): 883–891. October 2022. doi:10.1093/stmcls/sxac051. PMID 35904997. 
  35. ↑ 35.0 35.1 "MicroRNAs regulate p21(Waf1/Cip1) protein expression and the DNA damage response in human embryonic stem cells". Stem Cells 30 (7): 1362–72. July 2012. doi:10.1002/stem.1108. PMID 22511267. 
  36. ↑ "p14ARF links the tumour suppressors RB and p53". Nature 395 (6698): 124–5. September 1998. doi:10.1038/25867. PMID 9744267. Bibcode: 1998Natur.395..124B. 
  37. ↑ "Genome's guardian gets a tan started". New Scientist. March 17, 2007. https://www.newscientist.com/channel/health/mg19325955.800-genomes-guardian-gets-a-tan-started.html. Retrieved 2007-03-29. 
  38. ↑ "Central role of p53 in the suntan response and pathologic hyperpigmentation". Cell 128 (5): 853–64. March 2007. doi:10.1016/j.cell.2006.12.045. PMID 17350573. 
  39. ↑ "Functions of p53 in pluripotent stem cells". Oxford Academic 11 (1): 71–78. 2020. doi:10.1007/s13238-019-00665-x. PMID 31691903. 
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  158. ↑ "Characterization of cells and gene-targeted mice deficient for the p53-binding kinase homeodomain-interacting protein kinase 1 (HIPK1)". Proceedings of the National Academy of Sciences of the United States of America 100 (9): 5431–6. April 2003. doi:10.1073/pnas.0530308100. PMID 12702766. Bibcode: 2003PNAS..100.5431K. 
  159. ↑ "Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2". Nature Cell Biology 4 (1): 1–10. January 2002. doi:10.1038/ncb715. PMID 11740489. 
  160. ↑ "Identification and characterization of HIPK2 interacting with p73 and modulating functions of the p53 family in vivo". The Journal of Biological Chemistry 277 (35): 32020–8. August 2002. doi:10.1074/jbc.M200153200. PMID 11925430. 
  161. ↑ "Interaction with p53 enhances binding of cisplatin-modified DNA by high mobility group 1 protein". The Journal of Biological Chemistry 276 (10): 7534–40. March 2001. doi:10.1074/jbc.M008143200. PMID 11106654. 
  162. ↑ "HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences". The Journal of Biological Chemistry 277 (9): 7021–8. March 2002. doi:10.1074/jbc.M108417200. PMID 11748221. 
  163. ↑ "Hsp70 family member, mot-2/mthsp70/GRP75, binds to the cytoplasmic sequestration domain of the p53 protein". Experimental Cell Research 274 (2): 246–53. April 2002. doi:10.1006/excr.2002.5468. PMID 11900485. 
  164. ↑ "The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription". Proceedings of the National Academy of Sciences of the United States of America 97 (12): 6763–8. June 2000. doi:10.1073/pnas.100110097. PMID 10823891. Bibcode: 2000PNAS...97.6763S. 
  165. ↑ "The candidate tumor suppressor ING1b can stabilize p53 by disrupting the regulation of p53 by MDM2". Cancer Research 62 (17): 4890–3. September 2002. PMID 12208736. 
  166. ↑ "The candidate tumour suppressor p33ING1 cooperates with p53 in cell growth control". Nature 391 (6664): 295–8. January 1998. doi:10.1038/34675. PMID 9440695. Bibcode: 1998Natur.391..295G. 
  167. ↑ 167.0 167.1 "p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity". Cancer Research 63 (10): 2373–8. May 2003. PMID 12750254. 
  168. ↑ "Two wobble-splicing events affect ING4 protein subnuclear localization and degradation". Experimental Cell Research 314 (17): 3130–41. October 2008. doi:10.1016/j.yexcr.2008.08.002. PMID 18775696. 
  169. ↑ "The non-ankyrin C terminus of Ikappa Balpha physically interacts with p53 in vivo and dissociates in response to apoptotic stress, hypoxia, DNA damage, and transforming growth factor-beta 1-mediated growth suppression". The Journal of Biological Chemistry 277 (12): 10323–31. March 2002. doi:10.1074/jbc.M106607200. PMID 11799106. 
  170. ↑ 170.0 170.1 "Cellular stress and DNA damage invoke temporally distinct Mdm2, p53 and PML complexes and damage-specific nuclear relocalization". Journal of Cell Science 116 (Pt 19): 3917–25. October 2003. doi:10.1242/jcs.00714. PMID 12915590. 
  171. ↑ 171.0 171.1 "PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms". Cancer Cell 3 (2): 117–30. February 2003. doi:10.1016/S1535-6108(03)00021-7. PMID 12620407. 
  172. ↑ 172.0 172.1 "ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways". Cell 92 (6): 725–34. March 1998. doi:10.1016/S0092-8674(00)81401-4. PMID 9529249. 
  173. ↑ "MdmX is a RING finger ubiquitin ligase capable of synergistically enhancing Mdm2 ubiquitination". The Journal of Biological Chemistry 277 (51): 49668–75. December 2002. doi:10.1074/jbc.M208593200. PMID 12393902. 
  174. ↑ "Isolation and identification of the human homolog of a new p53-binding protein, Mdmx". Genomics 43 (1): 34–42. July 1997. doi:10.1006/geno.1997.4775. PMID 9226370. https://repository.ubn.ru.nl/bitstream/2066/142231/1/142231.pdf. 
  175. ↑ "RB18A, whose gene is localized on chromosome 17q12-q21.1, regulates in vivo p53 transactivating activity". Cancer Research 60 (23): 6585–9. December 2000. PMID 11118038. 
  176. ↑ "Identification of RB18A, a 205 kDa new p53 regulatory protein which shares antigenic and functional properties with p53". Oncogene 15 (25): 3013–24. December 1997. doi:10.1038/sj.onc.1201492. PMID 9444950. 
  177. ↑ "JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases". Oncogene 15 (19): 2277–87. November 1997. doi:10.1038/sj.onc.1201401. PMID 9393873. 
  178. ↑ "Death-associated protein 4 binds MST1 and augments MST1-induced apoptosis". The Journal of Biological Chemistry 277 (50): 47991–8001. December 2002. doi:10.1074/jbc.M202630200. PMID 12384512. 
  179. ↑ "Physical and functional interactions of neuronal growth suppressor necdin with p53". The Journal of Biological Chemistry 274 (23): 16242–8. June 1999. doi:10.1074/jbc.274.23.16242. PMID 10347180. 
  180. ↑ "Stress-dependent nucleolin mobilization mediated by p53-nucleolin complex formation". Molecular and Cellular Biology 22 (16): 6014–22. August 2002. doi:10.1128/MCB.22.16.6014-6022.2002. PMID 12138209. 
  181. ↑ "NUMB controls p53 tumour suppressor activity". Nature 451 (7174): 76–80. January 2008. doi:10.1038/nature06412. PMID 18172499. Bibcode: 2008Natur.451...76C. 
  182. ↑ 182.0 182.1 182.2 "High-throughput sequencing identifies STAT3 as the DNA-associated factor for p53-NF-kappaB-complex-dependent gene expression in human heart failure". Genome Medicine 2 (6). June 2010. doi:10.1186/gm158. PMID 20546595. 
  183. ↑ 183.0 183.1 "Ribosomal protein L11 negatively regulates oncoprotein MDM2 and mediates a p53-dependent ribosomal-stress checkpoint pathway". Molecular and Cellular Biology 23 (23): 8902–12. December 2003. doi:10.1128/MCB.23.23.8902-8912.2003. PMID 14612427. 
  184. ↑ "Parc: a cytoplasmic anchor for p53". Cell 112 (1): 29–40. January 2003. doi:10.1016/S0092-8674(02)01255-2. PMID 12526791. 
  185. ↑ "Poly(ADP-ribose) binds to specific domains of p53 and alters its DNA binding functions". The Journal of Biological Chemistry 273 (19): 11839–43. May 1998. doi:10.1074/jbc.273.19.11839. PMID 9565608. 
  186. ↑ "Involvement of PIAS1 in the sumoylation of tumor suppressor p53". Molecular Cell 8 (3): 713–8. September 2001. doi:10.1016/S1097-2765(01)00349-5. PMID 11583632. 
  187. ↑ "Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage". The Journal of Biological Chemistry 277 (50): 47976–9. December 2002. doi:10.1074/jbc.C200538200. PMID 12388558. 
  188. ↑ "The prolyl isomerase Pin1 reveals a mechanism to control p53 functions after genotoxic insults". Nature 419 (6909): 853–7. October 2002. doi:10.1038/nature01120. PMID 12397362. Bibcode: 2002Natur.419..853Z. 
  189. ↑ "Enhancement of p53-dependent gene activation by the transcriptional coactivator Zac1". Oncogene 20 (17): 2134–43. April 2001. doi:10.1038/sj.onc.1204298. PMID 11360197. 
  190. ↑ "Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway". The Journal of Biological Chemistry 276 (46): 43305–12. November 2001. doi:10.1074/jbc.M106050200. PMID 11551930. 
  191. ↑ "Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways". Oncogene 21 (43): 6633–40. September 2002. doi:10.1038/sj.onc.1205850. PMID 12242661. 
  192. ↑ "PACT: cloning and characterization of a cellular p53 binding protein that interacts with Rb". Oncogene 14 (2): 145–55. January 1997. doi:10.1038/sj.onc.1200825. PMID 9010216. 
  193. ↑ "Prohibitin induces the transcriptional activity of p53 and is exported from the nucleus upon apoptotic signaling". The Journal of Biological Chemistry 278 (48): 47853–61. November 2003. doi:10.1074/jbc.M305171200. PMID 14500729. 
  194. ↑ "Regulation of p53 activity in nuclear bodies by a specific PML isoform". The EMBO Journal 19 (22): 6185–95. November 2000. doi:10.1093/emboj/19.22.6185. PMID 11080164. 
  195. ↑ "The function of PML in p53-dependent apoptosis". Nature Cell Biology 2 (10): 730–6. October 2000. doi:10.1038/35036365. PMID 11025664. 
  196. ↑ 196.0 196.1 "Proteasome activator PA28 gamma regulates p53 by enhancing its MDM2-mediated degradation". The EMBO Journal 27 (6): 852–64. March 2008. doi:10.1038/emboj.2008.25. PMID 18309296. 
  197. ↑ "Nuclear FAK promotes cell proliferation and survival through FERM-enhanced p53 degradation". Molecular Cell 29 (1): 9–22. January 2008. doi:10.1016/j.molcel.2007.11.031. PMID 18206965. 
  198. ↑ "Human securin interacts with p53 and modulates p53-mediated transcriptional activity and apoptosis". Nature Genetics 32 (2): 306–11. October 2002. doi:10.1038/ng997. PMID 12355087. 
  199. ↑ "p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction". The EMBO Journal 15 (8): 1992–2002. April 1996. doi:10.1002/j.1460-2075.1996.tb00550.x. PMID 8617246. 
  200. ↑ "Interaction of p53 with the human Rad51 protein". Nucleic Acids Research 25 (19): 3868–74. October 1997. doi:10.1093/nar/25.19.3868. PMID 9380510. 
  201. ↑ "Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation". Cell 112 (6): 779–91. March 2003. doi:10.1016/S0092-8674(03)00193-4. PMID 12654245. 
  202. ↑ "Molecular basis of Pirh2-mediated p53 ubiquitylation". Nature Structural & Molecular Biology 15 (12): 1334–42. December 2008. doi:10.1038/nsmb.1521. PMID 19043414. 
  203. ↑ "The interaction of p53 with replication protein A mediates suppression of homologous recombination". Oncogene 23 (56): 9025–33. December 2004. doi:10.1038/sj.onc.1207982. PMID 15489903. 
  204. ↑ "UV-induced DNA incision and proliferating cell nuclear antigen recruitment to repair sites occur independently of p53-replication protein A interaction in p53 wild type and mutant ovarian carcinoma cells". Carcinogenesis 22 (12): 1971–8. December 2001. doi:10.1093/carcin/22.12.1971. PMID 11751427. 
  205. ↑ "Inhibiting S100B restores p53 levels in primary malignant melanoma cancer cells". The Journal of Biological Chemistry 279 (32): 34071–7. August 2004. doi:10.1074/jbc.M405419200. PMID 15178678. 
  206. ↑ 206.0 206.1 "Covalent modification of p73alpha by SUMO-1. Two-hybrid screening with p73 identifies novel SUMO-1-interacting proteins and a SUMO-1 interaction motif". The Journal of Biological Chemistry 275 (46): 36316–23. November 2000. doi:10.1074/jbc.M004293200. PMID 10961991. 
  207. ↑ 207.0 207.1 "p14ARF interacts with DAXX: effects on HDM2 and p53". Cell Cycle 7 (12): 1836–50. June 2008. doi:10.4161/cc.7.12.6025. PMID 18583933. 
  208. ↑ 208.0 208.1 "SWI/SNF complex interacts with tumor suppressor p53 and is necessary for the activation of p53-mediated transcription". The Journal of Biological Chemistry 277 (25): 22330–7. June 2002. doi:10.1074/jbc.M111987200. PMID 11950834. 
  209. ↑ "A direct interaction between the survival motor neuron protein and p53 and its relationship to spinal muscular atrophy". The Journal of Biological Chemistry 277 (4): 2852–9. January 2002. doi:10.1074/jbc.M108769200. PMID 11704667. 
  210. ↑ "Wild-type p53 binds to the TATA-binding protein and represses transcription". Proceedings of the National Academy of Sciences of the United States of America 89 (24): 12028–32. December 1992. doi:10.1073/pnas.89.24.12028. PMID 1465435. Bibcode: 1992PNAS...8912028S. 
  211. ↑ "Pax-6 interactions with TATA-box-binding protein and retinoblastoma protein". Investigative Ophthalmology & Visual Science 40 (7): 1343–50. June 1999. PMID 10359315. 
  212. ↑ "Tumor suppressor activity of AP2alpha mediated through a direct interaction with p53". The Journal of Biological Chemistry 277 (47): 45028–33. November 2002. doi:10.1074/jbc.M208924200. PMID 12226108. 
  213. ↑ "Functional interaction between DP-1 and p53". Molecular and Cellular Biology 16 (10): 5888–95. October 1996. doi:10.1128/mcb.16.10.5888. PMID 8816502. 
  214. ↑ "p53 and metabolism: Inside the TIGAR". Cell 126 (1): 30–2. July 2006. doi:10.1016/j.cell.2006.06.032. PMID 16839873. 
  215. ↑ "The interaction between p53 and DNA topoisomerase I is regulated differently in cells with wild-type and mutant p53". Proceedings of the National Academy of Sciences of the United States of America 96 (18): 10355–60. August 1999. doi:10.1073/pnas.96.18.10355. PMID 10468612. Bibcode: 1999PNAS...9610355G. 
  216. ↑ "Subnuclear distribution of topoisomerase I is linked to ongoing transcription and p53 status". Proceedings of the National Academy of Sciences of the United States of America 99 (3): 1235–40. February 2002. doi:10.1073/pnas.022631899. PMID 11805286. Bibcode: 2002PNAS...99.1235M. 
  217. ↑ 217.0 217.1 "Human topoisomerase IIalpha and IIbeta interact with the C-terminal region of p53". Experimental Cell Research 255 (1): 86–94. February 2000. doi:10.1006/excr.1999.4772. PMID 10666337. 
  218. ↑ "Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor". The EMBO Journal 21 (14): 3863–72. July 2002. doi:10.1093/emboj/cdf383. PMID 12110597. 
  219. ↑ "Comparison of BRCT domains of BRCA1 and 53BP1: a biophysical analysis". Protein Science 13 (3): 617–25. March 2004. doi:10.1110/ps.03461404. PMID 14978302. 
  220. ↑ "The 8-kDa dynein light chain binds to p53-binding protein 1 and mediates DNA damage-induced p53 nuclear accumulation". The Journal of Biological Chemistry 280 (9): 8172–9. March 2005. doi:10.1074/jbc.M411408200. PMID 15611139. 
  221. ↑ "Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure". Genes & Development 16 (5): 583–93. March 2002. doi:10.1101/gad.959202. PMID 11877378. 
  222. ↑ "Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor". Acta Crystallographica D 58 (Pt 10 Pt 2): 1826–9. October 2002. doi:10.1107/S0907444902010910. PMID 12351827. Bibcode: 2002AcCrD..58.1826D. 
  223. ↑ 223.0 223.1 "Two cellular proteins that bind to wild-type but not mutant p53". Proceedings of the National Academy of Sciences of the United States of America 91 (13): 6098–102. June 1994. doi:10.1073/pnas.91.13.6098. PMID 8016121. Bibcode: 1994PNAS...91.6098I. 
  224. ↑ "The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M". Molecular and Cellular Biology 16 (7): 3884–92. July 1996. doi:10.1128/MCB.16.7.3884. PMID 8668206. 
  225. ↑ "TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity". The Journal of Biological Chemistry 278 (39): 37722–9. September 2003. doi:10.1074/jbc.M301979200. PMID 12851404. 
  226. ↑ "p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis". Molecular Cell 8 (1): 85–94. July 2001. doi:10.1016/S1097-2765(01)00284-2. PMID 11511362. 
  227. ↑ "A TSG101/MDM2 regulatory loop modulates MDM2 degradation and MDM2/p53 feedback control". Proceedings of the National Academy of Sciences of the United States of America 98 (4): 1619–24. February 2001. doi:10.1073/pnas.98.4.1619. PMID 11172000. Bibcode: 2001PNAS...98.1619L. 
  228. ↑ "Supramolecular complex formation between Rad6 and proteins of the p53 pathway during DNA damage-induced response". Molecular and Cellular Biology 23 (7): 2463–75. April 2003. doi:10.1128/MCB.23.7.2463-2475.2003. PMID 12640129. 
  229. ↑ "Associations of UBE2I with RAD52, UBL1, p53, and RAD51 proteins in a yeast two-hybrid system". Genomics 37 (2): 183–6. October 1996. doi:10.1006/geno.1996.0540. PMID 8921390. https://zenodo.org/record/1229705. 
  230. ↑ "Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1". Cell 108 (3): 345–56. February 2002. doi:10.1016/S0092-8674(02)00630-X. PMID 11853669. 
  231. ↑ "Identification of c-Cbl as a new ligase for insulin-like growth factor-I receptor with distinct roles from Mdm2 in receptor ubiquitination and endocytosis". Cancer Research 68 (14): 5669–77. July 2008. doi:10.1158/0008-5472.CAN-07-6364. PMID 18632619. 
  232. ↑ "The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex". The EMBO Journal 27 (13): 1863–74. July 2008. doi:10.1038/emboj.2008.115. PMID 18566590. 
  233. ↑ "CARPs enhance p53 turnover by degrading 14-3-3sigma and stabilizing MDM2". Cell Cycle 7 (5): 670–82. March 2008. doi:10.4161/cc.7.5.5701. PMID 18382127. 
  234. ↑ "Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2". Proceedings of the National Academy of Sciences of the United States of America 105 (12): 4838–43. March 2008. doi:10.1073/pnas.0712216105. PMID 18359851. Bibcode: 2008PNAS..105.4838A. 
  235. ↑ "Specific inhibition of Mdm2-mediated neddylation by Tip60". Cell Cycle 7 (2): 222–31. January 2008. doi:10.4161/cc.7.2.5185. PMID 18264029. 
  236. ↑ "Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization". Nature 416 (6881): 648–53. April 2002. doi:10.1038/nature737. PMID 11923872. Bibcode: 2002Natur.416..648L. 
  237. ↑ "p53 Modulates the exonuclease activity of Werner syndrome protein". The Journal of Biological Chemistry 276 (37): 35093–102. September 2001. doi:10.1074/jbc.M103332200. PMID 11427532. 
  238. ↑ "Hyaluronidase induction of a WW domain-containing oxidoreductase that enhances tumor necrosis factor cytotoxicity". The Journal of Biological Chemistry 276 (5): 3361–70. February 2001. doi:10.1074/jbc.M007140200. PMID 11058590. 
  239. ↑ "Direct interaction of p53 with the Y-box binding protein, YB-1: a mechanism for regulation of human gene expression". Oncogene 19 (54): 6194–202. December 2000. doi:10.1038/sj.onc.1204029. PMID 11175333. 
  240. ↑ "YPEL3, a p53-regulated gene that induces cellular senescence". Cancer Research 70 (9): 3566–75. May 2010. doi:10.1158/0008-5472.CAN-09-3219. PMID 20388804. 
  241. ↑ "ATM-dependent activation of p53 involves dephosphorylation and association with 14-3-3 proteins". Nature Genetics 19 (2): 175–8. June 1998. doi:10.1038/542. PMID 9620776. 
  242. ↑ "Physical interaction between p53 and primary response gene Egr-1". International Journal of Oncology 18 (4): 863–70. April 2001. doi:10.3892/ijo.18.4.863. PMID 11251186. 
  243. ↑ "ZBP-89 promotes growth arrest through stabilization of p53". Molecular and Cellular Biology 21 (14): 4670–83. July 2001. doi:10.1128/MCB.21.14.4670-4683.2001. PMID 11416144. 
  244. ↑ "MiR-34, SIRT1 and p53: the feedback loop". Cell Cycle 8 (5): 712–5. March 2009. doi:10.4161/cc.8.5.7753. PMID 19221490. 
  245. ↑ "CircRNA_014511 affects the radiosensitivity of bone marrow mesenchymal stem cells by binding to miR-29b-2-5p". Bosnian Journal of Basic Medical Sciences 19 (2): 155–163. May 2019. doi:10.17305/bjbms.2019.3935. PMID 30640591. 



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