IN-SILICO ANALYSIS OF DELETERIOUS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OF LEUKEMIA INHIBITORY FACTOR (LIF), AND THEIR CONFORMATIONAL PREDICTIONS
Main Article Content
Keywords
LIF, nsSNPs, Molecular docking, Molecular dynamic simulation
Abstract
Leukemia inhibitory factor (LIF) is a multifunctional gene belonging to the interleukin-6 cytokine family. It plays crucial roles in various biological processes such as neuron development, wound healing, maintenance of adrenocorticotropic hormonal secretions in the pituitary glands, reproductive system, and alveolus development. Previous studies have associated LIF polymorphisms with female infertility, schizophrenia (SCZ), and osteoporosis. However, comprehensive computational analyses examining the functional and structural impacts of damaging non-synonymous single-nucleotide polymorphisms (nsSNPs) in LIF have not been conducted. The main objective of this study was to identify and classify nsSNPs that have the most detrimental effects on the LIF gene. A total of nine deleterious mutations (C156F, C153G, L147P, Y111C, Q70H, Y66C, Y66H, T120N, and V164M) were detected, which resulted in altered protein structure. Subsequently, these deleterious mutations were assessed for potential post-translational modification sites using molecular docking and molecular dynamic simulation techniques. The results revealed that the C156F mutant displayed greater conservation and structural dissimilarity compared to the other mutants. Docking analysis demonstrated that EC330 inhibits LIF/LIF-R signaling, thereby impeding LIF's tumor-promoting effects. This finding suggests that EC330 could be a potential candidate for targeted cancer therapy in cases where LIF is overexpressed in malignancies.
References
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14. Kuphal S, Wallner S, Bosserhoff AKJE, pathology m. Impact of LIF (leukemia inhibitory factor) expression in malignant melanoma. 2013;95(2):156-65.
15. Mashayekhi F, Salehi ZJJoCN. Expression of leukemia inhibitory factor in the cerebrospinal fluid of patients with multiple sclerosis. 2011;18(7):951-4.
16. Ancey C, Corbi P, Froger J, Delwail A, Wijdenes J, Gascan H, et al. Secretion of IL-6, IL-11 and LIF by human cardiomyocytes in primary culture. 2002;18(4):199-205.
17. Fukada K, Korsching S, Towle MFJGF. Tissue-specific and ontogenetic regulation of LIF protein levels determined by quantitative enzyme immunoassay. 1997;14(4):279-95.
18. Chesnokova V, Melmed SJE. Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation. 2000;141(11):4032-40.
19. Morel DS, Taupin J-L, Potier M, Deminière C, Potaux L, Gualde N, et al. Renal synthesis of leukaemia inhibitory factor (LIF), under normal and inflammatory conditions. 2000;12(3):265-71.
20. Gadient RA, Patterson PHJSc. Leukemia inhibitory factor, Interleukin 6, and other cytokines using the GP130 transducing receptor: roles in inflammation and injury. 1999;17(3):127-37.
21. Kellokumpu‐Lehtinen P, Talpaz M, Harris D, Van Q, Kurzrock R, Estrov ZJIjoc. Leukemia‐inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways. 1996;66(4):515-9.
22. Paiva P, Menkhorst E, Salamonsen L, Dimitriadis EJC, reviews gf. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. 2009;20(4):319-28.
23. Burdon T, Smith A, Savatier PJTicb. Signalling, cell cycle and pluripotency in embryonic stem cells. 2002;12(9):432-8.
24. Mattei S, Colombo MP, Melani C, Silvani A, Parmiani G, Herlyn MJIjoc. Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. 1994;56(6):853-7.
25. Kamohara H, Sakamoto K, Ishiko T, Mita S, Masuda Y, Abe T, et al. Human carcinoma cell lines produce biologically active leukemia inhibitory factor (LIF). 1994;85(2):131-40.
26. Ohata Y, Tsuchiya M, Hirai H, Yamaguchi S, Akashi T, Sakamoto K, et al. Leukemia inhibitory factor produced by fibroblasts within tumor stroma participates in invasion of oral squamous cell carcinoma. 2018;13(2):e0191865.
27. Bilal A, Naveed N. A brief note on cancer and its treatment. Occup Med Health Aff. 2021;9(7):1-3.
28. Králícková M, Síma R, Martínek P, Vanecek T, Ulcová-Gallová Z, Síma P, et al. [The leukemia inhibitory factor gene mutations in the population of infertile women: the heterozygote transition G to A on the position 3400 does not affect the outcome of the infertility treatment]. Ceska gynekologie. 2007;72(4):293-8.
29. Giess R, Tanasescu I, Steck T, Sendtner MJMhr. Leukaemia inhibitory factor gene mutations in infertile women. 1999;5(6):581-6.
30. Okahisa Y, Ujike H, Kunugi H, Ishihara T, Kodama M, Takaki M, et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. 2010;34(1):172-6.
31. Niaei G, Taghavi BA, Niaei AJIJoPH. V64M Mutation in Leukemia Inhibitory Factor Gene in Women Infertility. 2017;46(7):1003-4.
32. Tajeddin N, Ahadi AM, Javadi G, Ayat H. Investigation of Polymorphisms in the Upstream Sequence of LIF and LIFR Genes in the Infertile Women. 2021;23(1):e95239.
33. Moudi M, Sargazi S, Heidari Nia M, Saravani R, Shirvaliloo M, Shakiba M. Polymorphism in the 3′-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses. Journal of Molecular Neuroscience. 2020;70(12):2093-101.
34. George Priya Doss C, Nagasundaram N, Chakraborty C, Chen L, Zhu H. Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach. Human Genomics. 2013;7(1):10.
35. Desai M, Chauhan JB. Computational analysis for the determination of deleterious nsSNPs in human MTHFD1 gene. Computational biology and chemistry. 2017;70:7-14.
36. Bilal A, Iqbal A, Rauf A, Azam AR. Top outbreaks of 21st century: a review.
37. Webb B, Sali A. Comparative Protein Structure Modeling Using MODELLER. Current protocols in bioinformatics. 2016;54:5.6.1-5.6.37.
38. Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods in molecular biology (Clifton, NJ). 2015;1263:243-50.
39. Jejurikar BL, Rohane SHJAJoRiC. Drug Designing in Discovery Studio. 2021;14(2):135-8.
40. Ahmed F, Kumar M, Raghava GP. Prediction of polyadenylation signals in human DNA sequences using nucleotide frequencies. In silico biology. 2009;9(3):135-48.
41. Kamaraj B, Rajendran V, Sethumadhavan R, Kumar CV, Purohit R. Mutational analysis of FUS gene and its structural and functional role in amyotrophic lateral sclerosis 6. Journal of biomolecular structure & dynamics. 2015;33(4):834-44.
42. Arshad M, Bhatti A, John P. Identification and in silico analysis of functional SNPs of human TAGAP protein: A comprehensive study. PloS one. 2018;13(1):e0188143.
43. Singh D, Rahi A, Kumari R, Gupta V, Gautam G, Aggarwal S, et al. Computational and mutational analysis of TatD DNase of Bacillus anthracis. Journal of cellular biochemistry. 2019.
44. Karchin RJBib. Next generation tools for the annotation of human SNPs. 2009;10(1):35-52.
45. Doss CGP, Sudandiradoss C, Rajasekaran R, Choudhury P, Sinha P, Hota P, et al. Applications of computational algorithm tools to identify functional SNPs. 2008;8(4):309-16.
46. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al. Human gene mutation database (HGMD®): 2003 update. 2003;21(6):577-81.
47. Niaei G, Amir Taghavi B, Niaei A. V64M Mutation in Leukemia Inhibitory Factor Gene in Women Infertility. Iran J Public Health. 2017;46(7):1003-4.
48. Ishida R, Ezura Y, Iwasaki H, Nakazawa I, Kajita M, Kodaira M, et al. Linkage disequilibrium and haplotype analysis among four novel single-nucleotide polymorphisms in the human leukemia inhibitory factor (LIF) gene. 2001;46(10):557-9.
49. Johnson MM, Houck J, Chen CJCE, Biomarkers P. Screening for deleterious nonsynonymous single-nucleotide polymorphisms in genes involved in steroid hormone metabolism and response. 2005;14(5):1326-9.
50. Ma B, Elkayam T, Wolfson H, Nussinov RJPotNAoS. Protein–protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. 2003;100(10):5772-7.
51. Bilal A, Ahmad S, Tanvir F, Tariq M, Ramzan K, Saleem M, et al. PREDICTIVE MODELING OF N-ACETYL TRANSFERASE 2 SINGLE NUCLEOTIDE POLYMORPHISMS AND BREAST CANCER RISK USING IN-SILCO APPROACHES. THE JOURNAL OF MICROBIOLOGY AND MOLECULAR GENETICS. 2022;3(2):105-21.
52. Bilal A, Ahmad S, Nisa FU, Ali F, Ramzan K, Tariq M, et al. ROLE OF TUMOR NECROSIS FACTOR-? ETA (TNF-?) IN GASTRIC CANCER: SINGLE NUCLEOTIDE POLYMORPHISMS ANALYSIS-AN IN-SILICO STUDY. THE JOURNAL OF MICROBIOLOGY AND MOLECULAR GENETICS. 2022;3(3):191-206.
53. Thusberg J, Olatubosun A, Vihinen MJHm. Performance of mutation pathogenicity prediction methods on missense variants. 2011;32(4):358-68.
54. Ferrer-Costa C, Orozco M, de la Cruz XJJomb. Characterization of disease-associated single amino acid polymorphisms in terms of sequence and structure properties. 2002;315(4):771-86.
55. Bross P, Corydon TJ, Andresen BS, Jørgensen MM, Bolund L, Gregersen NJHm. Protein misfolding and degradation in genetic diseases. 1999;14(3):186-98.
56. Shaw GJBi. Polymorphism and single nucleotide polymorphisms (SNP s). 2013;112(5):664-5.
57. Khan IA, Mort M, Buckland PR, O'Donovan MC, Cooper DN, Chuzhanova NAJIsb. In silico discrimination of single nucleotide polymorphisms and pathological mutations in human gene promoter regions by means of local DNA sequence context and regularity. 2006;6(1, 2):23-34.
58. Nair H, Santhamma B, Nickisch K. Cytotoxic agents that preferentially target leukemia inhibitory factor (LIF) for the treatment of malignancies and as new contraceptive agents. Google Patents; 2018.
2. SIMPSON RJ, HILTON DJ, NICE EC, RUBIRA MR, METCALF D, GEARING DP, et al. Structural characterization of a murine myeloid leukaemia inhibitory factor. 1988;175(3):541-7.
3. Robinson R, Grey L, Staunton D, Vankelecom H, Vernallis A, Moreau J-F, et al. The crystal structure and biological function of leukemia inhibitory factor: implications for receptor binding. 1994;77(7):1101-16.
4. Baumann H, Wong GJTJoI. Hepatocyte-stimulating factor III shares structural and functional identity with leukemia-inhibitory factor. 1989;143(4):1163-7.
5. Boulanger MJ, Bankovich AJ, Kortemme T, Baker D, Garcia KCJMc. Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130. 2003;12(3):577-89.
6. Nicola NA, Babon JJJC, reviews gf. Leukemia inhibitory factor (LIF). 2015;26(5):533-44.
7. Lin T-A, Wu T-S, Li Y-J, Yang C-N, Illescas Ralda MM, Chang H-HJJocm. Role and mechanism of LIF in oral squamous cell carcinoma progression. 2020;9(2):295.
8. Gulluoglu S, Sahin M, Tuysuz EC, Yaltirik CK, Kuskucu A, Ozkan F, et al. Leukemia inhibitory factor promotes aggressiveness of chordoma. 2017;25(7):1177.
9. Wang D, Liu K, Yang Y, Wang T, Rao Q, Guo W, et al. Prognostic value of leukemia inhibitory factor and its receptor in pancreatic adenocarcinoma. 2020;16(3):4461-73.
10. Liu S-C, Chang Y-SJM, Oncology C. Role of leukemia inhibitory factor in nasopharyngeal carcinogenesis. 2014;1(1):e29900.
11. Atlas HPJE-Ic. Available online: https://www. proteinatlas. org. 2021.
12. Qian L, Xu F, Wang X, Jiang M, Wang J, Song W, et al. LncRNA expression profile of ΔNp63α in cervical squamous cancers and its suppressive effects on LIF expression. 2017;96:114-22.
13. Li X, Yang Q, Yu H, Wu L, Zhao Y, Zhang C, et al. LIF promotes tumorigenesis and metastasis of breast cancer through the AKT-mTOR pathway. 2014;5(3):788.
14. Kuphal S, Wallner S, Bosserhoff AKJE, pathology m. Impact of LIF (leukemia inhibitory factor) expression in malignant melanoma. 2013;95(2):156-65.
15. Mashayekhi F, Salehi ZJJoCN. Expression of leukemia inhibitory factor in the cerebrospinal fluid of patients with multiple sclerosis. 2011;18(7):951-4.
16. Ancey C, Corbi P, Froger J, Delwail A, Wijdenes J, Gascan H, et al. Secretion of IL-6, IL-11 and LIF by human cardiomyocytes in primary culture. 2002;18(4):199-205.
17. Fukada K, Korsching S, Towle MFJGF. Tissue-specific and ontogenetic regulation of LIF protein levels determined by quantitative enzyme immunoassay. 1997;14(4):279-95.
18. Chesnokova V, Melmed SJE. Leukemia inhibitory factor mediates the hypothalamic pituitary adrenal axis response to inflammation. 2000;141(11):4032-40.
19. Morel DS, Taupin J-L, Potier M, Deminière C, Potaux L, Gualde N, et al. Renal synthesis of leukaemia inhibitory factor (LIF), under normal and inflammatory conditions. 2000;12(3):265-71.
20. Gadient RA, Patterson PHJSc. Leukemia inhibitory factor, Interleukin 6, and other cytokines using the GP130 transducing receptor: roles in inflammation and injury. 1999;17(3):127-37.
21. Kellokumpu‐Lehtinen P, Talpaz M, Harris D, Van Q, Kurzrock R, Estrov ZJIjoc. Leukemia‐inhibitory factor stimulates breast, kidney and prostate cancer cell proliferation by paracrine and autocrine pathways. 1996;66(4):515-9.
22. Paiva P, Menkhorst E, Salamonsen L, Dimitriadis EJC, reviews gf. Leukemia inhibitory factor and interleukin-11: critical regulators in the establishment of pregnancy. 2009;20(4):319-28.
23. Burdon T, Smith A, Savatier PJTicb. Signalling, cell cycle and pluripotency in embryonic stem cells. 2002;12(9):432-8.
24. Mattei S, Colombo MP, Melani C, Silvani A, Parmiani G, Herlyn MJIjoc. Expression of cytokine/growth factors and their receptors in human melanoma and melanocytes. 1994;56(6):853-7.
25. Kamohara H, Sakamoto K, Ishiko T, Mita S, Masuda Y, Abe T, et al. Human carcinoma cell lines produce biologically active leukemia inhibitory factor (LIF). 1994;85(2):131-40.
26. Ohata Y, Tsuchiya M, Hirai H, Yamaguchi S, Akashi T, Sakamoto K, et al. Leukemia inhibitory factor produced by fibroblasts within tumor stroma participates in invasion of oral squamous cell carcinoma. 2018;13(2):e0191865.
27. Bilal A, Naveed N. A brief note on cancer and its treatment. Occup Med Health Aff. 2021;9(7):1-3.
28. Králícková M, Síma R, Martínek P, Vanecek T, Ulcová-Gallová Z, Síma P, et al. [The leukemia inhibitory factor gene mutations in the population of infertile women: the heterozygote transition G to A on the position 3400 does not affect the outcome of the infertility treatment]. Ceska gynekologie. 2007;72(4):293-8.
29. Giess R, Tanasescu I, Steck T, Sendtner MJMhr. Leukaemia inhibitory factor gene mutations in infertile women. 1999;5(6):581-6.
30. Okahisa Y, Ujike H, Kunugi H, Ishihara T, Kodama M, Takaki M, et al. Leukemia inhibitory factor gene is associated with schizophrenia and working memory function. 2010;34(1):172-6.
31. Niaei G, Taghavi BA, Niaei AJIJoPH. V64M Mutation in Leukemia Inhibitory Factor Gene in Women Infertility. 2017;46(7):1003-4.
32. Tajeddin N, Ahadi AM, Javadi G, Ayat H. Investigation of Polymorphisms in the Upstream Sequence of LIF and LIFR Genes in the Infertile Women. 2021;23(1):e95239.
33. Moudi M, Sargazi S, Heidari Nia M, Saravani R, Shirvaliloo M, Shakiba M. Polymorphism in the 3′-UTR of LIF but Not in the ATF6B Gene Associates with Schizophrenia Susceptibility: a Case-Control Study and In Silico Analyses. Journal of Molecular Neuroscience. 2020;70(12):2093-101.
34. George Priya Doss C, Nagasundaram N, Chakraborty C, Chen L, Zhu H. Extrapolating the effect of deleterious nsSNPs in the binding adaptability of flavopiridol with CDK7 protein: a molecular dynamics approach. Human Genomics. 2013;7(1):10.
35. Desai M, Chauhan JB. Computational analysis for the determination of deleterious nsSNPs in human MTHFD1 gene. Computational biology and chemistry. 2017;70:7-14.
36. Bilal A, Iqbal A, Rauf A, Azam AR. Top outbreaks of 21st century: a review.
37. Webb B, Sali A. Comparative Protein Structure Modeling Using MODELLER. Current protocols in bioinformatics. 2016;54:5.6.1-5.6.37.
38. Dallakyan S, Olson AJ. Small-molecule library screening by docking with PyRx. Methods in molecular biology (Clifton, NJ). 2015;1263:243-50.
39. Jejurikar BL, Rohane SHJAJoRiC. Drug Designing in Discovery Studio. 2021;14(2):135-8.
40. Ahmed F, Kumar M, Raghava GP. Prediction of polyadenylation signals in human DNA sequences using nucleotide frequencies. In silico biology. 2009;9(3):135-48.
41. Kamaraj B, Rajendran V, Sethumadhavan R, Kumar CV, Purohit R. Mutational analysis of FUS gene and its structural and functional role in amyotrophic lateral sclerosis 6. Journal of biomolecular structure & dynamics. 2015;33(4):834-44.
42. Arshad M, Bhatti A, John P. Identification and in silico analysis of functional SNPs of human TAGAP protein: A comprehensive study. PloS one. 2018;13(1):e0188143.
43. Singh D, Rahi A, Kumari R, Gupta V, Gautam G, Aggarwal S, et al. Computational and mutational analysis of TatD DNase of Bacillus anthracis. Journal of cellular biochemistry. 2019.
44. Karchin RJBib. Next generation tools for the annotation of human SNPs. 2009;10(1):35-52.
45. Doss CGP, Sudandiradoss C, Rajasekaran R, Choudhury P, Sinha P, Hota P, et al. Applications of computational algorithm tools to identify functional SNPs. 2008;8(4):309-16.
46. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NS, et al. Human gene mutation database (HGMD®): 2003 update. 2003;21(6):577-81.
47. Niaei G, Amir Taghavi B, Niaei A. V64M Mutation in Leukemia Inhibitory Factor Gene in Women Infertility. Iran J Public Health. 2017;46(7):1003-4.
48. Ishida R, Ezura Y, Iwasaki H, Nakazawa I, Kajita M, Kodaira M, et al. Linkage disequilibrium and haplotype analysis among four novel single-nucleotide polymorphisms in the human leukemia inhibitory factor (LIF) gene. 2001;46(10):557-9.
49. Johnson MM, Houck J, Chen CJCE, Biomarkers P. Screening for deleterious nonsynonymous single-nucleotide polymorphisms in genes involved in steroid hormone metabolism and response. 2005;14(5):1326-9.
50. Ma B, Elkayam T, Wolfson H, Nussinov RJPotNAoS. Protein–protein interactions: structurally conserved residues distinguish between binding sites and exposed protein surfaces. 2003;100(10):5772-7.
51. Bilal A, Ahmad S, Tanvir F, Tariq M, Ramzan K, Saleem M, et al. PREDICTIVE MODELING OF N-ACETYL TRANSFERASE 2 SINGLE NUCLEOTIDE POLYMORPHISMS AND BREAST CANCER RISK USING IN-SILCO APPROACHES. THE JOURNAL OF MICROBIOLOGY AND MOLECULAR GENETICS. 2022;3(2):105-21.
52. Bilal A, Ahmad S, Nisa FU, Ali F, Ramzan K, Tariq M, et al. ROLE OF TUMOR NECROSIS FACTOR-? ETA (TNF-?) IN GASTRIC CANCER: SINGLE NUCLEOTIDE POLYMORPHISMS ANALYSIS-AN IN-SILICO STUDY. THE JOURNAL OF MICROBIOLOGY AND MOLECULAR GENETICS. 2022;3(3):191-206.
53. Thusberg J, Olatubosun A, Vihinen MJHm. Performance of mutation pathogenicity prediction methods on missense variants. 2011;32(4):358-68.
54. Ferrer-Costa C, Orozco M, de la Cruz XJJomb. Characterization of disease-associated single amino acid polymorphisms in terms of sequence and structure properties. 2002;315(4):771-86.
55. Bross P, Corydon TJ, Andresen BS, Jørgensen MM, Bolund L, Gregersen NJHm. Protein misfolding and degradation in genetic diseases. 1999;14(3):186-98.
56. Shaw GJBi. Polymorphism and single nucleotide polymorphisms (SNP s). 2013;112(5):664-5.
57. Khan IA, Mort M, Buckland PR, O'Donovan MC, Cooper DN, Chuzhanova NAJIsb. In silico discrimination of single nucleotide polymorphisms and pathological mutations in human gene promoter regions by means of local DNA sequence context and regularity. 2006;6(1, 2):23-34.
58. Nair H, Santhamma B, Nickisch K. Cytotoxic agents that preferentially target leukemia inhibitory factor (LIF) for the treatment of malignancies and as new contraceptive agents. Google Patents; 2018.
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Jan 23, 2024
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How to Cite
Maham Afzal, Umer Ali, Adeel Riaz, Fouzia Tanvir, Asif Bilal, & Sibtain Ahmad. (2024). IN-SILICO ANALYSIS OF DELETERIOUS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OF LEUKEMIA INHIBITORY FACTOR (LIF), AND THEIR CONFORMATIONAL PREDICTIONS. Journal of Population Therapeutics and Clinical Pharmacology, 31(1), 2792-2811. https://doi.org/10.53555/jptcp.v31i1.5166
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Author Biographies
Maham Afzal
Department of Biochemistry, University of Okara, Okara Pakistan
Umer Ali
Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA
Adeel Riaz
Department of Biochemistry, University of Okara, Okara Pakistan
Fouzia Tanvir
Department of Zoology, University of Okara, Okara Pakistan
Asif Bilal
Department of Zoology, University of Okara, Okara Pakistan
Sibtain Ahmad
Institute of Animal and Dairy Sciences, Faculty of Animal Husbandry, University of Agriculture, Faisalabad, Pakistan
How to Cite
Maham Afzal, Umer Ali, Adeel Riaz, Fouzia Tanvir, Asif Bilal, & Sibtain Ahmad. (2024). IN-SILICO ANALYSIS OF DELETERIOUS SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) OF LEUKEMIA INHIBITORY FACTOR (LIF), AND THEIR CONFORMATIONAL PREDICTIONS. Journal of Population Therapeutics and Clinical Pharmacology, 31(1), 2792-2811. https://doi.org/10.53555/jptcp.v31i1.5166