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Biomedical subjects

K Senger

Publications and source records attributed to K Senger.

9 recordsLinked to original sources
PubMed2000

Gene repression by coactivator repulsion.

We show that the IRF-2 oncoprotein represses virus-induced IFN-beta gene transcription via a novel mechanism. Virus infection induces recruitment of IRF-2 to some of the endogenous IFN-beta enhancers as part of the enhanceosome. Enhanceosomes bearing IRF-2 cannot activate transcription, due to the presence of a domain in IRF-2 that prevents enhanceosome-dependent recruitment of the CBP-Pol II holoenzyme complex. As a consequence, IRF-2 incorporation into enhanceosomes restricts the number of IFN-beta promoters directing transcription. Remarkably, deletion of the IRF-2 gene increases IFN-beta expression by expanding the number of cells capable of inducing IFN-beta gene transcription in response to virus infection.

Animals↗
PubMed2000

Transfection of alpha(1,3)fucosyltransferase antisense sequences impairs the proliferative and tumorigenic ability of human colon carcinoma cells.

Sialyl Lewis x and sialyl Lewis a are oncodevelopmental antigens involved in the pathogenesis of colon adenocarcinoma. Biosynthesis of these glycans is controlled by alpha(1,3/1,4)fucosyltransferases. We report the disruption of sialyl Lewis x/a biosynthesis and inhibition of colon carcinoma cell proliferation by stable transfection of antisense sequences directed at the human Lewis alpha(1,3/1,4)fucosyltransferase gene, FUT3, and the plasma alpha(1,3)fucosyltransferase gene, FUT6. COLO-205 cells expressed high levels of sialyl Lewis x/a, alpha(1,3)fucosyltransferase activity, and FUT3/6 transcripts, but COLO</205-derived antisense transfectant cell lines AS5C and AS7A did not. Sense transfectant S6G expressed higher levels of fucosyltransferase than parental COLO-205. Cellular proliferation assays showed marked correlative decreases in the growth of antisense lines and, conversely, increased growth of sense transfectants. Subcutaneous tumors created by injection of nude mice with antisense transfectant cell lines grew more slowly than those arising from control COLO-205 and sense transfectants. These results provide target validation for inhibition of carcinoma proliferation with antisense sequences directed at human fucosyltransferases.

Animals↗
PubMed1999

Mechanism by which the IFN-beta enhanceosome activates transcription.

We demonstrate that in contrast to previous findings by using simple synthetic promoters or activators, the natural IFN-beta enhanceosome activates transcription by causing a dramatic increase of the rate by which preinitiation complexes assemble at the promoter. This effect totally depends on the recruitment of the CBP-PolII holoenzyme by the enhanceosome, because its depletion from the extract decelerates the rate of transcription. However, addition of the CBP-PolII holoenzyme back to these extracts fully restores the speed by which the enhanceosome activates transcription. Strikingly, preincubation of the enhanceosome with the CBP-RNA PolII holoenzyme complex results in instant assembly of preinitiation complexes. In contrast, individual IFN-beta gene activators function solely by increasing the number of functional preinitiation complexes and not the rate of their assembly. Thus, fast recruitment of the CBP-RNA PolII holoenzyme complex is critical for the rapid activation of IFN-beta gene expression by virus infection.

Enhancer Elements, Genetic↗
PubMed1998

Acetylation of HMG I(Y) by CBP turns off IFN beta expression by disrupting the enhanceosome.

The transcriptional coactivators CBP and P/CAF are required for activation of transcription from the IFN beta enhanceosome. We show that CBP and P/CAF acetylate HMG I(Y), the essential architectural component required for enhanceosome assembly, at distinct lysine residues, causing distinct effects on transcription. Thus, in the context of the enhanceosome, acetylation of HMG I by CBP, but not by P/CAF, leads to enhanceosome destabilization and disassembly. We demonstrate that acetylation of HMG I(Y) by CBP is essential for turning off IFN beta gene expression. Finally, we show that the acetyltransferase activities of CBP and P/CAF modulate both the strength of the transcriptional response and the kinetics of virus-dependent activation of the IFN beta gene.

Acetylation↗
PubMed1995

Changes in study design, gender issues, and other characteristics of clinical research published in three major medical journals from 1971 to 1991.

OBJECTIVE: To examine trends in study design and other characteristics of original research published in JAMA, Lancet, and the New England Journal of Medicine (NEJM) between 1971 and 1991. DESIGN: A retrospective cross-sectional study of original clinical research published in JAMA, Lancet, and NEJM during 1971, 1981, and 1991. MEASUREMENTS: Four hundred forty-four articles were independently reviewed by at least two investigators and classified according to study design and other preselected study characteristics. Changes over time were analyzed by chi-square tests for categorical variables and analysis of variance for continuous variables. MAIN RESULTS: Clinical results doubled, from 17% of all articles in 1971 to 35% in 1991 (p < 0.004), while case series decreased from 30% to 4% (p < 0.0001). Of 118 clinical trials, randomized controlled trials increased from 31% to 76% (p < 0.003) and nonrandomized controlled trials decreased from 42% to 8% (p < 0.002). Multicenter studies increased from 10% to 39% (p < 0.0001) and the prevalence of health services research increased from none in 1971 to 12% in 1991 (p < 0.001). The proportion of the studies explicitly excluding women from the subject population decreased from 11% in 1971 to 3% in 1991 (p < 0.03). In 1991 7% of the studies were composed entirely of men subjects, while only 0.7% of the studies were specific to men's health. Twelve percent of the studies in 1991 were specific to women's health. Between 1971 and 1991 there was no change in the prevalence of women first authors or studies addressing women's or minorities' health issues. CONCLUSIONS: Several important changes in clinical research studies published in JAMA, Lancet, and NEJM have taken place between 1971 and 1991. Clinical trials have increased in frequency, largely replacing studies containing ten or fewer subjects. Health services research has increased in prevalence, reflecting growing interest in studies addressing the delivery of health care. Our data support the hypothesis that exclusion of women from clinical research studies is an important contributor to the paucity of data concerning women's health.

Clinical Trials as Topic↗
PubMedDate not supplied

Financial indicators.

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Costs and Cost Analysis↗