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1.
Int J Mol Sci ; 22(1)2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33401705

RESUMO

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) is an essential protein that regulates cellular processes such as cell proliferation, apoptosis, and differentiation. It is known to bind with several proteins to carry out various cellular functions. In this study, we report for the first time that IGFBP-3 is a histone 3 (H3) binding protein. Sub-cellular fractionation was performed to separate into cytosolic fraction, nucleic acid binding protein fraction and insoluble nuclear fraction. Using ligand blot analysis, we identified a ~15 kDa protein that can interact with IGFBP-3 in the insoluble nuclear fraction. The 15 kDa protein was confirmed as histone 3 by far-Western blot analysis and co-immunoprecipitation experiments. A dot-blot experiment further validated the binding of IGFBP-3 with H3. The intensity of IGFBP-3 on dot-blot showed a proportional increase with H3 concentrations between 2.33 pmol-37.42 pmol. Our results support the presence of protein-protein interaction between IGFBP-3 and H3. The physical binding between IGFBP-3 and H3 could indicate its yet another cellular role in regulating the chromatin remodeling for gene transcription.


Assuntos
Células-Tronco Embrionárias/metabolismo , Histonas/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Animais , Linhagem Celular Tumoral , Humanos , Imunoprecipitação , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Ligantes , Camundongos , Ligação Proteica
2.
Front Cell Dev Biol ; 8: 286, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32478064

RESUMO

Insulin-like growth factor (IGF) binding protein-3 (IGFBP-3), one of the six members of the IGFBP family, is a key protein in the IGF pathway. IGFBP-3 can function in an IGF-dependent as well as in an IGF-independent manner. The IGF-dependent roles of IGFBP-3 include its endocrine role in the delivery of IGFs from the site of synthesis to the target cells that possess IGF receptors and the activation of associated downstream signaling. IGF-independent role of IGFBP-3 include its interactions with the proteins of the extracellular matrix and the proteins of the plasma membrane, its translocation through the plasma membrane into the cytoplasm and into the nucleus. The C-terminal domain of IGFBP-3 has the ability to undergo cell penetration therefore, generating a short 8-22-mer C-terminal domain peptides that can be conjugated to drugs or genes for effective intracellular delivery. This has opened doors for biotechnological applications of the molecule in molecular medicine. The aim of this this review is to summarize the complex roles of IGFBP-3 within the cell, including its mechanisms of cellular uptake and its translocation into the nucleus, various molecules with which it is capable of interacting, and its ability to regulate IGF-independent cell growth, survival and apoptosis. This would pave way into understanding the modus operandi of IGFBP-3 in regulating IGF-independent processes and its pleiotropic ability to bind with potential partners thus regulating several cellular functions implicated in metabolic diseases, including cancer.

3.
Artigo em Inglês | MEDLINE | ID: mdl-29412865

RESUMO

INTRODUCTION: Cancer, a multi-step, multifactorial and multi-gene disease, not only damages the genomic integrity of the cell but also hinders the DNA repair mechanisms of the body. Gene-gene and gene environment interactions amongst the genetic polymorphisms together modulate the susceptibility towards a cancer. We have studied the high order gene interactions between the genetic polymorphism of detoxifying genes (CYP1A1, Ahr, XRCC and GST1) that play a key role in the metabolism of the xenobiotics and have been proved to be prognostic markers for lung cancer METHODS: 237 cases and 250 controls have been genotyped using PCR-RFLP technique. In order to find out the association, unconditional logistic regression approach was used and to analyse high order interactions MDR and CART was used. RESULTS: In the MDR analysis, the best model was one factor model which included GSTM1 (CVC 10/10, Prediction error = 0.43, p < .001). The best three factor model comprised of XRCC1 632, XRCC1 206, GSTM1 (CVC 10/10, Prediction error = 0.45, p < .0001). The CART analysis exhibited that Node 1 carrying mutant type of GSTM1 imposed the highest risk towards lung cancer (OR = 11.0, 95%C.I. = 6.05-20.03, p = .000001). Wild type of GSTM1 when combined with mutant type of CYP1A1 M2 and XRCC1 632, an 8 fold risk towards lung cancer was observed (95%C.I. = 4.07-16.29, p = .00001). The high order interactions were used to predict the prognosis of lung cancer patients. Of all the genetic variants, XRCC1 632, GSTM1 and AhR rs2066853 was the most important determinant of overall survival of lung cancer patients CONCLUSION: Through the study we introduced the concept of polygenic approach to get an insight about the various polymorphic variants in determining cancer susceptibility. Lesser number of subjects were found in the high risk subgroups. Further studies with larger sample size are required to warranty the above findings.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Citocromo P-450 CYP1A1/genética , Glutationa Transferase/genética , Neoplasias Pulmonares/genética , Polimorfismo de Nucleotídeo Único , Receptores de Hidrocarboneto Arílico/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética , Adulto , Idoso , Estudos de Casos e Controles , Reparo do DNA , Feminino , Interação Gene-Ambiente , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Índia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Xenobióticos/farmacologia
4.
Sci Rep ; 8(1): 12969, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-30154572

RESUMO

Breast cancer is the most common cancer in women worldwide. Hormone receptor breast cancers are the most common ones and, about 2 out of every 3 cases of breast cancer are estrogen receptor (ER) positive. Selective ER modulators, such as tamoxifen, are the first line of endocrine treatment of breast cancer. Despite the expression of hormone receptors some patients develop tamoxifen resistance and 50% present de novo tamoxifen resistance. Recently, we have demonstrated that activated mammalian target of rapamycin (mTOR) is positively associated with overall survival and recurrence free survival in ER positive breast cancer patients who were later treated with tamoxifen. Since altered expression of protein kinase B (PKB)/Akt in breast cancer cells affect N-myristoyltransferase 1 (NMT1) expression and activity, we investigated whether mTOR, a downstream target of PKB/Akt, regulates NMT1 in ER positive breast cancer cells (MCF7 cells). We inhibited mTOR by treating MCF7 cells with rapamycin and observed that the expression of NMT1 increased with rapamycin treatment over the period of time with a concomitant decrease in mTOR phosphorylation. We further employed mathematical modelling to investigate hitherto not known relationship of mTOR with NMT1. We report here for the first time a collection of models and data validating regulation of NMT1 by mTOR.


Assuntos
Aciltransferases/biossíntese , Adenocarcinoma/enzimologia , Neoplasias da Mama/enzimologia , Estrogênios , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/enzimologia , Serina-Treonina Quinases TOR/fisiologia , Aciltransferases/genética , Indução Enzimática , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Modelos Biológicos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fosforilação , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Estrogênio/análise , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
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