Structural and Functional Analysis of KIT Gene Encoding Receptor Tyrosine Kinase and its Interaction with Sunitinib and HDAC Inhibitors: An in silico Approach

Vanajothi, Ramar; Rajamanikandan, Sundaraj; Sudha, A.; Srinivasan, Pappu

doi:10.3923/pjbs.2012.121.131

Cited by 6 publications

(4 citation statements)

References 23 publications

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“…In order to combine the results of the various tools, consensus predictors have been developed to allow comparison between methods that use different analytical approaches [ 10 ] [ 31 ]. Studies using combination of different prediction tools have identified deleterious mutations in genes involved in different biological processes, including, for example, cancer (breast cancer 1, early onset— BRCA1 gene) [ 32 ], STIL gene [ 33 ], Centromere-associated protein-E gene (CENP-E) [ 34 ], leukemia (c-abl oncogene 1— ABL1 gene) [ 35 ], lipoprotein metabolism (ATP-binding cassette transporter A1— ABCA1 gene) [ 36 ], cardiomyopathy (beta myosin heavy chain— MyH7 gene) [ 28 ], oxidative stress (superoxide dismutase 2— SOD2 gene) [ 37 ], amyotrophic lateral sclerosis (superoxide dismutase 1— SOD1 gene) [ 38 ], and melanogenesis (receptor tyrosine kinase— KIT gene [ 39 ], oculocutaneous albinism type 2— OCA2 —P protein gene [ 40 ], tyrosinase— TYR gene [ 41 ], and tyrosinase-related protein 1— TYRP1 gene [ 42 ]), resulting in the establishment of the mutations with the highest pathogenic prediction.…”

Section: Introductionmentioning

confidence: 99%

Prediction of the Damage-Associated Non-Synonymous Single Nucleotide Polymorphisms in the Human MC1R Gene

2015

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The melanocortin 1 receptor (MC1R) is involved in the control of melanogenesis. Polymorphisms in this gene have been associated with variation in skin and hair color and with elevated risk for the development of melanoma. Here we used 11 computational tools based on different approaches to predict the damage-associated non-synonymous single nucleotide polymorphisms (nsSNPs) in the coding region of the human MC1R gene. Among the 92 nsSNPs arranged according to the predictions 62% were classified as damaging in more than five tools. The classification was significantly correlated with the scores of two consensus programs. Alleles associated with the red hair color (RHC) phenotype and with the risk of melanoma were examined. The R variants D84E, R142H, R151C, I155T, R160W and D294H were classified as damaging by the majority of the tools while the r variants V60L, V92M and R163Q have been predicted as neutral in most of the programs The combination of the prediction tools results in 14 nsSNPs indicated as the most damaging mutations in MC1R (L48P, R67W, H70Y, P72L, S83P, R151H, S172I, L206P, T242I, G255R, P256S, C273Y, C289R and R306H); C273Y showed to be highly damaging in SIFT, Polyphen-2, MutPred, PANTHER and PROVEAN scores. The computational analysis proved capable of identifying the potentially damaging nsSNPs in MC1R, which are candidates for further laboratory studies of the functional and pharmacological significance of the alterations in the receptor and the phenotypic outcomes.

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Section: Introductionmentioning

confidence: 99%

Prediction of the Damage-Associated Non-Synonymous Single Nucleotide Polymorphisms in the Human MC1R Gene

2015

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“…Upon activation by its cytokine ligand, stem cell factor (SCF), this protein phosphorylates multiple intracellular proteins that play a role in in the proliferation, differentiation, migration, and apoptosis of many cell types and thereby plays an important role in hematopoiesis, stem cell maintenance, gametogenesis, melanogenesis, and in mast cell development, migration, and function. This protein can be a membrane-bound or soluble protein [34,45]. Regarding the MLH1 gene, the F261fs*7 mutation was found.…”

Section: Discussionmentioning

confidence: 99%

“…The KIT proto-oncogene transcribes the homologous receptor of the feline viral sarcoma v-kit, also called CD117 (c-Kit), which, with its binding to the physiological ligand, produces dimerization, which leads to transphosphorylation. This, in turn, reorients the domain intracellular membrane, freeing it from the autoinhibitory conformation that it acquires in an inactive state, and facilitating its catalytic function [34]. Like the previous receptor, some of these phosphorylation sites in the inner membrane domain of c-Kit bind with SH2 domains, forming docking sites for signaling and activation of the pathway (PI3K, Akt, TSC1/2, mTOR1/2, and transcription factor) [38].…”

Section: Discussionmentioning

confidence: 99%

Mutations in the PIK3C2B, ERBB3, KIT, and MLH1 Genes and their Relationship with Resistance to Temozolomide in Patients with High-grade Gliomas

Gómez¹,

Martínez²,

Flórez³

et al. 2023

Preprint

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Background. The treatment for patients with high-grade gliomas includes radiation therapy and temozolomide. However, some patients do not respond to temozolomide because they have a methylation reversal mechanism through the enzyme O6-methylguanine-DNA-methyltransferase. This biomarker has been used as a prognostic factor in patients receiving treatment with temozolomide. However, not all patients respond in the same way, which suggests the existence of other genes involved in resistance to temozolomide. Materials and Methods. A group of 31 patients with high-grade gliomas was recruited and were clinically, image pattern, and pathologically characterized. The sequencing of 324 genes related to different types of cancer was performed to detect mutations. Subsequently, a statistical analysis was conducted to determine the mutated genes that were most related to resistance to treatment. Results. The genes related to the second relapse of patients with high-grade glioma after the use of temozolomide according to Stupp protocol and metronomic dose were PIK3C2B, KIT, ERBB3, and MLH1. Conclusions. Considering the results obtained, we suggest that the mutations in the four genes and the methylation of the gene promoter that codes for MGMT protein could be related to the clinical evolution of patients with high-grade gliomas and its response to treatment with temozolomide.

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“…It correlates this multiple sequence alignment with different protein structure and calculates the position-specific independent count (PSIC) score ranging from 0 to 1. The range of PSIC scores categories the SNPs as benign (0-0.2), possible damaging (0.2-0.85), and probably damaging (0.85-1) ( 22) (Ramensky et al, 2002;Vanajothi et al, 2012;Bhavaniramya et al, 2019). (Available at: http:// genetics.bwh.harvard.edu/pph).…”

Section: Polymorphism Phenotyping (Polyphen-2)mentioning

confidence: 99%

Prediction of deleterious non-synonymous SNPs of human TLR2 gene associated with bacterial meningitis and hearing impairment by computational approach

Manikandan¹

2022

ijhs

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Background: Bacterial meningitis is the most serious infection of the central nervous system and often occurs in children under the age of 5 years and leads to hearing loss, learning disabilities. Several studies have reported the genetic variation in a gene that is involved in the innate immune system and affects the susceptibility, severity of bacterial infection during meningitis. Methodology: Hence the present study was performed to insights the single nucleotide polymorphisms in pathogen recognition genes especially those that play an essential role in the innate immune system. Toll-like receptor 2 (TLR2) was selected to analyze the association of TLR2 in bacterial meningitis. The coding and non-coding SNPs of the human TLR2 gene was retrieved from the NCBI database and were subjected to various computational prediction tools including SIFT, PolyPhen-2, Imutnat, to predict the high-risk deleterious SNPs and the effect of single amino acid substitutions and structural and functional impact of these mutations was predicted with project HOPE, SNP-GO tools. Results: The result revealed that among the 501 non-synonymous, 9 deleterious SNPs were sorted by SFIT, Polyphen-2 and I mutant serve with SFIT score, DDG score, and PISC score which are equal to 1.

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Structural and Functional Analysis of KIT Gene Encoding Receptor Tyrosine Kinase and its Interaction with Sunitinib and HDAC Inhibitors: An in silico Approach

Cited by 6 publications

References 23 publications

Prediction of the Damage-Associated Non-Synonymous Single Nucleotide Polymorphisms in the Human MC1R Gene

Prediction of the Damage-Associated Non-Synonymous Single Nucleotide Polymorphisms in the Human MC1R Gene

Mutations in the PIK3C2B, ERBB3, KIT, and MLH1 Genes and their Relationship with Resistance to Temozolomide in Patients with High-grade Gliomas

Prediction of deleterious non-synonymous SNPs of human TLR2 gene associated with bacterial meningitis and hearing impairment by computational approach

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