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Synthetic transcriptional factor

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https://www.readbyqxmd.com/read/29032144/peroxisome-proliferator-activated-receptor-%C3%AE-ppar%C3%AE-a-master-gatekeeper-in-cns-injury-and-repair
#1
REVIEW
Wei Cai, Tuo Yang, Huan Liu, Lijuan Han, Kai Zhang, Xiaoming Hu, Xuejing Zhang, Ke-Jie Yin, Yanqin Gao, Michael V L Bennett, Rehana K Leak, Jun Chen
Peroxisome proliferator-activated receptor γ (PPARγ) is a widely expressed ligand-modulated transcription factor that governs the expression of genes involved in inflammation, redox equilibrium, trophic factor production, insulin sensitivity, and the metabolism of lipids and glucose. Synthetic PPARγ agonists (e.g. thiazolidinediones) are used to treat Type II diabetes and have the potential to limit the risk of developing brain injury by mitigating the influence of comorbidities. If brain injury develops, PPARγ serves as a master gatekeeper of cytoprotective stress responses, improving the chances of survival and recovery of homeostatic equilibrium...
October 11, 2017: Progress in Neurobiology
https://www.readbyqxmd.com/read/29028954/1-benzyl-indole-3-carbinol-is-a-highly-potent-new-small-molecule-inhibitor-of-wnt-%C3%AE-catenin-signaling-in-melanoma-cells-that-coordinately-inhibits-cell-proliferation-and-disrupts-expression-of-microphthalmia-associated-transcription-factor-isoform-m
#2
Aishwarya Kundu, Michelle G Khouri, Sheila Aryana, Gary L Firestone
1-Benzyl-indole-3-carbinol (1-benzyl-I3C), a synthetic analogue of the crucifer derived natural phytochemical I3C, displayed significantly wider sensitivity and anti-proliferative potency in melanoma cells than the natural compound. Unlike I3C, which targets mainly oncogenic BRAF-expressing cells, 1-benzyl I3C effectively inhibited proliferation of melanoma cells with a more extensive range of mutational profiles, including those expressing wild type BRAF. In both cultured melanoma cell lines and in vivo in melanoma cell-derived tumor xenografts, 1-benzyl-I3C disrupted canonical Wnt/β-catenin signaling that resulted in the down regulation of β-catenin protein levels with a concomitant increase in levels of the β-catenin destruction complex components GSK3β and Axin...
September 23, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/29026640/directing-the-osteoblastic-and-chondrocytic-differentiations-of-mesenchymal-stem-cells-matrix-vs-induction-media
#3
Jing He, Jianglong Guo, Bo Jiang, Ruijuan Yao, Yao Wu, Fang Wu
While both induction culture media and matrix have been reported to regulate the stem cell fate, little is known about which factor plays a more decisive role in directing the MSC differentiation lineage as well as the underlying mechanisms. To this aim, we seeded MSCs on HA-collagen and HA-synthetic hydrogel matrixes, which had demonstrated highly different potentials toward osteoblastic and chondrocytic differentiation lineages, respectively, and cultured them with osteogenic, chondrogenic and normal culture media, respectively...
October 2017: Regenerative Biomaterials
https://www.readbyqxmd.com/read/29025359/brca1-or-cdk12-loss-sensitizes-cells-to-chk1-inhibitors
#4
Hana Paculová, Juraj Kramara, Šárka Šimečková, Radek Fedr, Karel Souček, Ondřej Hylse, Kamil Paruch, Marek Svoboda, Martin Mistrík, Jiří Kohoutek
A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination-mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds...
October 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
https://www.readbyqxmd.com/read/29020632/activation-of-the-p53-transcriptional-program-sensitizes-cancer-cells-to-cdk7-inhibitors
#5
Sampada Kalan, Ramon Amat, Miriam Merzel Schachter, Nicholas Kwiatkowski, Brian J Abraham, Yanke Liang, Tinghu Zhang, Calla M Olson, Stéphane Larochelle, Richard A Young, Nathanael S Gray, Robert P Fisher
Cdk7, the CDK-activating kinase and transcription factor IIH component, is a target of inhibitors that kill cancer cells by exploiting tumor-specific transcriptional dependencies. However, whereas selective inhibition of analog-sensitive (AS) Cdk7 in colon cancer-derived cells arrests division and disrupts transcription, it does not by itself trigger apoptosis efficiently. Here, we show that p53 activation by 5-fluorouracil or nutlin-3 synergizes with a reversible Cdk7(as) inhibitor to induce cell death. Synthetic lethality was recapitulated with covalent inhibitors of wild-type Cdk7, THZ1, or the more selective YKL-1-116...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28988820/atf4-induced-metabolic-reprograming-is-a-synthetic-vulnerability-of-the-p62-deficient-tumor-stroma
#6
Juan F Linares, Thekla Cordes, Angeles Duran, Miguel Reina-Campos, Tania Valencia, Christopher S Ahn, Elias A Castilla, Jorge Moscat, Christian M Metallo, Maria T Diaz-Meco
Tumors undergo nutrient stress and need to reprogram their metabolism to survive. The stroma may play a critical role in this process by providing nutrients to support the epithelial compartment of the tumor. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation by the direct control of ATF4 stability through its p62-mediated polyubiquitination. ATF4 upregulation by p62 deficiency in the stroma activates glucose carbon flux through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine generation as a source of nitrogen for stroma and tumor epithelial proliferation...
September 27, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28985507/randomized-crispr-cas-transcriptional-perturbation-screening-reveals-protective-genes-against-alpha-synuclein-toxicity
#7
Ying-Chou Chen, Fahim Farzadfard, Nava Gharaei, William C W Chen, Jicong Cao, Timothy K Lu
The genome-wide perturbation of transcriptional networks with CRISPR-Cas technology has primarily involved systematic and targeted gene modulation. Here, we developed PRISM (Perturbing Regulatory Interactions by Synthetic Modulators), a screening platform that uses randomized CRISPR-Cas transcription factors (crisprTFs) to globally perturb transcriptional networks. By applying PRISM to a yeast model of Parkinson's disease (PD), we identified guide RNAs (gRNAs) that modulate transcriptional networks and protect cells from alpha-synuclein (αSyn) toxicity...
October 5, 2017: Molecular Cell
https://www.readbyqxmd.com/read/28984438/engineering-the-genetic-code-in-cells-and-animals-biological-considerations-and-impacts
#8
Lei Wang
Expansion of the genetic code allows unnatural amino acids (Uaas) to be site-specifically incorporated into proteins in live biological systems, thus enabling novel properties selectively introduced into target proteins in vivo for basic biological studies and for engineering of novel biological functions. Orthogonal components including tRNA and aminoacyl-tRNA synthetase (aaRS) are expressed in live cells to decode a unique codon (often the amber stop codon UAG) as the desired Uaa. Initially developed in E...
October 6, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28981191/retinoic-acid-receptor-%C3%AE-regulates-synthetic-events-in-human-platelets
#9
Hansjörg Schwertz, Jesse W Rowley, Guy A Zimmerman, Andrew S Weyrich, Matthew T Rondina
BACKGROUND: Translational control mechanisms in platelets are incompletely defined. Here, we determined whether the nuclear transcription factor RARα controls protein translational events in human platelets. METHODS: Isolated human platelets were treated with the pan-RAR agonist all-trans-retinoic acid (atRA). Global and targeted translational events were examined. RESULTS: Stimulation of platelets with (atRA) significantly increased global protein expression...
October 5, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28978934/regulation-of-antilipopolysaccharide-factors-alfpm3-and-alfpm6-in-penaeus-monodon
#10
Pitchayanan Kamsaeng, Anchalee Tassanakajon, Kunlaya Somboonwiwat
ALFPm6, a member of antimicrobial peptide in the antilipopolysaccharide factor (ALF) family from Penaeus monodon, plays important roles in shrimp immunity against pathogens. However, its antimicrobial activity and underlying mechanism have not been reported. The synthetic cyclic ALFPm6#29-52 peptide (cALFPm6#29-52) corresponding to the ALFPm6 LPS-binding domain can agglutinate and exhibited bacterial killing activity toward a Gram-negative bacterium, Escherichia coli 363 and Gram-positive bacteria, Bacillus megaterium, Aerococcus viridans, and Micrococcus luteus, with MIC values of 25-50 μM...
October 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28977654/de-novo-design-and-synthesis-of-a-30-cistron-translation-factor-module
#11
Tyson R Shepherd, Liping Du, Josefine Liljeruhm, Samudyata, Jinfan Wang, Marcus O D Sjödin, Magnus Wetterhall, Tetsuya Yomo, Anthony C Forster
Two of the many goals of synthetic biology are synthesizing large biochemical systems and simplifying their assembly. While several genes have been assembled together by modular idempotent cloning, it is unclear if such simplified strategies scale to very large constructs for expression and purification of whole pathways. Here we synthesize from oligodeoxyribonucleotides a completely de-novo-designed, 58-kb multigene DNA. This BioBrick plasmid insert encodes 30 of the 31 translation factors of the PURE translation system, each His-tagged and in separate transcription cistrons...
September 4, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977482/phenotypic-consequences-of-rna-polymerase-dysregulation-in-escherichia-coli
#12
Paramita Sarkar, Amy Switzer, Christine Peters, Joe Pogliano, Sivaramesh Wigneshweraraj
Many bacterial adaptive responses to changes in growth conditions due to biotic and abiotic factors involve reprogramming of gene expression at the transcription level. The bacterial RNA polymerase (RNAP), which catalyzes transcription, can thus be considered as the major mediator of cellular adaptive strategies. But how do bacteria respond if a stress factor directly compromises the activity of the RNAP? We used a phage-derived small protein to specifically perturb bacterial RNAP activity in exponentially growing Escherichia coli...
August 23, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977454/in-silico-design-of-context-responsive-mammalian-promoters-with-user-defined-functionality
#13
Adam J Brown, Suzanne J Gibson, Diane Hatton, David C James
Comprehensive de novo-design of complex mammalian promoters is restricted by unpredictable combinatorial interactions between constituent transcription factor regulatory elements (TFREs). In this study, we show that modular binding sites that do not function cooperatively can be identified by analyzing host cell transcription factor expression profiles, and subsequently testing cognate TFRE activities in varying homotypic and heterotypic promoter architectures. TFREs that displayed position-insensitive, additive function within a specific expression context could be rationally combined together in silico to create promoters with highly predictable activities...
August 30, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28973928/mycobacterium-tuberculosis-inhibits-human-innate-immune-responses-via-the-production-of-tlr2-antagonist-glycolipids
#14
Landry Blanc, Martine Gilleron, Jacques Prandi, Ok-Ryul Song, Mi-Seon Jang, Brigitte Gicquel, Daniel Drocourt, Olivier Neyrolles, Priscille Brodin, Gérard Tiraby, Alain Vercellone, Jérôme Nigou
Mycobacterium tuberculosis is a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by which M. tuberculosis circumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate of M. tuberculosis of the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity...
October 2, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28968519/using-synthetic-biology-to-study-gene-regulatory-evolution
#15
REVIEW
Justin Crocker, Garth R Ilsley
Transcriptional enhancers specify the precise time, level, and location of gene expression. Disentangling and characterizing the components of enhancer activity in multicellular eukaryotic development has proven challenging because enhancers contain activator and repressor binding sites for multiple factors that each exert nuanced, context-dependent control of enhancer activity. Recent advances in synthetic biology provide an almost unlimited ability to create and modify regulatory elements and networks, offering unprecedented power to study gene regulation...
September 29, 2017: Current Opinion in Genetics & Development
https://www.readbyqxmd.com/read/28967863/chromatin-accessibility-underlies-synthetic-lethality-of-swi-snf-subunits-in-arid1a-mutant-cancers
#16
Timothy W R Kelso, Devin K Porter, Maria Luisa Amaral, Maxim N Shokhirev, Christopher Benner, Diana C Hargreaves
ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here, we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation...
October 2, 2017: ELife
https://www.readbyqxmd.com/read/28961802/efficient-inference-for-sparse-latent-variable-models-of-transcriptional-regulation
#17
Zhenwen Dai, Mudassar Iqbal, Neil D Lawrence, Magnus Rattray
Motivation: Regulation of gene expression in prokaryotes involves complex co-regulatory mechanisms involving large numbers of transcriptional regulatory proteins and their target genes. Uncovering these genome-scale interactions constitutes a major bottleneck in systems biology. Sparse latent factor models, assuming activity of transcription factors (TFs) as unobserved, provide a biologically interpretable modelling framework, integrating gene expression and genome-wide binding data, but at the same time pose a hard computational inference problem...
August 26, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28950701/development-of-transcription-factor-based-designer-macrolide-biosensors-for-metabolic-engineering-and-synthetic-biology
#18
Christian Kasey, Mounir Zerrad, Yiwei Li, Thomas Ashton Cropp, Gavin J Williams
Macrolides are a large group of natural products that display broad and potent biological activities and are biosynthesized by type I polyketide synthases (PKSs) and associated enzymatic machinery. There is an urgent need to access macrolides and unnatural macrolide derivatives for drug discovery, drug manufacture, and probe development. Typically, efforts to engineer the biosynthesis of macrolides and macrolide analogues in various microbial hosts are hampered by the complexity of macrolide biosynthetic pathways and our limited ability to rationally reprogram type I PKSs and post-PKS machinery...
September 26, 2017: ACS Synthetic Biology
https://www.readbyqxmd.com/read/28947735/a-role-for-tau-protein-in-maintaining-ribosomal-dna-stability-and-cytidine-deaminase-deficient-cell-survival
#19
Elias Bou Samra, Géraldine Buhagiar-Labarchède, Christelle Machon, Jérôme Guitton, Rosine Onclercq-Delic, Michael R Green, Olivier Alibert, Claude Gazin, Xavier Veaute, Mounira Amor-Guéret
Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival...
September 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28938653/overexpression-of-emt-inducing-transcription-factors-as-a-potential-poor-prognostic-factor-for-hepatocellular-carcinoma-in-asian-populations-a-meta-analysis
#20
Tao Wan, Tianwei Zhang, Xiaoying Si, Yanming Zhou
BACKGROUND AND OBJECTIVES: The clinical relevance of epithelial to mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) progression has been highlighted during the last decade. The zinc finger E-box binding homeobox (ZEB) family, the zinc-finger transcriptional repressor (SNAI) family, and the basic helix-loop-helix transcription factor (Twist) family, known as the prominent EMT-inducing transcription factors (EMT-TFs), played a crucial role in the process of EMT. Here, this meta-analysis aimed to evaluate the prognostic value of EMT-TFs high expression in patients with HCC after hepatectomy...
August 29, 2017: Oncotarget
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