1,720,983 research outputs found
Mechanisms of transcriptional repression of cell-cycle G2/M promoters by p63
No full textp63 is a developmentally regulated transcription factor related to p53, which activates and represses specific genes. The human AEC (Ankyloblepharon-Ectodermal dysplasia-Clefting) and EEC (Ectrodactyly-Ectodermal dysplasia-Cleft lip/palate) syndromes are caused by missense mutations of p63, within the DNA-binding domain (EEC) or in the C-terminal sterile alpha motif domain (AEC). We show here that p63 represses transcription of cell-cycle G(2)/M genes by binding to multiple CCAAT core promoters in immortalized and primary keratinocytes. The CCAAT-activator NF-Y and Delta Np63 alpha are associated in vivo and a conserved alpha-helix of the NF-YC histone fold is required. p63 AEC mutants, but not an EEC mutant, are incapable to bind NF-Y. Delta Np63 alpha, but not the AEC mutants repress CCAAT-dependent transcription of G(2)/M genes. Chromatin immunoprecipitation recruitment assays establish that the AEC mutants are not recruited to G(2)/M promoters, while normally present on 14-3-3 sigma, which contains a sequence-specific binding site. Surprisingly, the EEC C306R mutant activates transcription. Upon keratinocytes differentiation, NF-Y and p63 remain bound to G(2)/M promoters, while HDACs are recruited, histones deacetylated, Pol II displaced and transcription repressed. Our data indicate that NF-Y is a molecular target of p63 and that inhibition of growth activating genes upon differentiation is compromised by AEC missense mutations
Identification of p63 target genes in keratinocytes
No full textOne single gene, p63, coding for a developmentally regulated transcription factor, causes three human syndromes, the Hay Wells AEC, the EEC and the split hand/split foot malformation (SHFM). The molecular defects have been charaterized and reside in dominant negative missense mutations within the DNA-binding domain (EEC), or in the C-termnal SAM domain (AEC). More specifically p63 seems to play a master regulatory role in the keratinocites stem cell compartment. The p63 transcriptional circuitry is still poorly understood, mainly because the genes targeted and the proteins regulating its activity are essentially unknown. It was shown that the related p73 protein inhibits transcription by interacting with the common activator NF-Y, a protein that regulates most of the cell growth genes: I verified that p63 is also capable to interact in vivo. interestingly, all AEC mutants affecting the SAM domain were incapable to associate NF-Y, suggesting that inhibition of growth regulated genes through NF-Y might be an important function of p63. I have functionally inactivated the p63 gene in HaCat cells by siRNA technology and identified genes activated and repressed by Affimetrix microarray analysis. To confirm the data, I set up the Chromatin Immunoprecipitations (ChIP) technique from the same cell line and in human primary keratinocytes. More than 30 new p63 target gene were identified. The products of these genes have been tested upon differentiation of HaCat cells and in normal human skin sections: my data suggest that the DN is a pro-growth, anti-differentiation isoform, with the capacity to both activate and repress transcription. Furthermore, some of the genes under p63 control confirm its central role at the cross-road between cell growth and differentiation, as demonstrated by immunostaining on p63-/- mice
THE P53-PARALOG DNP73 ONCOGENE IS REPRESSED BY alpha-IFN/STAT2 THROUGH THE RECRUITMENT OF YY1 AND HDAC1 TRANSCRIPTIONAL REPRESSORS
No full textGoing 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
MODULATION OF THE EPIGENETIC REGULATION OF CCCDNA FUNCTION CONTRIBUTES TO IFN alpha INHIBITION OF HBV REPLICATION
No full textVariations 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
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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