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Journal ArticleDOI

Breast cancer mutation in GATA3 zinc finger 1 induces conformational changes leading to the closer binding of ZnFn2 with a wrapping architecture.

29 May 2019-Journal of Biomolecular Structure & Dynamics (J Biomol Struct Dyn)-Vol. 38, Iss: 6, pp 1810-1821
TL;DR: The findings indicate that the somatic mutation M294K, reported in the GATA3 gene destabilizes the unbound structure but, when it forms the DNA-complex, its overall structural stability is restored by the wrapping architecture of ZnFn2 around the DNA in the palindromic region, leading to the enhanced kinetic stability.
Abstract: GATA3 is a transcription factor, known to regulate the transcriptional network and several pathways using two zinc fingers. Its mutation is associated with a higher risk of breast cancer. The molecular mechanisms of these mutations are poorly understood. It recognizes -GATA- sites on the DNA, using its two zinc fingers ZnFn1 and ZnFn2. Mutations in ZnFn2 have been studied in the past and well known but recently ZnFn1 mutations are also being reported very frequently in breast cancer patients and there is very less knowledge available regarding the binding modes and mechanism. Here, we have investigated the structural and functional impact of GATA3 mutation M294K on the DNA-binding property. The structure was obtained and mutation was induced before subjecting it to the molecular docking followed by MD simulation. Our findings indicate that the somatic mutation M294K, reported in the GATA3 gene destabilizes the unbound structure but, when it forms the DNA-complex, its overall structural stability is restored by the wrapping architecture of ZnFn2 around the DNA in the palindromic region, leading to the enhanced kinetic stability. The mutation not only affects the ZnFn1 region alone but also influences the whole complex by inducing the conformational changes in the linker region between the two zinc fingers, bringing the two zinc fingers to closer proximity representing the flexibility in binding sites. Our findings provide a better understanding of ZnFn1 mutations and the possibility of a different strategy to target these genes for their clinical relevance.Communicated by Ramaswamy H. Sarma.
Citations
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Journal ArticleDOI
TL;DR: Analysis of the gene expression data revealed that high expression of NMUR1 and NCAM1 in luminal A breast cancer statistically correlated with poor prognosis, whereas the low expression levels of CDC7, KIF18A, STIL, and CKS2 in basal-like breast cancer statistical correlated withpoor prognosis.
Abstract: Breast cancer subtypes are statistically associated with prognosis. The search for markers of breast tumor heterogeneity and the development of precision medicine for patients are the current focuses of the field. We used a bioinformatic approach to identify key disease-causing genes unique to the luminal A and basal-like subtypes of breast cancer. First, we retrieved gene expression data for luminal A breast cancer, basal-like breast cancer, and normal breast tissue samples from The Cancer Genome Atlas database. The differentially expressed genes unique to the 2 breast cancer subtypes were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We constructed protein–protein interaction networks of the differentially expressed genes. Finally, we analyzed the key modules of the networks, which we combined with survival data to identify the unique cancer genes associated with each breast cancer subtype. We identified 1114 differentially expressed genes in luminal A breast cancer and 1042 differentially expressed genes in basal-like breast cancer, of which the subtypes shared 500. We observed 614 and 542 differentially expressed genes unique to luminal A and basal-like breast cancer, respectively. Through enrichment analyses, protein–protein interaction network analysis, and module mining, we identified 8 key differentially expressed genes unique to each subtype. Analysis of the gene expression data in the context of the survival data revealed that high expression of NMUR1 and NCAM1 in luminal A breast cancer statistically correlated with poor prognosis, whereas the low expression levels of CDC7, KIF18A, STIL, and CKS2 in basal-like breast cancer statistically correlated with poor prognosis. NMUR1 and NCAM1 are novel key disease-causing genes for luminal A breast cancer, and STIL is a novel key disease-causing gene for basal-like breast cancer. These genes are potential targets for clinical treatment.

14 citations


Cites background from "Breast cancer mutation in GATA3 zin..."

  • ...Karn and Emerson suggested that mutations in GATA3 resulted in differential gene expression in ER-positive breast tumors, which affected prognosis [8]....

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Journal ArticleDOI
TL;DR: GATA3 may represent a promising target for the prevention and treatment of obesity by regulating thermogenic capacity by interacting with transcriptional coactivator PGC-1α to increase the expression of UCP-1.
Abstract: Objective Obesity is recognized as the cause of multiple metabolic diseases and is rapidly increasing worldwide. As obesity is due to an imbalance in energy homeostasis, the promotion of energy consumption through browning of white adipose tissue (WAT) has emerged as a promising therapeutic strategy to counter the obesity epidemic. However, the molecular mechanisms of the browning process are not well understood. In this study, we investigated the effects of the GATA family of transcription factors on the browning process. Methods We used qPCR to analyze the expression of GATA family members during WAT browning. In order to investigate the function of GATA3 in the browning process, we used the lentivirus system for the ectopic expression and knockdown of GATA3. Western blot and real-time qPCR analyses revealed the regulation of thermogenic genes upon ectopic expression and knockdown of GATA3. Luciferase reporter assays, co-immunoprecipitation, and chromatin immunoprecipitation were performed to demonstrate that GATA3 interacts with proliferator-activated receptor-γ co-activator-1α (PGC-1α) to regulate the promoter activity of uncoupling protein-1 (UCP-1). Enhanced energy expenditure by GATA3 was confirmed using oxygen consumption assays, and the mitochondrial content was assessed using MitoTracker. Furthermore, we examined the in vivo effects of lentiviral GATA3 overexpression and knockdown in inguinal adipose tissue of mice. Results Gata3 expression levels were significantly elevated in the inguinal adipose tissue of mice exposed to cold conditions. Ectopic expression of GATA3 enhanced the expression of UCP-1 and thermogenic genes upon treatment with norepinephrine whereas GATA3 knockdown had the opposite effect. Luciferase reporter assays using the UCP-1 promoter region showed that UCP-1 expression was increased in a dose-dependent manner by GATA3 regardless of norepinephrine treatment. GATA3 was found to directly bind to the promoter region of UCP-1. Furthermore, our results indicated that GATA3 interacts with the transcriptional coactivator PGC-1α to increase the expression of UCP-1. Taken together, we demonstrate that GATA3 has an important role in enhancing energy expenditure by increasing the expression of thermogenic genes both in vitro and in vivo. Conclusion GATA3 may represent a promising target for the prevention and treatment of obesity by regulating thermogenic capacity.

9 citations

Journal ArticleDOI
TL;DR: The present study highlights the importance of different variants of GATA3 which have potential impact on neoplastic progression in breast cancer and may facilitate development of precise and personalized therapeutics.
Abstract: Breast cancer (BC) is the main cancer in women having multiple receptor based tumour subtypes. Large scale genome sequencing studies of BC have identified several genes among which GATA3 is reported as a highly mutated gene followed by TP53 and PIK3CA. GATA3 is a crucial transcription factor, and was initially identified as a DNA-binding protein involved in the regulation of immune cell functions. Different missense mutations in the region of the DNA-binding domain of GATA3 are associated with BC and other neoplastic disorders. In this study, computational based approaches have been exploited to reveal associations of various mutations on structure, stability, conformation and function of GATA3. Our findings have suggested that, all analysed missense mutations were deleterious and highly pathogenic in nature. A molecular dynamics simulation study showed that all mutations led to structural destabilisation by reducing protein globularity and flexibility, by altering secondary structural configuration and decreasing protein ligand stability. Essential dynamics analysis indicated that mutations in GATA3 decreased protein mobility and increased its conformational instability. Furthermore, residue network analysis showed that the mutations affected the signal transduction of important residues that potentially influenced GATA3-DNA binding. The present study highlights the importance of different variants of GATA3 which have potential impact on neoplastic progression in breast cancer and may facilitate development of precise and personalized therapeutics.

7 citations

22 Mar 2021
TL;DR: In this paper, the impact of the identified mutations on the structure of the proteins was analyzed and molecular dynamics was carried out to evaluate the stability of the modeled proteins, and the mutations identified can be useful in recognizing patients with breast cancer who are likely to develop remote metastases.
Abstract: Understanding the correlation between heterogeneity in terms of genomic alterations and metastatic behavior is crucial in improving outcomes for breast cancer patients. Exome sequence that encode proteins generally encompasses around 2% of the genome, and is believed to harbor up to 85% of all disease causing variants. In this study, whole exome data from primary, metastatic and matched normal breast cancer samples submitted by Memorial Sloan Kettering Cancer Center (PRJNA273304) was deep dived using GATK pipeline, specifically Haplotypecaller was employed for variant calling and filtered using annovar. Impact of the identified mutations on the structure of the proteins was also analyzed. Variation in TOGARAM2, C3orf18, S100Z, MYH15, EPB41L4A, LARP1B, NAALADL2, OR2W3 and OR2AK2 were found in all nine primary and metastatic samples. None of these variants were previously reported to be associated with any disease conditions. Based on the structural availability of templates, MODELLER was utilized to build the three-dimensional structures of S100Z, MYH15, NAALADL2, OR2W3 and OR2AK2, and validated using the web based PROCHECK server. Lastly, molecular dynamics was carried out to evaluate the stability of the modeled proteins. Except OR2W3, all other mutant proteins exhibited significant RMSD deviation in the simulation studies substantiating the role of mutations. We conclude that the mutations identified can be useful in recognizing patients with breast cancer who are likely to develop remote metastases.

1 citations

Journal ArticleDOI
TL;DR: In this paper , the impact of significant germline variants in DNA repair and Tumour Suppressor genes on head and neck cancer (HNC) development was predicted, which may serve as prognostic markers for developing preventive measures against HNC.
Abstract: Abstract Head and neck cancer (HNC), the sixth most common cancer globally, stands first in India, especially Northeast India, where tobacco usage is predominant, which introduces various carcinogens leading to malignancies by accumulating DNA damages. Consequently, the present work aimed to predict the impact of significant germline variants in DNA repair and Tumour Suppressor genes on HNC development. WES in Ion ProtonTM platform on ‘discovery set’ (n = 15), followed by recurrence assessment of the observed variants on ‘confirmation set’ (n = 40) using Sanger Sequencing was performed on the HNC-prevalent NE Indian populations. Initially, 53 variants were identified, of which seven HNC-linked DNA damage response gene variants were frequent in the studied populations. Different tools ascertained the biological consequences of these variants, of which the non-coding variants viz. EXO1_rs4150018, RAD52_rs6413436, CHD5_rs2746066, HACE1_rs6918700 showed risk, while FLT3_rs2491227 and BMPR1A_rs7074064 conferred protection against HNC by affecting transcriptional regulation and splicing mechanism. Molecular Dynamics Simulation of the full-length p53 model predicted that the observed coding TP53_rs1042522 variant conferred HNC-risk by altering the structural dynamics of the protein, which displayed difficulty in the transition between active and inactive conformations due to high-energy barrier. Subsequent pathway and gene ontology analysis revealed that EXO1, RAD52 and TP53 variants affected the Double-Strand Break Repair pathway, whereas CHD5 and HACE1 variants inactivated DNA repair cascade, facilitating uncontrolled cell proliferation, impaired apoptosis and malignant transformation. Conversely, FLT3 and BMPR1A variants protected against HNC by controlling tumorigenesis, which requires experimental validation. These findings may serve as prognostic markers for developing preventive measures against HNC.
References
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Journal ArticleDOI
TL;DR: A status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions.
Abstract: This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions There will be an estimated 181 million new cancer cases (170 million excluding nonmelanoma skin cancer) and 96 million cancer deaths (95 million excluding nonmelanoma skin cancer) in 2018 In both sexes combined, lung cancer is the most commonly diagnosed cancer (116% of the total cases) and the leading cause of cancer death (184% of the total cancer deaths), closely followed by female breast cancer (116%), prostate cancer (71%), and colorectal cancer (61%) for incidence and colorectal cancer (92%), stomach cancer (82%), and liver cancer (82%) for mortality Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts CA: A Cancer Journal for Clinicians 2018;0:1-31 © 2018 American Cancer Society

58,675 citations


"Breast cancer mutation in GATA3 zin..." refers background in this paper

  • ...Cancer is one of the most challenging disease existing in the modern world, causing >9 million annual death (Bray et al., 2018)....

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  • ...Cancer incidences and mortality reported by GLOBOCAN 2018, WHO indicate that lung cancer tops the list, followed by breast cancer, colorectal, prostate, stomach, liver, and others, respectively (Bray et al., 2018; Ferlay et al., 2012)....

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Journal ArticleDOI
TL;DR: The goals of the PDB are described, the systems in place for data deposition and access, how to obtain further information and plans for the future development of the resource are described.
Abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.

34,239 citations

Journal ArticleDOI
TL;DR: The GLOBOCAN series of the International Agency for Research on Cancer (IARC) as mentioned in this paper provides estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012.
Abstract: Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).

24,414 citations

01 Jan 2002

19,213 citations


"Breast cancer mutation in GATA3 zin..." refers methods in this paper

  • ...The mutation was carried out manually (Figure 1) at position 294 to mutate Methionine (M) into Lysine (K) by using PyMol software (DeLano, 2002)....

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Journal ArticleDOI
17 Aug 2000-Nature
TL;DR: Variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals were characterized using complementary DNA microarrays representing 8,102 human genes, providing a distinctive molecular portrait of each tumour.
Abstract: Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

14,768 citations


"Breast cancer mutation in GATA3 zin..." refers background in this paper

  • ...Breast cancer is a highly complex form of cancer, classified into six subtypes based on the transcriptomic data as – Luminal A; Luminal B; HER2 positive; basal like; claudin-low and normal breast-like (Perou et al., 2000; Sorlie et al., 2001)....

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