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Crystallization and preliminary crystallographic studies of the NCoA-1/SRC-1 PAS-B domain bound to the LXXLL motif of the STAT6 transactivation
No full textInsight into the molecular recognition mechanism of the coactivator NCoA1 by STAT6
Full text linkAbstractCrucial for immune and anti-inflammatory cellular responses, signal transducer and activator of transcription 6 (STAT6) regulates transcriptional activation in response to interleukin-4 and -13 -induced tyrosine phosphorylation by direct interaction with coactivators. The interaction of STAT6 with nuclear coactivator 1 (NCoA1) is mediated by a short region of the STAT6 transactivation domain that includes the motif LXXLL and interacts with the PAS-B domain of NCoA1. Despite the availability of an X-ray structure of the PAS-B domain/ Leu794-Gly814-STAT6 complex, the mechanistic details of this interaction are still poorly understood. Here, we determine the structure of the NCoA1257–385/STAT6783–814 complex using Nuclear Magnetic Resonance (NMR) and X-ray crystallography. The STAT6783–814 peptide binds with additional N-terminal amino acids to NCoA1257–385, compared to the STAT6794–814 peptide, explaining its higher affinity. Secondary and tertiary structures existing in the free peptide are more highly populated in the complex, suggesting binding by conformational selection.</jats:p
p160/SRC/NCoA coactivators form complexes via specific interaction of their PAS-B domain with the CID/AD1 domain
No full textTranscriptional activation involves the ordered recruitment of coactivators via direct interactions between distinct binding domains and recognition motifs. The p160/SRC/NCoA coactivator family comprises three members (NCoA-1, -2 and -3), which are organized in multiprotein coactivator complexes. We had identified the PAS-B domain of NCoA-1 as an LXXLL motif binding domain. Here we show that NCoA family members are able to interact with other full-length NCoA proteins via their PAS-B domain and they specifically interact with the CBP-interaction domain (CID/AD1) of NCoA-1. Peptide competition, binding experiments and mutagenesis of LXXLL motifs point at distinct binding motif specificities of the NCoA PAS-B domains. NMR studies of different NCoA-1-PAS-B/LXXLL peptide complexes revealed similar although not identical binding sites for the CID/AD1 and STAT6 transactivation domain LXXLL motifs. In mechanistic studies, we found that overexpression of the PAS-B domain is able to disturb the binding of NCoA-1 to CBP in cells and that a CID/AD1 peptide competes with STAT6 for NCoA-1 in vitro. Moreover, the expression of an endogenous androgen receptor target gene is affected by the overexpression of the NCoA-1 or NCoA-3 PAS-B domains. Our study discloses a new, complementary mechanism for the current model of coactivator recruitment to target gene promoters
Epigenetic gene regulation of differentiation and epithelial-mesenchymal transition in mammary epithelial cells
Full text linkDifferentiation and epithelial-mesenchymal transition (EMT) in mammary epithelial cell were analyzed with respect to the epigenetic gene regulation.
In the first part, the chromatin accessibility at the beta-casein promoter and the role of histone 3 lysine 9 Dimethylation (H3K9me2) in transcriptional regulation of beta-casein gene in HC11 cells were studied. Moreover, the function of the JmjC domain-containing demethylase Jmjd1a in beta-casein expression was also analyzed. The results revealed that the beta-casein promoter is inaccessible in HC11 cells, and the inaccessibility is independent of hormone treatment. Moreover, the repressive histone mark H3K9me2 is associated at beta-casein promoter. Since the associated H3K9me2 is correlated to chromatin inaccessibility, it probably represses the beta-casein gene. Although the overexpression of Jmjd1a essential domains reduces global H3K9me2 level, beta-casein expression is still not upregulated. This is, at least in part, due to the inhibitory effect of Jmjd1a domains on transcription machinery.
In the second part, the role of histone 3 lysine 27 Trimethylation (H3K27me3) in regulation of EMT was analyzed. The finding revealed that H3K27me3 regulates EMT at levels of marker genes, Snail, but not the master regulator. The promoters of both epithelial marker Cdh1 and the mesenchymal marker Acta2 are associated with H3K27me3 and the associations correlate to gene transcription. In addition, Snail is a target of H3K27me3, since removal of H3K27me3 by both DZNep and Suz12 knockdown can equally enhance the TGFβ3 mediated induction of Snail mRNA. TGFβ3 is essential. Finally, the CBF-A/KAP-1/FTS-1 complex might not be regulated by H3K27me3. Besides, DZNep is identified to be a novel EMT inducer and the effect results, at least in part, from the activation of the CBF-A/KAP-1/FTS-1 complex
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Untersuchung molekularer Grundlagen der Pathogenese des klassischen Hodgkin Lymphoms
Full text linkDas klassische Hodgkin Lymphom (cHL) ist eines der häufigsten Lymphome der westlichen Welt. Repräsentativ für das cHL sind seine Tumorzellen, die Hodgkin- und Reed-Sternberg (HRS)-Zellen. Charakteristisch für diese Zellen ist unter anderem die konstitutive Aktivierung verschiedener Signalwege zu denen auch der Janus Kinasen / Signal Transducer and Activator of Transcription (JAK/STAT)-Signalweg gehört. In unserer Arbeitsgruppe wurde bereits STAT6 als wichtiger Überlebensfaktor für HRS-Zellen nachgewiesen und mittels Genexpressionsanalysen konnten neue potentielle STAT6-Zielgene identifiziert werden.
Im Rahmen dieser Arbeit wurden einige dieser Gene als direkte STAT6-Zielgene identifiziert. Über deren Regulation STAT6 an der gestörten Entwicklung der HRS-Zellen bzw. an der Inhibition der Apoptose beteiligt ist. Des Weiteren wurden STAT6 und STAT1 als antagonistische Regulatoren der Apoptose in HRS-Zellen identifiziert.
Neben der konstitutiven Aktivierung verschiedener Signaltransduktionswege ist das cHL durch die geringe oder gar nicht vorhandene Expression B-Zell-spezifischer Gene gekennzeichnet. In dieser Arbeit konnte gezeigt werden, dass die nicht exprimierten Gene mit trimethyliertem H3K27, einer Histon-Modifikation für stillgelegtes Chromatin, assoziiert sind. Die Inhibierung dieser Modifikation bzw. der für sie verantwortlichen Proteine des Polycomb Repressive Complex 2 (PRC2) durch verschiedene Ansätze führte zu einer erhöhten Expression der B-Zell-spezifischen Gene und der Induktion von Apoptose in cHL-Zelllinien.
Zusammen tragen diese Ergebnisse zum besseren Verständnis molekularer Zusammenhänge der pathologischen Veränderungen in HRS-Zellen bei und liefern mit den Überlebensfaktoren STAT6 und PRC2 für HRS-Zellen neue Ansatzpunkte für Therapiemöglichkeiten des cHL
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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