Biology:p53

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Short description: Mammalian protein found in Homo sapiens

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

p53, also known as Tumor protein P53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory 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 15 protein isoforms.

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.[9] TP53 orthologs[10] have been identified in most mammals for which complete genome data are available.

Human TP53 gene

In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72 of exon 4. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer.[11] A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males.[12] A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer.[13] One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women.[14] A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.[15]

Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk[16] and endometrial cancer risk.[17] A 2011 study of a Brazilian birth cohort found an association between the non-mutant arginine TP53 and individuals without a family history of cancer.[18] Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.[19]

Function

DNA damage and repair

p53 plays a role in regulation or progression through the cell cycle, apoptosis, and genomic stability by means of several mechanisms:

  • It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging.[20]
  • It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition—if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle.
  • It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable.
  • It is essential for the senescence response to short telomeres.
p53 pathway: In a normal cell, p53 is inactivated by its negative regulator, mdm2. Upon DNA damage or other stresses, various pathways will lead to the dissociation of the p53 and mdm2 complex. Once activated, p53 will induce a cell cycle arrest to allow either repair and survival of the cell or apoptosis to discard the damaged cell. How p53 makes this choice is currently unknown.

WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.

When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.[21] Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs.

The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity, thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein.

The p53 and RB1 pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other.[22]

p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning.[23][24]

Stem cells

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

In human embryonic stem cells (hESCs)s, p53 is maintained at low inactive levels.[25] This is because activation of p53 leads to rapid differentiation of hESCs.[26] 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.[27] p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.[25]

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.[28] 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.[29][30] 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.[31] 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.[32]

Other

An overview of the molecular mechanism of action of p53 on the angiogenesis.[33]

Apart from the cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting angiogenesis.[33] 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.[34][35]

p53 by regulating Leukemia Inhibitory Factor has been shown to facilitate implantation in the mouse and possibly humans reproduction.[36]

Regulation

p53 acts as a cellular stress sensor. It is normally kept at low levels by being constantly marked for degradation by the E3 ubiquitin ligase protein MDM2.[37] p53 is activated in response to myriad stressors – including DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress,[38] osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.

The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.

In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Mdm2 also acts as an ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. On activation of p53, Mdm2 is also activated, setting up a feedback loop. p53 levels can show oscillations (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether the cells survive the stress, or die.[39]

MI-63 binds to MDM2, reactivating p53 in situations where p53's function has become inhibited.[40]

A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway . This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.[41]

Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells.

USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.[42]

Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis.[43] Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.

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.

If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome.

The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene.[44] Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.[45]

Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging.[46] Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option.[47][48] The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus.[49]

Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.[50]

The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation (see a stochastic model of this process in [51]). The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.[52]

Patterns of p53 expression.png

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:[53]

  • 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.[54][55]

Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13.[56]

One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.[57][58]

Experimental analysis of p53 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.[52]

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. Recents 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 provides cancer stem cell potential in different tissues.[7][59][60][61] TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.[62]

The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This "damped" oscillation is both clinically documented [63] and mathematically modelled.[64][65] Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery.

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 was given in 1979 describing the apparent molecular mass.

The TP53 gene from the mouse was first cloned by Peter Chumakov of The Academy of Sciences of the USSR in 1982,[66] and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science).[67][68] The human TP53 gene was cloned in 1984[3] and the full length clone in 1985.[69]

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.[70][71] p53 went on to be identified as a transcription factor by Guillermina Lozano working at MD Anderson Cancer Center.[72]

Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation.[73] 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.[74]

In 1993, p53 was voted molecule of the year by Science magazine.[75]

Structure

File:P53 Schematic.tif

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

p53 has seven domains:

  1. an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes.[76]
  2. activation domain 2 (AD2) important for apoptotic activity: residues 43–63.
  3. proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64–92.
  4. central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102–292. This region is responsible for binding the p53 co-repressor LMO3.[77]
  5. Nuclear Localization Signaling (NLS) domain, residues 316–325.
  6. homo-oligomerisation domain (OD): residues 307–355. Tetramerization is essential for the activity of p53 in vivo.
  7. C-terminal involved in downregulation of DNA binding of the central domain: residues 356–393.[78]

Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53.

Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner.[79]

SDS-PAGE analysis indicates that p53 is a 53-kilodalton (kDa) protein. However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is.[80]

Isoforms

As with 95% of human genes, TP53 encodes more than one protein. All these p53 proteins are called the p53 isoforms.[1] These proteins range in size from 3.5 to 43.7 kDa. Several isoforms were discovered in 2005, and so far 12 human p53 isoforms have been identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone.[7]

The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a proline and X can be any amino acid). It is required among others for p53 mediated apoptosis.[81] Some isoforms lack the proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene.[59] Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain.

The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms.[7]

Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental analysis of p53 mutations for more details).

Interactions

p53 has been shown to interact with:


See also

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. ↑ "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. 
  10. ↑ "OrthoMaM phylogenetic marker: TP53 coding sequence". http://www.orthomam.univ-montp2.fr/orthomam/data/cds/detailMarkers/ENSG00000141510_TP53.xml. 
  11. ↑ "TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies". The Lancet. Oncology 10 (8): 772–84. August 2009. doi:10.1016/S1470-2045(09)70187-1. PMID 19625214. 
  12. ↑ "TP53 codon 72 polymorphism is associated with pancreatic cancer risk in males, smokers and drinkers". Molecular Medicine Reports 4 (3): 489–95. 2011. doi:10.3892/mmr.2011.449. PMID 21468597. 
  13. ↑ "P53 gene polymorphisms and breast cancer risk in Arab women". Medical Oncology 28 (3): 709–15. September 2011. doi:10.1007/s12032-010-9505-4. PMID 20443084. 
  14. ↑ "Effects of MDM2 promoter polymorphisms and p53 codon 72 polymorphism on risk and age at onset of squamous cell carcinoma of the head and neck". Molecular Carcinogenesis 50 (9): 697–706. September 2011. doi:10.1002/mc.20806. PMID 21656578. 
  15. ↑ "p53 codon 72 polymorphism and the risk of lung cancer in a Korean population". Lung Cancer 73 (3): 264–7. September 2011. doi:10.1016/j.lungcan.2010.12.017. PMID 21316118. 
  16. ↑ "TP53 codon 72 polymorphism and colorectal cancer susceptibility: a meta-analysis". Molecular Biology Reports 38 (8): 4847–53. November 2011. doi:10.1007/s11033-010-0619-8. PMID 21140221. 
  17. ↑ "TP53 Arg72Pro polymorphism and endometrial cancer risk: a meta-analysis". Medical Oncology 28 (4): 1129–35. December 2011. doi:10.1007/s12032-010-9597-x. PMID 20552298. 
  18. ↑ "TP53 gene polymorphism: importance to cancer, ethnicity and birth weight in a Brazilian cohort". Journal of Biosciences 36 (5): 823–31. December 2011. doi:10.1007/s12038-011-9147-5. PMID 22116280. 
  19. ↑ "The polymorphisms of P53 codon 72 and MDM2 SNP309 and renal cell carcinoma risk in a low arsenic exposure area". Toxicology and Applied Pharmacology 257 (3): 349–55. December 2011. doi:10.1016/j.taap.2011.09.018. PMID 21982800. 
  20. ↑ Developmental Biology, 10th ed.. Sunderland, MA USA: Sinauer Associates, Inc. Publishers. pp. 588. 
  21. ↑ National Center for Biotechnology Information (1998). "Skin and Connective Tissue". The p53 tumor suppressor protein. United States National Institutes of Health. https://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowSection&rid=gnd.section.107. Retrieved 2008-05-28. 
  22. ↑ "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. 
  23. ↑ "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. 
  24. ↑ "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. 
  25. ↑ 25.0 25.1 "p53 regulates cell cycle and microRNAs to promote differentiation of human embryonic stem cells". PLOS Biology 10 (2): e1001268. 2012. doi:10.1371/journal.pbio.1001268. PMID 22389628. 
  26. ↑ "Activation of p53 by nutlin leads to rapid differentiation of human embryonic stem cells". Oncogene 27 (40): 5277–87. September 2008. doi:10.1038/onc.2008.166. PMID 18521083. 
  27. ↑ "Critical role for P53 in regulating the cell cycle of ground state embryonic stem cells". Stem Cell Reports 14 (2): 175–183. February 2020. doi:10.1016/j.stemcr.2020.01.001. PMID 32004494. 
  28. ↑ "HIF-2α suppresses p53 to enhance the stemness and regenerative potential of human embryonic stem cells". Stem Cells 30 (8): 1685–95. August 2012. doi:10.1002/stem.1142. PMID 22689594. 
  29. ↑ "Context-dependent enhancement of induced pluripotent stem cell reprogramming by silencing Puma". Stem Cells 30 (5): 888–97. May 2012. doi:10.1002/stem.1054. PMID 22311782. 
  30. ↑ "A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity". Nature 460 (7259): 1149–53. August 2009. doi:10.1038/nature08287. PMID 19668189. Bibcode: 2009Natur.460.1149M. 
  31. ↑ "Regulation of p53 is critical for vertebrate limb regeneration". Proceedings of the National Academy of Sciences of the United States of America 110 (43): 17392–7. October 2013. doi:10.1073/pnas.1310519110. PMID 24101460. Bibcode: 2013PNAS..11017392Y. 
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  147. ↑ 147.0 147.1 "p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity". Cancer Research 63 (10): 2373–8. May 2003. PMID 12750254. 
  148. ↑ "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. 
  149. ↑ "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. 
  150. ↑ 150.0 150.1 "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. 
  151. ↑ 151.0 151.1 "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. 
  152. ↑ 152.0 152.1 "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. 
  153. ↑ "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. 
  154. ↑ "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. 
  155. ↑ "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. 
  156. ↑ "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. 
  157. ↑ "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. 
  158. ↑ "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. 
  159. ↑ "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. 
  160. ↑ "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. 
  161. ↑ "NUMB controls p53 tumour suppressor activity". Nature 451 (7174): 76–80. January 2008. doi:10.1038/nature06412. PMID 18172499. Bibcode: 2008Natur.451...76C. 
  162. ↑ 162.0 162.1 162.2 "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): 37. June 2010. doi:10.1186/gm158. PMID 20546595. 
  163. ↑ 163.0 163.1 "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. 
  164. ↑ "Parc: a cytoplasmic anchor for p53". Cell 112 (1): 29–40. January 2003. doi:10.1016/S0092-8674(02)01255-2. PMID 12526791. 
  165. ↑ "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. 
  166. ↑ "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. 
  167. ↑ "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. 
  168. ↑ "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. 
  169. ↑ "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. 
  170. ↑ "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. 
  171. ↑ "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. 
  172. ↑ "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. 
  173. ↑ "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. 
  174. ↑ "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. 
  175. ↑ "The function of PML in p53-dependent apoptosis". Nature Cell Biology 2 (10): 730–6. October 2000. doi:10.1038/35036365. PMID 11025664. 
  176. ↑ 176.0 176.1 "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. 
  177. ↑ "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. 
  178. ↑ "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. 
  179. ↑ "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. 
  180. ↑ "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. 
  181. ↑ "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. 
  182. ↑ "Molecular basis of Pirh2-mediated p53 ubiquitylation". Nature Structural & Molecular Biology 15 (12): 1334–42. December 2008. doi:10.1038/nsmb.1521. PMID 19043414. 
  183. ↑ "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. 
  184. ↑ "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. 
  185. ↑ "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. 
  186. ↑ 186.0 186.1 "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. 
  187. ↑ 187.0 187.1 "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. 
  188. ↑ 188.0 188.1 "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. 
  189. ↑ "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. 
  190. ↑ "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. 
  191. ↑ "Pax-6 interactions with TATA-box-binding protein and retinoblastoma protein". Investigative Ophthalmology & Visual Science 40 (7): 1343–50. June 1999. PMID 10359315. 
  192. ↑ "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. 
  193. ↑ "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. 
  194. ↑ "p53 and metabolism: Inside the TIGAR". Cell 126 (1): 30–2. July 2006. doi:10.1016/j.cell.2006.06.032. PMID 16839873. 
  195. ↑ "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. 
  196. ↑ "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. 
  197. ↑ 197.0 197.1 "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. 
  198. ↑ "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. 
  199. ↑ "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. 
  200. ↑ "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. 
  201. ↑ "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. 
  202. ↑ "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. 
  203. ↑ 203.0 203.1 "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. 
  204. ↑ "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. 
  205. ↑ "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. 
  206. ↑ "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. 
  207. ↑ "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. 
  208. ↑ "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. 
  209. ↑ "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. 
  210. ↑ "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. 
  211. ↑ "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. 
  212. ↑ "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. 
  213. ↑ "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. 
  214. ↑ "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. 
  215. ↑ "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. 
  216. ↑ "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. 
  217. ↑ "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. 
  218. ↑ "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. 
  219. ↑ "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. 
  220. ↑ "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. 
  221. ↑ "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. 
  222. ↑ "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. 
  223. ↑ "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. 
  224. ↑ "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. 
  225. ↑ "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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