Transcriptional Control of Gene Expression in Hepatic Cells

Ciliberto, Gennaro; Colantuoni, Vittorio; Francesco, Raffaele De; Simone, Vincenzo De; Monaci, Paolo; Nicosia, Alfredo; Ramji, Dipak Purshottam; Toniatti, Carlo; Cortese, Riccardo

doi:10.1007/978-1-4684-6811-3_7

Cited by 2 publications

(5 citation statements)

References 383 publications

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“…The human hepatoma Hep3B cell line is an extensively used model system for investigating the mechanisms that are involved in the IL-6-mediated regulation of gene transcription, with demonstrated similarities to what is seen in vivo (4,31). We have previously investigated the effect of IL-6 on C/EBPb and C/EBPd expression in Hep3B cells (27).…”

Section: Il-6 Reduces the Steady-state Levels Of C/ebpa Mrna And Poly...mentioning

confidence: 99%

“…2A) via transient transfection assays in Hep3B cells (23). These cells have been used extensively for the analysis of promoter elements that are involved in both the constitutive and regulated expression of genes in hepatocytes from different species, including the C/EBP family (4,31). Indeed, we have shown previously that the activity of the C/EBPb and C/EBPd gene promoters in these cells is increased following exposure to IL-6 (36,37).…”

Section: Il-6 Reduces the Steady-state Levels Of C/ebpa Mrna And Poly...mentioning

confidence: 99%

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Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein- gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region

Foka

Irvine

Köçkar

et al. 2003

Nucleic Acids Research

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The cytokine interleukin-6 (IL-6) plays key roles in the immune and inflammatory responses, acute-phase reaction and hematopoiesis. Such biological actions of IL-6 are characterised by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanism by which IL-6 suppresses transcription remains largely unclear. We have, therefore, investigated this aspect using the Xenopus laevis CCAAT/enhancer binding protein-alpha (C/EBPalpha) gene promoter as a model. We show by transient transfection assays of various promoter-luciferase DNA constructs into hepatoma cells that a C/EBP recognition sequence in the proximal promoter region is essential for the IL-6-mediated repression. Electrophoretic mobility shift assays showed that C/EBPalpha was the major protein that bound to this site and, consistent with its expression pattern, the binding was reduced when the cells were exposed to IL-6. Co-transfection assays revealed for the first time that the ability of C/EBPalpha, but not C/EBPbeta or Sp1, to transactivate the promoter was decreased dramatically when the cells were incubated with IL-6. These studies, therefore, identify a novel mechanism for IL-6-mediated repression of gene transcription that involves a reduction in C/EBPalpha-mediated activation.

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Section: Il-6 Reduces the Steady-state Levels Of C/ebpa Mrna And Poly...mentioning

confidence: 99%

Section: Il-6 Reduces the Steady-state Levels Of C/ebpa Mrna And Poly...mentioning

confidence: 99%

Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein- gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region

Foka

Irvine

Köçkar

et al. 2003

Nucleic Acids Research

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“…These two factors have been implicated with the liver-enriched expression of many other genes (8,16,19). HNF4 bound to elements A and C in extracts of HepG2 cells, but not COS1 or HeLa extracts.…”

Section: Discussionmentioning

confidence: 99%

Regions Flanking Exon 1 Regulate Constitutive Expression of the Human Antithrombin Gene

Fernandez-Rachubinski

Weiner

Blajchman

1996

Journal of Biological Chemistry

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We have identified cis-acting elements and trans-acting factors that regulate constitutive expression of the human antithrombin gene. The activity of the sequences flanking the first exon of the gene was investigated using a luciferase-based reporter assay in transiently transfected HepG2, COS1, BSC40, and HeLa cells. Deletion analysis allowed the mapping of two elements able to promote antithrombin gene transcription in HepG2 and COS1 cells. The first element is located upstream of the first exon (؊150/؉68 nucleotides). The second element is in the first intervening sequence (؉300/؉700 nucleotides) and functions in an orientation opposite to that of the first. Footprint analysis showed three protected areas in the 5 upstream element at ؊92/؊68 (element A), ؊14/؉37 (element B), and ؊126/؊100 nucleotides (element C). These elements acted as enhancers in luciferase reporter assays. Gel retardation analysis demonstrated that two liver-enriched transcription factors, hepatocyte nuclear factor 4 (HNF4) and CCAAT enhancer-binding protein (C/EBPa), bound to the 5 upstream element. HNF4 bound to elements A and C, whereas C/EBPa bound to element B. Element A also interacted with the ubiquitous nuclear hormone receptors chicken ovalbumin upstream promoter transcription factor 1 (COUP-TF1), thyroid hormone receptor ␣ (TR␣), peroxisome proliferator-activated receptor ␣(PPAR␣), and retinoid X receptor ␣ (RXR␣). In HepG2 and BSC40 cells, HNF4, C/EBP␣, and RXR␣ activated luciferase expression from a reporter construct containing the 5-upstream minimal antithrombin gene promoter, while COUP-TF1, TR␣, and HNF3 (␣ or ␤) repressed such expression. Our results show that constitutive expression of the human antithrombin gene depends in part upon the interplay of these transcription factors and suggest that signaling pathways regulated by these factors can modulate antithrombin gene transcription. Human antithrombin (AT)1 is a major inhibitor of a number of serine esterases implicated in blood coagulation (1, 2). The AT gene contains 7 exons and 6 intervening sequences (IVS) in a 14-kilobase pair region of the long arm of chromosome 1. The mechanisms underlying AT gene expression are not well known. The AT gene is expressed primarily in the liver, with lower levels in the kidney and brain (2). AT gene expression is believed to be constitutive, but developmental and hormonal factors are known to influence AT levels in plasma (2). At the transcriptional level, an early report by Prochownik described enhancer activity of a Ϫ340/ϩ1200 nucleotide (nt) fragment of the AT gene (3), while Ochoa et al. (4), investigating the regulation of expression of the human transferrin gene, identified a sequence at Ϫ480/Ϫ458 nt that contained the core motif TCT-TTGACCT. This element, named TF-DRI, was shown to be homologous with an element at Ϫ89/Ϫ75 nt in the human AT gene, and generated shifts in liver nuclear extracts in a tissuespecific manner (4). These observations prompted us to characterize in greater detail elements in this area of the human AT...

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“…la mutation. On ne peut toutefois pas ignorer les modulations de la transcription dues à des coopéra tions de fixation ou d'activation, résultant d'interactions entre fac teurs [26] . Ce domaine d'étude, bien qu'en plein essor, n'a guère été pris en compte en ce qui con cerne le promoteur du gène FJ)(LLY dm.…”

Section: +13unclassified

“…Enfin, le gène FIX est soumis à un contrôle au cours du développe ment : une étude chez la souris montre que le taux hépatique des ARNm correspondants augmente significativement dans la période périnatale et atteint son maximum à l'âge adulte [25]. Il est maintenant bien connu que la région 5' flanquante de la plupart des gènes à expression préférentiel lement ou strictement hépatique est sous la dépendance d'un ou de plu sieurs fac teurs de transcription appartenant à au moins quatre fa milles de protéines, dont les repré sentants principaux sont appelés res pectivement H F-1, HNF-3, HNF-4 et C/EBP [26] . En ce qui concerne le gène FIX, ce n'est que très récem ment que l'importance de certains de ces facteurs, et l'existence des domaines de fixation corre pondants sur la région promotrice du gène, viennent d'être appréciées, précisé ment lors des études portant sur l'hémophilie B Leyden.…”

unclassified

Hémophilie B Leyden : les corrections naturelles d'un déficit temporaire de transcription

Salier¹,

Kurachi²,

Kurachi³

1994

Med Sci (Paris)

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Transcriptional Control of Gene Expression in Hepatic Cells

Cited by 2 publications

References 383 publications

Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein- gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region

Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein- gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region

Regions Flanking Exon 1 Regulate Constitutive Expression of the Human Antithrombin Gene

Hémophilie B Leyden : les corrections naturelles d'un déficit temporaire de transcription

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