23,262 research outputs found

    Genomic analysis of the role of transcription factor C/EBPδ in the regulation of cell behaviour on nanometric grooves

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    C/EBPδ is a tumour suppressor transcription factor that induces gene expression involved in suppressing cell migration. Here we investigate whether C/EBPδ-dependent gene expression also affects cell responses to nanometric topology. We found that ablation of the C/EBPδ gene in mouse embryonal fibroblasts (MEFs) decreased cell size, adhesion and cytoskeleton spreading on 240 nm and 540 nm nanometric grooves. ChIP-SEQ and cDNA microarray analyses demonstrated that many binding sites for C/EBPδ, and the closely related C/EBPβ, exist throughout the mouse genome and control the upregulation or downregulation of many adjacent genes. We also identified a group of C/EBPδ-dependent, trans-regulated genes, whose promoters contained no C/EBPδ binding sites and yet their activity was regulated in a C/EBPδ-dependent manner. These genes include signalling molecules (e.g. SOCS3), cytoskeletal components (Tubb2, Krt16 and Krt20) and cytoskeletal regulators (ArhGEF33 and Rnd3) and are possibly regulated by cis-regulated diffusible mediators, such as IL6. Of particular note, SOCS3 was shown to be absolutely required for efficient cell spreading and contact guidance on 240 nm and 540 nm nanometric grooves. C/EBPδ is therefore involved in the complex regulation of multiple genes, including cytoskeletal components and signalling mediators, which influence the nature of cell interactions with nanometric topology

    DPA on quasi delay insensitive asynchronous circuits: formalization and improvement

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    The purpose of this paper is to formally specify a flow devoted to the design of Differential Power Analysis (DPA) resistant QDI asynchronous circuits. The paper first proposes a formal modeling of the electrical signature of QDI asynchronous circuits. The DPA is then applied to the formal model in order to identify the source of leakage of this type of circuits. Finally, a complete design flow is specified to minimize the information leakage. The relevancy and efficiency of the approach is demonstrated using the design of an AES crypto-processor.Comment: Submitted on behalf of EDAA (http://www.edaa.com/

    Proteomic analyses reveal distinct chromatin-associated and soluble transcription factor complexes.

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    The current knowledge on how transcription factors (TFs), the ultimate targets and executors of cellular signalling pathways, are regulated by protein-protein interactions remains limited. Here, we performed proteomics analyses of soluble and chromatin-associated complexes of 56 TFs, including the targets of many signalling pathways involved in development and cancer, and 37 members of the Forkhead box (FOX) TF family. Using tandem affinity purification followed by mass spectrometry (TAP/MS), we performed 214 purifications and identified 2,156 high-confident protein-protein interactions. We found that most TFs form very distinct protein complexes on and off chromatin. Using this data set, we categorized the transcription-related or unrelated regulators for general or specific TFs. Our study offers a valuable resource of protein-protein interaction networks for a large number of TFs and underscores the general principle that TFs form distinct location-specific protein complexes that are associated with the different regulation and diverse functions of these TFs

    Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3

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    INTRODUCTION: Involution of the mammary gland is a complex process of controlled apoptosis and tissue remodelling. The aim of the project was to identify genes that are specifically involved in this process. METHODS: We used Affymetrix oligonucleotide microarrays to perform a detailed transcript analysis on the mechanism of controlled involution after withdrawal of the pups at day seven of lactation. Some of the results were confirmed by semi-quantitative reverse transcriptase polymerase chain reaction, Western blotting or immunohistochemistry. RESULTS: We identified 145 genes that were specifically upregulated during the first 4 days of involution; of these, 49 encoded immunoglobulin genes. A further 12 genes, including those encoding the signal transducer and activator of transcription 3 (STAT3), the lipopolysaccharide receptor (CD14) and lipopolysaccharide-binding protein (LBP), were involved in the acute-phase response, demonstrating that the expression of acute-phase response genes can occur in the mammary gland itself and not only in the liver. Expression of LBP and CD14 was upregulated, at both the RNA and protein level, immediately after pup withdrawal; CD14 was strongly expressed in the luminal epithelial cells. Other genes identified suggested neutrophil activation early in involution, followed by macrophage activation late in the process. Immunohistochemistry and histological staining confirmed the infiltration of the involuting mammary tissue with neutrophils, plasma cells, macrophages and eosinophils. CONCLUSION: Oligonucleotide microarrays are a useful tool for identifying genes that are involved in the complex developmental process of mammary gland involution. The genes identified are consistent with an immune cascade, with an early acute-phase response that occurs in the mammary gland itself and resembles a wound healing process

    p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response.

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    Hyperproliferative keratinocytes induced by trauma, hyperkeratosis and/or inflammation display molecular signatures similar to those of palmoplantar epidermis. Inherited gain-of-function mutations in RHBDF2 (encoding iRHOM2) are associated with a hyperproliferative palmoplantar keratoderma and squamous oesophageal cancer syndrome (termed TOC). In contrast, genetic ablation of rhbdf2 in mice leads to a thinning of the mammalian footpad, and reduces keratinocyte hyperproliferation and migration. Here, we report that iRHOM2 is a novel target gene of p63 and that both p63 and iRHOM2 differentially regulate cellular stress-associated signalling pathways in normal and hyperproliferative keratinocytes. We demonstrate that p63-iRHOM2 regulates cell survival and response to oxidative stress via modulation of SURVIVIN and Cytoglobin, respectively. Furthermore, the antioxidant compound Sulforaphane downregulates p63-iRHOM2 expression, leading to reduced proliferation, inflammation, survival and ROS production. These findings elucidate a novel p63-associated pathway that identifies iRHOM2 modulation as a potential therapeutic target to treat hyperproliferative skin disease and neoplasia

    Negative regulation of the androgen receptor gene through a primate specific androgen response element present in the 5' UTR

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    Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. Acknowledgements This work was supported by funding from the Chief Scientist Office, Government of Scotland (Grant Nos CZB/4/477 and ETM/258). DNL was supported by the Association for International Cancer Research (Grant No. 03–127)Peer reviewedPublisher PD

    Feasibility of Using Bandwidth Efficient Modulation to Upgrade the CMS Tracker Readout Optical Links

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    Plans to upgrade the LHC after approximately 10 years of operation are currently being considered at CERN. A tenfold increase in luminosity delivered to the experiments is envisaged in the so-called Super LHC (SLHC). This will undoubtedly give rise to significantly larger data volumes from the detectors, requiring faster data readout. The possibility of upgrading the CMS Tracker analog readout optical links using a bandwidth efficient digital modulation scheme for deployment in the SLHC has been extensively explored at CERN. Previous theoretical and experimental studies determined the achievable data rate using a system based on Quadrature Amplitude Modulation (QAM) to be ~3-4Gbit/s (assuming no error correction is used and for an error rate of ~10-9). In this note we attempt to quantify the feasibility of such an upgrade in terms of hardware implementation complexity, applicability to the high energy physics (HEP) environment, technological feasibility and R&D effort required.Comment: CERN CMS Note. 16 pages, 10 figure

    An Sp1 Modulated Regulatory Region Unique to Higher Primates Regulates Human Androgen Receptor Promoter Activity in Prostate Cancer Cells

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    Funding: This work was supported by the Chief Scientist’s Office (CSO) of the Scottish Government (http://www.cso.scot.nhs.uk/): CWH (CZB-4-477) and IH (ETM/382).Peer reviewedPublisher PD
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