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Cells, Volume 7, Issue 3 (March 2018) – 7 articles

Cover Story (view full-size image): Cell identity and physiology is determined by differential gene expression, controlled in part by the post-translational modification of core histones of nucleosomes, the smallest unit of chromatin. Mono- and tri-methylation of lysine 4 of histone H3 are associated with accessible, active enhancers and promoters, respectively, and with transcription. These modifications are catalyzed by KMT2/MLL methyltransferases, which are organized in six different complexes. Here, we discuss how distinct KMT2 complexes are selectively recruited to specific sites in chromatin. View this paper
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14 pages, 1777 KiB  
Article
Characterization of Carotid Smooth Muscle Cells during Phenotypic Transition
by Haize Goikuria, Maria Del Mar Freijo, Reyes Vega Manrique, María Sastre, Elena Elizagaray, Ana Lorenzo, Koen Vandenbroeck and Iraide Alloza
Cells 2018, 7(3), 23; https://doi.org/10.3390/cells7030023 - 18 Mar 2018
Cited by 24 | Viewed by 5617
Abstract
Vascular smooth muscle cells (VSMCs) are central players in carotid atherosclerosis plaque development. Although the precise mechanisms involved in plaque destabilization are not completely understood, it is known that VSMC proliferation and migration participate in plaque stabilization. In this study, we analyzed expression [...] Read more.
Vascular smooth muscle cells (VSMCs) are central players in carotid atherosclerosis plaque development. Although the precise mechanisms involved in plaque destabilization are not completely understood, it is known that VSMC proliferation and migration participate in plaque stabilization. In this study, we analyzed expression patterns of genes involved in carotid atherosclerosis development (e.g., transcription factors of regulation of SMC genes) of VSMCs located inside or outside the plaque lesion that may give clues about changes in phenotypic plasticity during atherosclerosis. VSMCs were isolated from 39 carotid plaques extracted from symptomatic and asymptomatic patients by endarterectomy. Specific biomarker expression, related with VSMC phenotype, was analyzed by qPCR, western immunoblot, and confocal microscopy. MYH11, CNN1, SRF, MKL2, and CALD1 were significantly underexpressed in VSMCs from plaques compared with VSMCs from a macroscopically intact (MIT) region, while SPP1, KLF4, MAPLC3B, CD68, and LGALS3 were found significantly upregulated in plaque VSMCs versus MIT VSMCs. The gene expression pattern of arterial VSMCs from a healthy donor treated with 7-ketocholesterol showed high similarity with the expression pattern of carotid plaque VSMCs. Our results indicate that VSMCs isolated from plaque show a typical SMC dedifferentiated phenotype with macrophage-like features compared with VSMCs isolated from a MIT region of the carotid artery. Additionally, MYH11, KLF5, and SPP1 expression patterns were found to be associated with symptomatology of human carotid atherosclerosis. Full article
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24 pages, 2418 KiB  
Review
Receptor Tyrosine Kinase Ubiquitination and De-Ubiquitination in Signal Transduction and Receptor Trafficking
by William R. Critchley, Caroline Pellet-Many, Benjamin Ringham-Terry, Michael A. Harrison, Ian C. Zachary and Sreenivasan Ponnambalam
Cells 2018, 7(3), 22; https://doi.org/10.3390/cells7030022 - 15 Mar 2018
Cited by 41 | Viewed by 11099
Abstract
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. [...] Read more.
Receptor tyrosine kinases (RTKs) are membrane-based sensors that enable rapid communication between cells and their environment. Evidence is now emerging that interdependent regulatory mechanisms, such as membrane trafficking, ubiquitination, proteolysis and gene expression, have substantial effects on RTK signal transduction and cellular responses. Different RTKs exhibit both basal and ligand-stimulated ubiquitination, linked to trafficking through different intracellular compartments including the secretory pathway, plasma membrane, endosomes and lysosomes. The ubiquitin ligase superfamily comprising the E1, E2 and E3 enzymes are increasingly implicated in this post-translational modification by adding mono- and polyubiquitin tags to RTKs. Conversely, removal of these ubiquitin tags by proteases called de-ubiquitinases (DUBs) enables RTK recycling for another round of ligand sensing and signal transduction. The endocytosis of basal and activated RTKs from the plasma membrane is closely linked to controlled proteolysis after trafficking and delivery to late endosomes and lysosomes. Proteolytic RTK fragments can also have the capacity to move to compartments such as the nucleus and regulate gene expression. Such mechanistic diversity now provides new opportunities for modulating RTK-regulated cellular responses in health and disease states. Full article
(This article belongs to the Special Issue Receptor Tyrosine Kinases in Health and Disease)
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19 pages, 1855 KiB  
Review
Elucidating the Metabolic Plasticity of Cancer: Mitochondrial Reprogramming and Hybrid Metabolic States
by Dongya Jia, Jun Hyoung Park, Kwang Hwa Jung, Herbert Levine and Benny Abraham Kaipparettu
Cells 2018, 7(3), 21; https://doi.org/10.3390/cells7030021 - 13 Mar 2018
Cited by 160 | Viewed by 12497
Abstract
Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry [...] Read more.
Aerobic glycolysis, also referred to as the Warburg effect, has been regarded as the dominant metabolic phenotype in cancer cells for a long time. More recently, it has been shown that mitochondria in most tumors are not defective in their ability to carry out oxidative phosphorylation (OXPHOS). Instead, in highly aggressive cancer cells, mitochondrial energy pathways are reprogrammed to meet the challenges of high energy demand, better utilization of available fuels and macromolecular synthesis for rapid cell division and migration. Mitochondrial energy reprogramming is also involved in the regulation of oncogenic pathways via mitochondria-to-nucleus retrograde signaling and post-translational modification of oncoproteins. In addition, neoplastic mitochondria can engage in crosstalk with the tumor microenvironment. For example, signals from cancer-associated fibroblasts can drive tumor mitochondria to utilize OXPHOS, a process known as the reverse Warburg effect. Emerging evidence shows that cancer cells can acquire a hybrid glycolysis/OXPHOS phenotype in which both glycolysis and OXPHOS can be utilized for energy production and biomass synthesis. The hybrid glycolysis/OXPHOS phenotype facilitates metabolic plasticity of cancer cells and may be specifically associated with metastasis and therapy-resistance. Moreover, cancer cells can switch their metabolism phenotypes in response to external stimuli for better survival. Taking into account the metabolic heterogeneity and plasticity of cancer cells, therapies targeting cancer metabolic dependency in principle can be made more effective. Full article
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14 pages, 2856 KiB  
Review
Integrin Activation: Implications for Axon Regeneration
by Menghon Cheah and Melissa R. Andrews
Cells 2018, 7(3), 20; https://doi.org/10.3390/cells7030020 - 10 Mar 2018
Cited by 30 | Viewed by 11457
Abstract
Integrin activation is essential for creating functional transmembrane receptors capable of inducing downstream cellular effects such as cell migration, cell spreading, neurite outgrowth and axon regeneration. Integrins are bidirectional signalling molecules that mediate their effects by ‘inside–out’ and ‘outside–in’ signalling. This review will [...] Read more.
Integrin activation is essential for creating functional transmembrane receptors capable of inducing downstream cellular effects such as cell migration, cell spreading, neurite outgrowth and axon regeneration. Integrins are bidirectional signalling molecules that mediate their effects by ‘inside–out’ and ‘outside–in’ signalling. This review will provide a detailed overview of integrin activation focusing on intracellular activation in neurons and discussing direct implications in the regulation of neurite outgrowth and axon regeneration. Full article
(This article belongs to the Special Issue Cell Adhesion Molecules)
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10 pages, 1897 KiB  
Article
Construction and Analysis of Gene Co-Expression Networks in Escherichia coli
by Wei Liu, Li Li, Xuhe Long, Weixin You, Yuexian Zhong, Menglin Wang, Huan Tao, Shoukai Lin and Huaqin He
Cells 2018, 7(3), 19; https://doi.org/10.3390/cells7030019 - 8 Mar 2018
Cited by 26 | Viewed by 7709
Abstract
Network-based systems biology has become an important method for analyzing high-throughput gene expression data and gene function mining. Escherichia coli (E. coli) has long been a popular model organism for basic biological research. In this paper, weighted gene co-expression network analysis [...] Read more.
Network-based systems biology has become an important method for analyzing high-throughput gene expression data and gene function mining. Escherichia coli (E. coli) has long been a popular model organism for basic biological research. In this paper, weighted gene co-expression network analysis (WGCNA) algorithm was applied to construct gene co-expression networks in E. coli. Thirty-one gene co-expression modules were detected from 1391 microarrays of E. coli data. Further characterization of these modules with the database for annotation, visualization, and integrated discovery (DAVID) tool showed that these modules are associated with several kinds of biological processes, such as carbohydrate catabolism, fatty acid metabolism, amino acid metabolism, transportation, translation, and ncRNA metabolism. Hub genes were also screened by intra-modular connectivity. Genes with unknown functions were annotated by guilt-by-association. Comparison with a previous prediction tool, EcoliNet, suggests that our dataset can expand gene predictions. In summary, 31 functional modules were identified in E. coli, 24 of which were functionally annotated. The analysis provides a resource for future gene discovery. Full article
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7 pages, 628 KiB  
Perspective
Miro—Working beyond Mitochondria and Microtubules
by Bor Luen Tang
Cells 2018, 7(3), 18; https://doi.org/10.3390/cells7030018 - 4 Mar 2018
Cited by 11 | Viewed by 6853
Abstract
The small GTPase Miro is best known for its regulation of mitochondrial movement by engaging with the microtubule-based motor proteins kinesin and dynein. Very recent findings have now showed that Miro also targets peroxisomes and regulates microtubule-dependent peroxisome motility. Moreover, Miro recruits and [...] Read more.
The small GTPase Miro is best known for its regulation of mitochondrial movement by engaging with the microtubule-based motor proteins kinesin and dynein. Very recent findings have now showed that Miro also targets peroxisomes and regulates microtubule-dependent peroxisome motility. Moreover, Miro recruits and stabilizes the myosin motor Myo19 at the mitochondria to enable actin-based mitochondria movement, which is important for mitochondrial segregation during mitosis. Miro thus has much broader functions that previously known, and these new findings may have important implications on disease pathology. Full article
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31 pages, 879 KiB  
Review
Modes of Interaction of KMT2 Histone H3 Lysine 4 Methyltransferase/COMPASS Complexes with Chromatin
by Agnieszka Bochyńska, Juliane Lüscher-Firzlaff and Bernhard Lüscher
Cells 2018, 7(3), 17; https://doi.org/10.3390/cells7030017 - 2 Mar 2018
Cited by 65 | Viewed by 12989
Abstract
Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is [...] Read more.
Regulation of gene expression is achieved by sequence-specific transcriptional regulators, which convey the information that is contained in the sequence of DNA into RNA polymerase activity. This is achieved by the recruitment of transcriptional co-factors. One of the consequences of co-factor recruitment is the control of specific properties of nucleosomes, the basic units of chromatin, and their protein components, the core histones. The main principles are to regulate the position and the characteristics of nucleosomes. The latter includes modulating the composition of core histones and their variants that are integrated into nucleosomes, and the post-translational modification of these histones referred to as histone marks. One of these marks is the methylation of lysine 4 of the core histone H3 (H3K4). While mono-methylation of H3K4 (H3K4me1) is located preferentially at active enhancers, tri-methylation (H3K4me3) is a mark found at open and potentially active promoters. Thus, H3K4 methylation is typically associated with gene transcription. The class 2 lysine methyltransferases (KMTs) are the main enzymes that methylate H3K4. KMT2 enzymes function in complexes that contain a necessary core complex composed of WDR5, RBBP5, ASH2L, and DPY30, the so-called WRAD complex. Here we discuss recent findings that try to elucidate the important question of how KMT2 complexes are recruited to specific sites on chromatin. This is embedded into short overviews of the biological functions of KMT2 complexes and the consequences of H3K4 methylation. Full article
(This article belongs to the Section Cell Nuclei: Function, Transport and Receptors)
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