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Search Results: 1 - 10 of 206181 matches for " Andrew D Sharrocks "
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ELK1 Uses Different DNA Binding Modes to Regulate Functionally Distinct Classes of Target Genes
Zaneta Odrowaz,Andrew D. Sharrocks
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1002694
Abstract: Eukaryotic transcription factors are grouped into families and, due to their similar DNA binding domains, often have the potential to bind to the same genomic regions. This can lead to redundancy at the level of DNA binding, and mechanisms are required to generate specific functional outcomes that enable distinct gene expression programmes to be controlled by a particular transcription factor. Here we used ChIP–seq to uncover two distinct binding modes for the ETS transcription factor ELK1. In one mode, other ETS transcription factors can bind regulatory regions in a redundant fashion; in the second, ELK1 binds in a unique fashion to another set of genomic targets. Each binding mode is associated with different binding site features and also distinct regulatory outcomes. Furthermore, the type of binding mode also determines the control of functionally distinct subclasses of genes and hence the phenotypic response elicited. This is demonstrated for the unique binding mode where a novel role for ELK1 in controlling cell migration is revealed. We have therefore uncovered an unexpected link between the type of binding mode employed by a transcription factor, the subsequent gene regulatory mechanisms used, and the functional categories of target genes controlled.
The ETS Transcription Factors ELK1 and GABPA Regulate Different Gene Networks to Control MCF10A Breast Epithelial Cell Migration
Zaneta Odrowaz, Andrew D. Sharrocks
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049892
Abstract: Members of the ETS transcription factor family often target the same binding regions and hence have the potential to regulate the same genes and downstream biological processes. However, individual family members also preferentially bind to other genomic regions, thus providing the potential for controlling distinct transcriptional programmes and generating specific biological effects. The ETS transcription factor ELK1 controls cell migration in breast epithelial cells through targeting a cohort of genes, independently from another family member GABPA, and therefore achieves biological specificity. Here, we demonstrate that GABPA also controls cell migration in breast epithelial cells. However, GABPA controls the expression of a different network of target genes to ELK1. Both direct and indirect target genes for GABPA are identified and amongst the direct targets we confirm the importance of RAC1 and KIF20A for cell migration. Therefore, although ELK1 and GABPA ultimately control the same biological process, they do so by regulating different cohorts of target genes associated with cytoskeletal functions and cell migration control.
The ERK MAP kinase-PEA3/ETV4-MMP-1 axis is operative in oesophageal adenocarcinoma
Richard Keld, Baoqiang Guo, Paul Downey, Christian Gulmann, Yeng S Ang, Andrew D Sharrocks
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-313
Abstract: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in oesophageal adenocarcinomas and determined their role in oesophageal adenocarcinoma cell function. PEA3 plays an important role in controlling both the proliferation and invasive properties of OE33 oesophageal adenocarcinoma cells. A key target gene is MMP-1. The ERK MAP kinase pathway activates PEA3 subfamily members and also plays a role in these PEA3 controlled events, establishing the ERK-PEA3-MMP-1 axis as important in OE33 cells. PEA3 subfamily members are upregulated in human adenocarcinomas and expression correlates with MMP-1 expression and late stage metastatic disease. Enhanced ERK signaling is also more prevalent in late stage oesophageal adenocarcinomas.This study shows that the ERK-PEA3-MMP-1 axis is upregulated in oesophageal adenocarcinoma cells and is a potentially important driver of the metastatic progression of oesophageal adenocarcinomas.Oesophageal adenocarcinoma is a devastating disease that has been rising year on year over the past three decades and is the 6th highest cause of cancer mortality in the UK, accounting for around 5% of all cancers [1,2]. The escalating incidence is thought to be a result of the combination of an obesity epidemic, an aging population, and H. pylori eradication [3-5]. The disease is curable by surgery or endoscopic therapy if diagnosed at a very early stage [6] but usually, diagnosis is made at an advanced stage with the presence of lymph node and distant metastases [5]. There are few clear prognostic indicators of susceptibility to developing oesophageal adenocarcinoma although patients with Barrett's oesophagus are thought to be more at risk to developing oesophageal adenocarcinoma. However, the progression from Barrett's oesophagus to dysplasia and subsequent adenocarcinoma is unpredictable and poorly understood [7]. The lack of prognostic indicators results in presentation of patents at late disease stages, resulting
Basic fibroblast growth factor induces matrix metalloproteinase-13 via ERK MAP kinase-altered phosphorylation and sumoylation of Elk-1 in human adult articular chondrocytes
Hee-Jeong Im, Andrew D Sharrocks, Xia Lin, et al
Open Access Rheumatology: Research and Reviews , 2009, DOI: http://dx.doi.org/10.2147/OARRR.S7527
Abstract: asic fibroblast growth factor induces matrix metalloproteinase-13 via ERK MAP kinase-altered phosphorylation and sumoylation of Elk-1 in human adult articular chondrocytes Original Research (3598) Total Article Views Authors: Hee-Jeong Im, Andrew D Sharrocks, Xia Lin, et al Published Date October 2009 Volume 2009:1 Pages 151 - 161 DOI: http://dx.doi.org/10.2147/OARRR.S7527 Hee-Jeong Im,1–4 Andrew D Sharrocks,5 Xia Lin,6 Dongyao Yan,1 Jaesung Kim,1 Andre J van Wijnen,7 Robert A Hipskind8 1Departments of Biochemistry, 2Internal Medicine, 3Section of Rheumatology, Orthopedic Surgery, 4Rush University Medical Center, and Department of Bioengineering; University of Illinois at Chicago, IL USA; 5Faculty of Life Sciences, University of Manchester, Oxford Rd, Manchester, UK; 6Michael D DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA; 7Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA; 8Institute De Genetique Moleculaire de Montpellier, France Abstract: Degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) and release of basic fibroblast growth factor (bFGF) are principal aspects of the pathology of osteoarthritis (OA). ECM disruption leads to bFGF release, which activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway and its downstream target the Ets-like transcription factor Elk-1. Previously we demonstrated that the bFGF-ERK-Elk-1 signaling axis is responsible for the potent induction of MMP-13 in human primary articular chondrocytes. Here we report that, in addition to phosphorylation of Elk-1, dynamic posttranslational modification of Elk-1 by small ubiquitin-related modifier (SUMO) serves as an important mechanism through which MMP-13 gene expression is regulated. We show that bFGF activates Elk-1 mainly through the ERK pathway and that increased phosphorylation of Elk-1 is accompanied by decreased conjugation of SUMO to Elk-1. Reporter gene assays reveal that phosphorylation renders Elk-1 competent for induction of MMP-13 gene transcription, while sumoylation has the opposite effect. Furthermore, we demonstrate that the SUMO-conjugase Ubc9 acts as a key mediator for Elk-1 sumoylation. Taken together, our results suggest that sumoylation antagonizes the phosphorylation-dependent transactivation capacity of Elk-1. This attenuates transcription of its downstream target gene MMP-13 to maintain the integrity of cartilage ECM homeostasis.
Basic fibroblast growth factor induces matrix metalloproteinase-13 via ERK MAP kinase-altered phosphorylation and sumoylation of Elk-1 in human adult articular chondrocytes
Hee-Jeong Im,Andrew D Sharrocks,Xia Lin,et al
Open Access Rheumatology: Research and Reviews , 2009,
Abstract: Hee-Jeong Im,1–4 Andrew D Sharrocks,5 Xia Lin,6 Dongyao Yan,1 Jaesung Kim,1 Andre J van Wijnen,7 Robert A Hipskind81Departments of Biochemistry, 2Internal Medicine, 3Section of Rheumatology, Orthopedic Surgery, 4Rush University Medical Center, and Department of Bioengineering; University of Illinois at Chicago, IL USA; 5Faculty of Life Sciences, University of Manchester, Oxford Rd, Manchester, UK; 6Michael D DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA; 7Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA, USA; 8Institute De Genetique Moleculaire de Montpellier, FranceAbstract: Degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) and release of basic fibroblast growth factor (bFGF) are principal aspects of the pathology of osteoarthritis (OA). ECM disruption leads to bFGF release, which activates the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway and its downstream target the Ets-like transcription factor Elk-1. Previously we demonstrated that the bFGF-ERK-Elk-1 signaling axis is responsible for the potent induction of MMP-13 in human primary articular chondrocytes. Here we report that, in addition to phosphorylation of Elk-1, dynamic posttranslational modification of Elk-1 by small ubiquitin-related modifier (SUMO) serves as an important mechanism through which MMP-13 gene expression is regulated. We show that bFGF activates Elk-1 mainly through the ERK pathway and that increased phosphorylation of Elk-1 is accompanied by decreased conjugation of SUMO to Elk-1. Reporter gene assays reveal that phosphorylation renders Elk-1 competent for induction of MMP-13 gene transcription, while sumoylation has the opposite effect. Furthermore, we demonstrate that the SUMO-conjugase Ubc9 acts as a key mediator for Elk-1 sumoylation. Taken together, our results suggest that sumoylation antagonizes the phosphorylation-dependent transactivation capacity of Elk-1. This attenuates transcription of its downstream target gene MMP-13 to maintain the integrity of cartilage ECM homeostasis.Keywords: osteoarthritis, MMP-13, bFGF, SUMO, Elk-1
A Genome-Wide RNAi Screen Reveals MAP Kinase Phosphatases as Key ERK Pathway Regulators during Embryonic Stem Cell Differentiation
Shen-Hsi Yang,Tuzer Kalkan,Claire Morrisroe,Austin Smith,Andrew D. Sharrocks
PLOS Genetics , 2012, DOI: 10.1371/journal.pgen.1003112
Abstract: Embryonic stem cells and induced pluripotent stem cells represent potentially important therapeutic agents in regenerative medicine. Complex interlinked transcriptional and signaling networks control the fate of these cells towards maintenance of pluripotency or differentiation. In this study we have focused on how mouse embryonic stem cells begin to differentiate and lose pluripotency and, in particular, the role that the ERK MAP kinase and GSK3 signaling pathways play in this process. Through a genome-wide siRNA screen we have identified more than 400 genes involved in loss of pluripotency and promoting the onset of differentiation. These genes were functionally associated with the ERK and/or GSK3 pathways, providing an important resource for studying the roles of these pathways in controlling escape from the pluripotent ground state. More detailed analysis identified MAP kinase phosphatases as a focal point of regulation and demonstrated an important role for these enzymes in controlling ERK activation kinetics and subsequently determining early embryonic stem cell fate decisions.
A Role for Non-Covalent SUMO Interaction Motifs in Pc2/CBX4 E3 Activity
Jacqueline C. Merrill,Tiffany A. Melhuish,Michael H. Kagey,Shen-Hsi Yang,Andrew D. Sharrocks,David Wotton
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0008794
Abstract: Modification of proteins by the small ubiquitin like modifier (SUMO) is an essential process in mammalian cells. SUMO is covalently attached to lysines in target proteins via an enzymatic cascade which consists of E1 and E2, SUMO activating and conjugating enzymes. There is also a variable requirement for non-enzymatic E3 adapter like proteins, which can increase the efficiency and specificity of the sumoylation process. In addition to covalent attachment of SUMO to target proteins, specific non-covalent SUMO interaction motifs (SIMs) that are generally short hydrophobic peptide motifs have been identified.
Transcription factors Elk-1 and SRF are engaged in IL1-dependent regulation of ZC3H12A expression
Aneta Kasza, Paulina Wyrzykowska, Irena Horwacik, Piotr Tymoszuk, Danuta Mizgalska, Karren Palmer, Hanna Rokita, Andrew D Sharrocks, Jolanta Jura
BMC Molecular Biology , 2010, DOI: 10.1186/1471-2199-11-14
Abstract: Here we report that the proinflammatory cytokine IL-1β rapidly induces the synthesis of MCPIP in primary monocyte-derived macrophages and HepG2 cells. This up-regulation takes place through the MAP kinase pathway and following activation of the transcription factor Elk-1. Using a ZC3H12A reporter construct we have shown that a ZC3H12A promoter region, stretching from -76 to +60, mediates activation by IL-1β. This region contains binding sites for Elk-1 and its partner SRF. Chromatin immunoprecipitation analysis confirms in vivo binding of both transcription factors to this region of the ZC3H12A promoter.We conclude that the transcription factor Elk-1 plays an important role in the activation of ZC3H12A expression in response to IL-1β stimulation.MCPIP has RNase activity that prevents some immune disorders by direct control of the stability of a set of inflammatory transcripts [1,2]. MCPIP-deficient mice die within 12 weeks with the symptoms of severe inflammatory changes. Among transcripts destabilized by MCPIP are the mRNAs for IL-6, IL-12p40, calcitonin receptorand and IL-1β [1,2]. MCPIP contains a PIN domain, responsible for it's enzymatic activity and CCCH zinc finger domain, partially also engaged in the control of transcripts decay [1,2]. MCPIP is induced in human peripherial blood monocytes by monocyte chemoattractant protein (MCP-1) and this phenomenon resulted in the name of this protein as a MCP-1 inducible protein (MCPIP) [3]. The significance of MCPIP in the course of inflammation is manifested also in the development of cardiovascular diseases. Elevated level of MCPIP is associated with ischemic heart disease [3]. Recently it was found that Toll-like receptors are involved in the activation of mice Zc3h12a (gene encoding MCPIP). The activation of Zc3h12a was revealed by microarray analysis of RNA from macrophages of wild-type, Myd88-/- and Trif-/-mice stimulated with liposacharide (LPS) [1]. We have observed that the level of transcript for MCPIP is rap
Taking the Guesswork Out of Curriculum Design: Learning to Engineer Explicit Grammar Curricula through the Analysis of Multiple Influences on the Acquisition Process  [PDF]
Andrew D. Schenck, Wonkyung Choi
Open Journal of Modern Linguistics (OJML) , 2012, DOI: 10.4236/ojml.2012.23015
Abstract: While a study by Goldschneider and DeKeyser (2005) was able to explain how factors such as phonological salience, frequency, morphological regularity, semantic complexity, and syntactic complexity influence acquisition order, the examination of six similar morphological features provided only a limited perspective. The purpose of this study was to see if causal variables, both individually and cumulatively, could be used to predict acquisition orders with more highly disparate morphological and syntactic features. Results of Spearman rank calculations revealed that the integration of causal factors yielded the highest correlation to both the Processability Theory (rs = 0.821; p = 0.007) and Natural Order Hypothesis (rs = 0.529; p = 0.143), suggesting that these factors have a synergistic influence on morphosyntactic development. Methods to predict the acquisition of both syntactic and morphological features are suggested, along with an empirically-based method to guide explicit grammar instruction.
Building a Better Mousetrap: Replacing Subjective Writing Rubrics with More Empirically-Sound Alternatives for EFL Learners  [PDF]
Andrew D. Schenck, Eoin Daly
Creative Education (CE) , 2012, DOI: 10.4236/ce.2012.38193
Abstract: Although writing rubrics can provide valuable feedback, the criteria they use are often subjective, which compels raters to employ their own tacit biases. The purpose of this study is to see if discreet empirical characteristics of texts can be used in lieu of the rubric to objectively assess the writing quality of EFL learners. The academic paragraphs of 38 participants were evaluated according to several empirically calculable criteria related to cohesion, content, and grammar. Values were then compared to scores obtained from holistic scoring by multiple raters using a multiple regression formula. The resulting correlation between variables (R = .873) was highly significant, suggesting that more empirical, impartial means of writing evaluation can now be used in conjunction with technology to provide student feedback and teacher training.
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