Journal of Immunology and Clinical Research

Bioinformatics Assessment of p53 Interactions with Immunological ResponseRelated Protein

Review Article | Open Access

  • 1. Freitas e Silva, Biological Sciences Institute, Federal University of Goiás, Brazil
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Corresponding Authors
Kleber Santiago Freitas e Silva, Biological Sciences Institute, Federal University of Goiás, Alameda Palmeiras - Chácaras Califórnia, Goiânia - GO, 74710-310, Brazil

The p53 protein is a classic tumor suppressor protein related to cancer and a series of other diseases such as endometriosis, atherosclerosis, and infertility. It regulates cell cycle progression and protects DNA against several types of damage. The p53 structure comprises three main domains, the transactivation domain, a DNAbinding core domain and a C-terminal domain related to down regulation of the DNA binding domain. The protein p53 is indirectly related to the immunological response of tumorigenesis. Irregular protein-protein interactions of p53 may interfere with the immune scenery within tumor environment leading to inflammation. The interactome of p53 contains more than one thousand protein interactors. Proteins such as MDM2, MDM4, BRCA1, TP53BP1 and PML interact with p53 in order to maintain DNA integrity and genomic stability. Moreover, p53 interacts with immunological response-related proteins. Inflammation influences the onset of cancer, thus p53 could play immunological roles in tumorigenesis through immune response. Irregular protein-protein interactions of p53 may interfere with the immune scenery within tumor environment leading to inflammation and p53 interact with immunological response-related proteins such as CREBBP, SIRT1 and TRAF6. Here, we analyzed the interface of interaction between p53 and three binding partners, MDM2, CREBBP and SIRT1. We identified hot spots that could be of importance for the conformational structure of those proteins, their function and pattern of interaction with their partners. We have also shown that some of the hot spot amino acid residues present at the interface of interaction are polymorphic, which could disrupt the binding of p53 and partners, thus, leading to a higher susceptibility to cancer. Future studies should be performed in order to design small molecules that could Future studies should be conducted in order to design small molecules that could modulate the interaction between p53 and MDM2, CREBBP and SIRT1 in order to efficiency in the interaction, avoid disturbances immunological microenvironment of cells and the maintenance of genomic stability.


•    p53
•    TP53
•    Interactome
•    Immunological response-related proteins


Freitas e Silva KS (2018) Bioinformatics Assessment of p53 Interactions with Immunological Response-Related Proteins. J Immunol Clin Res 5(1): 1048.


The p53 protein, coded by the TP53 gene, is a classic tumor suppressor protein related to cancer [1] and a series of other diseases such as endometriosis [2], atherosclerosis [3], and infertility [4]. It regulates cell cycle progression and protects DNA against several types of damage [5]. TP53 is located in the locus at 17p13.1 and comprises highly conserved 11 exons. The protein has 393 amino acids and presents structural homology between among species, as it can be confirmed by sequence alignment performed by BLAST (https://www.ncbi.nlm.nih. gov). Amino acid sequence alignment of human p53 and Castor canadensis, for example, shows 81% of identity (Figure 1). The wild-type p53 has a tetrameric molecular structure [6] as shown in Figure 2A

The p53 protein is recruited when DNA undergoes exogenous or endogenous damage caused by a great variety of agents such as reactive oxygen species [7], hypoxia [8-10], nutrient [11-13] and micronutrient deprivation [14,15] and DNA replication stress [16]. Damaged DNA induces overexpression of p53 [14,17] and consequently it interacts with other proteins in order to trigger pathways related to repair [18], apoptosis [19] or cell cycle arrest [19,20]. The p53 protein structure (Figure 2B) is intrinsically related to its function. The conserved DNA binding motif of p53 ranges from amino acid residues 95 to 288 and encompasses approximately 66% of the entire protein. Mutations at this region are rather common and may increase cancer and other diseases susceptibility considerably [21]

Mutations in TP53 gene are generally of the missense type and lead to a reduced or total loss of p53 functions [22,23], altering its ability to bind to other proteins and fulfill its function. It has been suggested that TP53 mutations and consequently p53 protein structure anomalies drive tumor related inflammation and affect immunological aspects of several types of cancer onset. Impairment of p53 within tumor environment correlates to immunosuppression and immune evasion of cells with mitotic dysfunctions [24-26]. The p53 pathway in tumorous cells is highly dynamic and might be related to an immunological design to alleviate immunosuppression or immunosenescence besides improving antitumor immunity aspects.

DNA damage and genomic instability are closely related top53 dysfunction and the immunological response of tumorigenesis [27]. It is well known that inflammation influences the onset of cancer [28], thus p53 could play immunological roles in tumorigenesis through immune response. Irregular proteinprotein interactions of p53 may interfere with the immune scenery within tumor environment leading to inflammation [29].

Tumor suppression mediated by p53 takes place by autonomous or non-cell autonomous mechanisms. The former features p53 normal DNA damage response towards repair, apoptosis or growth arrest while the latter is related to the advancement of inflammation [30]. Tumorous cells formation and cancer progression along with metastases are driven by molecular and cellular components present in within tumor environment [31]. Immunological components of cancerous cell environment comprise extracellular matrix, cytokines, chemokines and immunosuppressive constituents that guarantee a landscape of inflammation in order protect cancer from immune surveillance and elimination [32-34].

It has been reported an increased elevated p53 activity in several tissues of patients affected by autoimmune diseases, which are governed by inflammation processes. The most common are rheumatoid arthritis [35], ulcerative inflammatory bowel diseases, Crohn’s disease [36] and Sjögren’s disease [37]. The protein p53 levels are considerably altered in those inflammatory diseases, which is an indication of its relation to inflammatory stress [38]


The 3-D structures used in the analysis are available in the PDB (protein databank; https://www.rcsb.org/) and the p53 monomer were modeled by the I-TASSER server [39]. We used KBDOCK in order to find protein domains and possible interaction between protein domains [40]. The protein docking was performed by ClusPro [41]. We used PyMol (https://pymol. org) for the visualization of the interface of interaction and the visualization of hot spots and polymorphic residues. The hot spots in the proteins under study were identified by KFC2 [42]. The server offers an automated analysis of a protein complex interface. The server analyses the structural environment around amino acid residues and checks for already known hot spots environments determined experimentally. The hot spot prediction is based on characteristics regarding conformation specificity (K-FADE) and biochemical features such as hydrophobicity (K-CON. Finally, the polymorphic residues were identified through the dbSNP (data base of single nucleotide polymorphism; https://www.ncbi.nlm.nih.gov/SNP).


The protein p53 conserved domains

The TP53 gene codes for a protein with 3 conserved domains. The first domain is the p53 transactivation motif or activation domain number 1, which binds to proteins with regulatory functions in order to activate p53 protein transcription by inducing the transcription factors. It is a very short motif with a single amphipathic alpha helix that extends from residues 6 to 9 [43]. The transactivation motif is formed by two complementary domains responsible for transcriptional activation. The major one is at residues 1 to 42 and the other at residues 55 to 75. This domain is especially related to regulation of apoptotic genes [44].

The p53 tetramerization motif is related to the protein oligomerization, which is essential for its DNA binding properties and consequently tumor suppression function [45]. It extends from residues 325 to 356. Oligomerization of p53 also plays important roles regarding its binding to other proteins belonging to DNA repair pathways, p53 turnover and post-translational modifications. The p53 DNA-binding domain attaches to damaged DNA and along with other proteins form a complex that stabilizes the DNA-protein complex (Figure 2A) [46]. The DNA binding motif is zinc dependent and rich in the amino acid arginine. It is the larger part of the protein and mutations, such as polymorphisms, are prone to disrupt p53 function and increase susceptibility to diseases [47].

Two domains are related to apoptosis, the activating domain number 2 and the proline-rich domain. The former span from residue 43 to 63 and the latter from residue 64 to 92. In addition, a nuclear localization signaling domain is located between residues 316 to 325. Finally, a C-terminal domain regulate the DNA binding feature of the activation domain 1, present at residues 356-393 [48].

Interactome of p53 and immunological response proteins

According to BioGRID database, Homo sapiens p53 interactome contains more than one thousand interactors. The large amount of proteins that interact with p53 shows how important it is for several biological processes. Some of the p53 protein partners are essential for the tumorigenesis suppression and maintenance of DNA homeostasis. Proteins such as MDM2 (proto-oncogene, E3 ubiquitin protein ligase) [49], MDM4 (p53 regulator) [50], BRCA1 (breast cancer 1, early onset)[51], TP53BP1 (tumor protein p53 binding protein 1) [52] and PML (promyelocytic leucemia) [53] interact with p53 in order to maintain DNA integrity.

MDM2 is a negative regulator of p53. MDM2 inhibits p53 transcription process by binding to the N-terminal transactivation domain and it also ubiquitinates p53 in order to maintain metabolic normal levels of the protein through a degradation pathway [54-57]. We propose an in silico model for the interaction of p53 and MDM2. Figure 3A shows the conformational structure of the p53 monomer and Figure 3B shows the N-terminal domain of MDM2, the latter comprises 119 amino acid residues and is basically formed by helical shape and a few residues on a β-strand. It has been experimentally shown that this domain of MDM2 interacts with p53 [58]. Figure 3C shows the lowest binding free energy of the complex formed by p53 and MDM2. We found only two hot spots within the interface of interaction of the complex (Figure 3C) and one of those hot spots is highly polymorphic (Table 1). The substitution of the hot spot residue by a different amino acid may reduce the efficiency of the interaction and increase the susceptibility to cancer and other disease [59-61].

The protein MDM4 is related to apoptosis pathways [62], it also negatively regulates p53 activity by binding to the transactivation domain and suppressing its function. It has been shown that p53 interacts with BRCA1 and mutated versions of those proteins may impair their interaction leading to genomic instability [51]. TP53BP1 is frequently down-regulated in patients with breast cancer. The protein is related to DNA double strand damage repair through homologous recombination [63].

It has been experimentally shown that p53 interacts with immunological response-related proteins [64]. CREBBP (cAMP response element binding protein) is virtually expressed in all tissues, participates in the transcriptional activation of several transcription factors [65]. CREBBP is a well-known protein that either activates or inhibits several cellular pathways such growth, differentiation, immune response, apoptosis and cell cycle arrest [66]. Interaction of p53 and CREBBP has been shown to play a role in DNA damage response [67-70], where CREBBP regulates p53 transactivation [68]. Figure 4A shows the conformational structure of CREBBP bromodomain, which if formed by 116 amino acid residues. More than 65% of the structure is found in helical form and this shape is related to the ability of the protein bind to partners. The interface of interaction between CREBBP and p53 is large and five hot spot residues were predicted for this region of interaction (Figure 4B). Interestingly, all of those hot spots residues are polymorphic (Table 1) and mutations on them increase the likelihood of cancer onset and immune deregulation of cells microenvironment [71-73], except on the Leu 93, which is normally a synonymous mutation.

The protein p53 also interacts with SIRT1 (Sirtuin 1 - NADdependent deacetylase sirtuin-1) [74]. SIRT1 epigenetically regulates p53 activity through deacetylation [75]. The relation of p53 and immunological response within tumor environment may relies on SIRT1 activities. SIRT1 inhibits NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) expression through deacetylation [76] and the latter belongs to the most important transcriptional regulator group of genes that leads to inflammation. In addition, SIRT1 also takes part in activation of T helper cells, influencing autoimmune diseases onset and progression [77]. Figure 5A shows the 3-D structure of SIRT1,

comprised by 356 residues and highly variable N- and C- terminal domains. The interface of interaction between p53 and SIRT1 (Figure 5B) has 14 hot spot amino acid residues and 10 residues are polymorphic, including one linked to a nonsense mutation (Table 1).

The protein TRAF6 (TNF receptor associated factor) activates signal transduction pathways for TNF (tumor necrosis factor) receptors as response to proinflammatory cytokines, interferon, interleukin and growth factors. TRAF6 interacts with p53 in mitochondria and interferes with its apoptosis and DNA damage response functions [78]. TRAF6 also regulates the p53translocation to mitochondria, thus participating in apoptosis processes through unrepaired DNA disruption. Downregulation of TRAF6 and poor levels of TRAF6-p53 interaction induces ubiquitination of p53 in the cytoplasm and consequently low levels of p53 in the face of DNA damage increases cancer and other diseases susceptibility [78].

Table 1: Hot spots prediction and polymorphisms that are likely to take place within the interface of interaction.

Interface Residues Score A* Score B* Polymorphism
p53 Phe 212 1.93 0.35 Ile
MDM2 Lys 94 1.67 0.14 -
p53 Leu 93 1.21 0.04 synonymous
p53 Phe 212 1.11 0.00 Ile
CREBBP Glu 1149 0.81 0.06 Gln
CREBBP Trp 1151 1.65 0.25 Arg, Cys
CREBBP Gln 1152 1.27 0.25 Gly, Hys
p53 Tyr 163 0.94 0.34 Cys, Asn, Hys
p53 Gln 165 1.67 0.15 Nonsense
p53 Arg 248 1.06 0.08 Gln
p53 Arg 249 0.45 0.26 Lys, Thr, Met
p53 Arg 273 0.90 0.23 Cys, Ser, Arg
p53 Phe 328 0.76 0.00 Synonymous
p53 Met 332 1.22 0.33 -
p53 Met 340 1.32 0.32 -
SIRT1 Tyr 185 1.40 0.36 -
SIRT1 Phe 187 1.40 0.26 Synonymous
SIRT1 Gln 189 0.74 0.10 Arg
SIRT1 Gln 190 1.32 0.13 Synonymous
SIRT1 Met 193 1.27 0.23 Val, Thr, Ile
SIRT1 Ile 201 0.36 0.13 -

Hot spot model based on structure characteristics. **Hot spot model based on biochemical characteristics (intermolecular hydrogen bonds).



Computational methods have made important tools available and have increased our knowledge about the complex multiprotein world. The identification of molecular and biochemical features of the interaction interface in protein-protein interactions (PPI) has driven the development of new ways of diagnose and treatment of diseases such as cancer. Here, we analyzed the interface of interaction between p53 and thee binding proteins. We proposed hot spots that could interfere with the conformational structure of the complex, its function and the efficiency of interaction with their binding partners. We compared the hot spot residues with polymorphic residues from the dbSNP database. Several hot spots involved in the PPIs were polymorphic, which could disrupt the interaction between p53 and its protein partners, leading to a higher susceptibility to cancer. Future studies should be conducted in order to design small molecules that could modulate the interaction between p53 and MDM2, CREBBP and SIRT1 in order to efficiency in the interaction, avoid disturbances immunological microenvironment of cells and the maintenance of genomic stability.


1. Mobaraki RN, Karimi M, Alikarami F, Farhadi E, Amini A, Bashash D, et al. RITA induces apoptosis in p53-null K562 leukemia cells by inhibiting STAT5, Akt, and NF-κB signaling pathways. Anticancer Drugs. 2018; 29: 847-853.

2. Silva KS, Moura KK. Genetic polymorphisms in patients with endometriosis: an analytical study in Goiânia (Central West of Brazil). Genet Mol Res. 2016; 15.

3. Lagares MH, Silva KSF, Barbosa AM, Rodrigues DA, Costa IR, Martins JVM, et al. Analysis of p53 gene polymorphism (codon 72) in symptomatic patients with atherosclerosis. Genet Mol Res. 2017; 16.

4. de Morais MP, Curado RF, E Silva KS, Moura KK, Arruda JT. Male idiopathic infertility and the TP53 polymorphism in codon 72. Genet Mol Res. 2016; 15.

5. Speidel D. The role of DNA damage responses in p53 biology. Arch Toxicol. 2015; 89: 501-517.

6. Kung CP, Murphy ME. The role of the p53 tumor suppressor in metabolism and diabetes. J Endocrinol. 2016; 231: R61-R75.

7. Zhang W, Huang C, Sun A, Qiao L, Zhang X, Huang J, et al. Hydrogen alleviates cellular senescence via regulation of ROS/p53/p21 pathway in bone marrow-derived mesenchymal stem cells in vivo. Biomed Pharmacother. 2018; 106: 1126-1134.

8. Leszczynska KB, Foskolou IP, Abraham AG, Anbalagan S, Tellier C, Haider S, et al. Hypoxia-induced p53 modulates both apoptosis and radiosensitivity via AKT. J Clin Invest. 2015; 125: 2385-2398.

9. Zhou CH, Zhang XP, Liu F, Wang W. Modeling the interplay between the HIF-1 and p53 pathways in hypoxia. Sci Rep. 2015; 5: 13834.

10. Timani KA, Liu Y, Fan Y, Mohammad KS, He JJ. Tip110 Regulates the Cross Talk between p53 and Hypoxia-Inducible Factor 1α under Hypoxia and Promotes Survival of Cancer Cells. Mol Cell Biol. 2015; 35: 2254-2264.

11. Guo X, Hu F, Zhang S, Zhao QD, Zong C, Ye F, et al. Inhibition of p53 increases chemosensitivity to 5-FU in nutrient-deprived hepatocarcinoma cells by suppressing autophagy. Cancer Lett. 2014; 346: 278-284.

12. Khan D, Katoch A, Das A, Sharathchandra A, Lal R, Roy P, et al. Reversible induction of translational isoforms of p53 in glucose deprivation. Cell Death Differ. 2015; 22: 1203-1218.

13. Minchenko DO, Danilovskyi SV, Kryvdiuk IV, Hlushchak NA, Kovalevska OV, Karbovskyi LL, et al. Acute L-glutamine deprivation affects the expression of TP53-related protein genes in U87 glioma cells. Fiziol Zh. 2014; 60: 11-21.

14. Ho E, Courtemanche C, Ames BN. Zinc deficiency induces oxidative DNA damage and increases p53 expression in human lung fibroblasts. J Nutr. 2003; 133: 2543-2548.

15. Yu X, Kogan S, Chen Y, Tsang AT, Withers T, Lin H, et al. Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics. Clin Cancer Res. 2018; 24: 4505-4517.

16. Romanova LY, Mushinski F, Kovalchuk AL. Transcriptional activation of p21Waf1 contributes to suppression of HR by p53 in response to replication arrest induced by camptothecin. Oncotarget. 2018; 9: 25427-25440.

17. Romeo M, Hutchison T, Malu A, White A, Kim J, Gardner R, et al. The human T-cell leukemia virus type-1 p30II protein activates p53 and induces the TIGAR and suppresses oncogene-induced oxidative stress during viral carcinogenesis. Virology. 2018; 518: 103-115.

18. Menon V, Povirk L. Involvement of p53 in the repair of DNA double strand breaks: multifaceted Roles of p53 in homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Subcell Biochem. 2014; 85: 321-336.

19. Iwasa H, Sarkar A, Shimizu T, Sawada T, Hossain S, Xu X, et al. UNC119 is a binding partner of tumor suppressor Ras-association domain family 6 and induces apoptosis and cell cycle arrest by MDM2 and p53. Cancer Sci. 2018; 109: 2767-2780.

20. Zhou J, Zhang C, Sui X, Cao S, Tang F, Sun S, et al. Histone deacetylase inhibitor chidamide induces growth inhibition and apoptosis in NK/T lymphoma cells through ATM-Chk2-p53-p21 signalling pathway. Invest New Drugs. 2018; 36: 571-580.

21. Vousden KH, Prives C. Blinded by the Light: The Growing Complexity of p53. Cell. 2009; 137: 413-431.

22. Kim JY, Park K, Jung HH, Lee E, Cho EY, Lee KH, et al. Association between Mutation and Expression of TP53 as a Potential Prognostic Marker of Triple-Negative Breast Cancer. Cancer Res Treat. 2016; 48: 1338-1350.

23. Zhou F, Zhang Y, Xu X, Luo J, Yang F, Wang L, et al. Establishment and characterization of three stable Basal/HER2-positive breast cancer cell lines derived from Chinese breast carcinoma with identical missense mutations in the DNA-binding domain of TP53. Cancer Cell Int. 2018; 18: 118. 

24. Cooks T, Harris CC, Oren M. Caught in the cross fire: p53 in inflammation. Carcinogenesis. 2014; 35: 1680-1690.

25. Son DS, Kabir SM, Dong YL, Lee E, Adunyah SE. Inhibitory effect of tumor suppressor p53 on proinflammatory chemokine expression in ovarian cancer cells by reducing proteasomal degradation of IκB. PLoS One. 2012; 7: e51116.

26. Yoshida Y, Shimizu I, Katsuumi G, Jiao S, Suda M, Hayashi Y, et al. p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload. J Mol Cell Cardiol. 2015; 85: 183-198.

27. Gudkov AV, Gurova KV, Komarova EA. Inflammation and p53: A Tale of Two Stresses. Genes Cancer. 2011; 2: 503-516. 28.Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010; 140: 883-899.

29. Guo G, Marrero L, Rodriguez P, Del Valle L, Ochoa A, Cui Y. Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network. Cancer Res. 2013; 73: 1668-1675.

30. Kiaris H, Chatzistamou I, Trimis G, Frangou-Plemmenou M, PafitiKondi A, Kalofoutis A. Evidence for nonautonomous effect of p53 tumor suppressor in carcinogenesis. Cancer Res. 2005; 65: 1627- 1630.

31. Kerkar SP, Restifo NP. Cellular constituents of immune escape within the tumor microenvironment. Cancer Res. 2012; 72: 3125-3130.

32. Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell. 2006; 124: 823-835.

33. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 2009; 182: 4499-4506.

34. Trinchieri G. Cancer and inflammation: an old intuition with rapidly evolving new concepts. Annu Rev Immunol. 2012; 30: 677-706.

35. Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS. Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci U S A. 2002; 99: 10025-10030.

36. Hussain SP, Amstad P, Raja K, Ambs S, Nagashima M, Bennett WP, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 2000; 60: 3333-3337.

37. Tapinos NI, Polihronis M, Moutsopoulos HM. Lymphoma development in Sjögren’s syndrome: Novel p53 mutations. Arthritis Rheum. 1999; 42: 1466-1472.

38. Staib F, Robles AI, Varticovski L, Wang XW, Zeeberg BR, Sirotin M, et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res. 2005; 65: 10255-10264.

39. Zhang Y. I-TASSER server for protein 3D structure prediction. BMC Bioinformatics. 2008; 9: 40.

40. Ghoorah AW, Devignes M-D, Smaïl-Tabbone M, Ritchie DW. KBDOCK 2013: a spatial classification of 3D protein domain family interactions. Nucleic Acids Res. 2014; 42: D389-D395.

41. Kozakov D, Hall DR, Xia B, Porter KA, Padhorny D, Yueh C, et al. The ClusPro web server for protein-protein docking. Nat Protoc. 2017; 12: 255-278.

42. Darnell SJ, Page D, Mitchell JC. An automated decision-tree approach to predicting protein interaction hot spots. Proteins. 2007; 68: 813- 823.

43. Finn RD, Attwood TK, Babbitt PC, Bateman A, Bork P, Bridge AJ, et al. InterPro in 2017-beyond protein family and domain annotations. Nucleic Acids Res. 2017; 45: D190-D199.

44. Venot C, Maratrat M, Dureuil C, Conseiller E, Bracco L, Debussche L. The requirement for the p53 proline-rich functional domain for mediation of apoptosis is correlated with specific PIG3 gene transactivation and with transcriptional repression. EMBO J. 1998; 17: 4668-4679.

45. Chène P. The role of tetramerization in p53 function. Oncogene. 2001; 20: 2611-2617.

46. Stroud JC, Lopez-Rodriguez C, Rao A, Chen L. Structure of a TonEBPDNA complex reveals DNA encircled by a transcription factor. Nat Struct Biol. 2002; 9: 90-94.

47. Larsen S, Yokochi T, Isogai E, Nakamura Y, Ozaki T, Nakagawara A. LMO3 interacts with p53 and inhibits its transcriptional activity. Biochem Biophys Res Commun. 2010; 392: 252-257.

48. Harms KL, Chen X. The C terminus of p53 family proteins is a cell fate determinant. Mol Cell Biol. 2005; 25: 2014-2030.

49. Huttlin EL, Ting L, Bruckner RJ, Gebreab F, Gygi MP, Szpyt J, et al. The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell. 2015; 162: 425-440.

50. Li X, Wang W, Wang J, Malovannaya A, Xi Y, Li W, et al. Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes. Mol Syst Biol. 2015; 11: 775.

51. Rasti M, Azimi T. TP53 Binding to BRCA1 and RAD51 in MCF7 and MDA-MB-468 Breast Cancer Cell Lines in vivo and in vitro. Avicenna J Med Biotechnol. 2015; 7: 76-79.

52. Cuella-Martin R, Oliveira C, Lockstone HE, Snellenberg S, Grolmusova N, Chapman JR. 53BP1 Integrates DNA Repair and p53-Dependent Cell Fate Decisions via Distinct Mechanisms. Mol Cell. 2016; 64: 51-64.

53. Yang Q, Liao L, Deng X, Chen R, Gray NS, Yates JR 3rd, et al. BMK1 is involved in the regulation of p53 through disrupting the PML-MDM2 interaction. Oncogene. 2013; 32: 3156-3164.

54. Huun J, Gansmo LB, Mannsåker B, Gjertrud T. Iversen, Jan SommerfeltPettersen, Jan Inge Øvrebø, et al. The Functional Roles of the MDM2 Splice Variants P2-MDM2-10 and MDM2-?5 in Breast Cancer Cells. Transl Oncol. 2017; 10: 806-817.

55. Bulatov E, Khaiboullina S, dos Reis HJ, Palotás A, Venkataraman K, Vijayalakshmi M, et al. Ubiquitin-Proteasome System: Promising Therapeutic Targets in Autoimmune and Neurodegenerative Diseases. BioNanoSci. 2016; 6: 341-344.

56. Bulatov E, Valiullina A, Sayarova R, Rizvanov A. Promising new therapeutic targets for regulation of inflammation and immunity: RING-type E3 ubiquitin ligases. Immunol Lett. 2018; 202: 44-51.

57. Bulatov E, Zagidullin A, Valiullina A, Sayarova R, Rizvanov A. Small Molecule Modulators of RING-Type E3 Ligases: MDM and Cullin Families as Targets. Front Pharmacol. 2018; 9: 450.

58. Uhrinova S, Uhrin D, Powers H, Watt K, Zheleva D, Fischer P, et al. Structure of free MDM2 N-terminal domain reveals conformational adjustments that accompany p53-binding. J Mol Biol. 2005; 350: 587- 598.

59. Lei C, Zhang W, Fan J, Qiao B, Chen Q, Liu Q, et al. MDM2 T309G polymorphism and esophageal cancer risk: a meta-analysis. Int J Clin Exp Med. 2015; 8: 13413-13416.

60. Alhopuro P, Ylisaukko-Oja S, Koskinen W, Bono P, Arola J, Järvinen HJ, et al. The MDM2 promoter polymorphism SNP309T→G and the risk of uterine leiomyosarcoma, colorectal cancer, and squamous cell carcinoma of the head and neck. J Med Genet. 2005; 42: 694-698. 

61. Hua W, Zhang A, Duan P, Zhu J, Zhao Y, He J, et al. MDM2 promoter del1518 polymorphism and cancer risk: evidence from 22,931 subjects. Onco Targets Ther. 2017; 10: 3773-3780.

62. Han H, Wang L, Xu J, Wang A. miR-128 induces pancreas cancer cell apoptosis by targeting MDM4. Exp Ther Med. 2018; 15: 5017-5022.

63. Li J, Xu X. DNA double-strand break repair: a tale of pathway choices. Acta Biochim. Biophys Sin (Shanghai). 2016; 48: 641-646.

64. Ruas JL, Berchner-Pfannschmidt U, Malik S, Gradin K, Fandrey J, Roeder RG, et al. Complex regulation of the transactivation function of hypoxia-inducible factor-1 alpha by direct interaction with two distinct domains of the CREB-binding protein/p300. J Biol Chem. 2010; 285: 2601-2609. 65.Smale ST. Transcriptional Regulation in the Innate Immune System. Curr Opin Immunol. 2012; 24: 51-57.

66. Kato Y, Shi Y, He X. Neuralization of the Xenopus Embryo by Inhibition of p300/ CREB-Binding Protein Function. J Neurosci. 1999; 19: 9364- 9373.

67. Giebler HA, Lemasson I, Nyborg JK. p53 Recruitment of CREB Binding Protein Mediated through Phosphorylated CREB: a Novel Pathway of Tumor Suppressor Regulation. Mol Cell Biol. 2000; 20: 4849-4858.

68. Grossman SR. p300/CBP/p53 interaction and regulation of the p53 response. Eur J Biochem. 2001; 268: 2773-2778.

69. Gu W, Shi XL, Roeder RG. Synergistic activation of transcription by CBP and p53. Nature. 1997; 387: 819-823.

70. Lill NL, Grossman SR, Ginsberg D, DeCaprio J, Livingston DM. Binding and modulation of p53 by p300/CBP coactivators. Nature. 1997; 387: 823-827.

71. Bentivegna A, Milani D, Gervasini C, Castronovo P, Mottadelli F, Manzini S, et al. Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients. BMC Med Genet. 2006; 7: 77.

72. Zhang J, Vlasevska S, Wells VA, Nataraj S, Holmes AB, Duval R, et al. The Crebbp acetyltransferase is a haploinsufficient tumor suppressor in B cell lymphoma. Cancer Discov. 2017; 7: 322-337.

73. Mullighan CG, Zhang J, Kasper LH, Lerach S, Payne-Turner D, Phillips LA, et al. CREBBP mutations in relapsed acute lymphoblastic leukaemia. Nature. 2011; 471: 235-239.

74. Yi J, Luo J. SIRT1 and p53, effect on cancer, senescence and beyond. Biochim Biophys Acta. 2010; 1804: 1684-1689.

75. Liu X, Ehmed E, Li B, Dou J, Qiao X, Jiang W, et al. Breast cancer metastasis suppressor 1 modulates SIRT1-dependent p53 deacetylation through interacting with DBC1. Am J Cancer Res. 2016; 6: 1441-1449.

76. Kauppinen A, Suuronen T, Ojala J, Kaarniranta K, Salminen A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell Signal. 2013; 25: 1939- 1948.

77. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science. 2015; 350: 1208-1213.

78. Zhang X, Li CF, Zhang L, Wu CY, Han L, Jin G, et al. TRAF6 restricts p53 mitochondrial translocation, apoptosis and tumor suppression. Mol Cell. 2016; 64: 803-814

Received : 01 Sep 2018
Accepted : 08 Oct 2018
Published : 09 Oct 2018
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