Tumor Necrosis Factor–α Induces A K B Sequence–Specific Dna–Binding Protein in Human Hepatoblastoma Hepg2 Cells

Banerjee, Ranjit; Karpen, Saul J.; Siekevitz, Miriam; Lengyel, Gabriella; Bauer, Joachim; Acs, George

doi:10.1002/hep.1840100620

Cited by 26 publications

(11 citation statements)

References 47 publications

(53 reference statements)

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“…Isolated hepatocytes and hepatocyte-derived cell lines respond rapidly to cytokines by increasing nuclear concentrations of NF-B and AP-1 (39,51,52). Consistent with these studies, we found rapid upregulation of hepatic NF-B and AP-1 levels after endotoxin challenge, although a direct role for either of these two factors in modulating ntcp gene expression is unknown.…”

Section: Discussionsupporting

confidence: 88%

Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.

Trauner¹,

Arrese²,

Lee³

et al. 1998

J. Clin. Invest.

243

207

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Sodium-dependent uptake of bile acids across the hepatic basolateral membrane is rapidly and profoundly diminished during sepsis, thus contributing to the pathogenesis of sepsisassociated cholestasis. This effect is mediated by endotoxin or effector cytokines, which reduce expression of several hepatobiliary transporters, including the sodium-dependent bile acid transporter gene, ntcp . We test here the hypothesis that endotoxin treatment leads to impaired binding activity of ntcp promoter trans -acting factors, resulting in reduction of ntcp mRNA expression. After endotoxin administration, ntcp mRNA levels reached their nadir by 16 h, and nuclear run-on assays demonstrated a marked reduction in ntcp gene transcription. At 16 h after treatment, nuclear binding activities of two key factors that transactivate the ntcp promoter, hepatocyte nuclear factor (HNF) 1 and Footprint B binding protein (FpB BP), decreased to 44 and 47% of pretreatment levels, respectively, while levels of the other known ntcp promoter transactivator, signal transducer and activator of transcription 5, were unaffected. In contrast, the universal inflammatory response factors nuclear factor B and activating protein 1 were both upregulated significantly. Examination of nuclear extracts obtained at sequential time points revealed that the maximal decrease in nuclear activities of both HNF1 and FpB BP preceded the nadir of ntcp mRNA expression by 6-10 h. Furthermore, these two nuclear factors returned towards normal levels before the recovery of ntcp mRNA levels observed by 48 h. Since HNF1 ␣ mRNA levels were unchanged at all time points, HNF1 is likely to be regulated posttranscriptionally by endotoxin. We conclude that the downregulation of ntcp gene expression by endotoxin is mediated at the level of transcription through tandem reductions in the nuclear binding activity of two critical transcription factors. These findings provide new insight into the coordinated downreg-

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Section: Discussionsupporting

confidence: 88%

Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.

Trauner¹,

Arrese²,

Lee³

et al. 1998

J. Clin. Invest.

243

207

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“…These cellular proteins bind to various regions of the HIV-1 LTR, which is important for viral gene regulation, as demonstrated by DNase footprinting and mutagenesis studies (Garcia et al, 1987). Previously, we have reported that HIV-1 LTR CAT gene and its several 5' deletion mutants (retaining the TAR sequence) are efficiently expressed in HepG2 cells in the absence of the cotransfected HIV-1 tat gene product, and only a five-fold enhancement of CAT expression is obtained in HepG2 cells (Banerjee et al, 1989) when this plasmid is cotransfected with a HIV-1 tat gene expressing plasmid p AR tat (Sodroski et ai, 1985;. This data initially suggested the presence of a competent cellular factor(s) in HepG2 cells as compared to the other cell types, which regulates the HIV-1 LTR expression, possibly, in a manner that mimics the action of a virally derived "Tat-like" protein in this cell line.…”

Section: Discussionmentioning

confidence: 95%

“…Samples were resolved by electrophoresis in 6% polyacrylamide gel and visualized by autoradiography. Synthetic oligonucleotides corresponding to the hepatitis B virus enhancer region (HBV-EI nucleotides 1,110-1,139), HBV-core promoter (CP nucleotides 1,658-1,680), the P¡ site of the human c-myc sequence (nucleotides -67 to -35), and the kappa B (KB) sequence of HIV-1 enhancer region, were used as nonspecific competitors as described before (Bentley and Groudine, 1986;Karpen et al, 1988;Banerjee et al, 1989).…”

Section: Gel Retardation Assaysmentioning

confidence: 99%

Identification of a Human Immunodeficiency Virus Type 1 TAR Binding Protein in Human Hepatoblastoma HepG2 Cells ThatTrans-Activates HIV-1 LTR-Directed Gene Expression

Pizzella¹,

Banerjee²

1994

DNA and Cell Biology

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Recently, we have shown that the human immunodeficiency virus (HIV-1) long terminal repeat (LTR) directed chloramphenicol acetyltransferase (CAT) gene is efficiently expressed in human hepatoblastoma HepG2 cells and these cells can support productive HIV-1 replication. In this study we show that HepG2 cells contain a nuclear factor that binds to the HIV-1 trans-activating region (TAR), which we named HepG2-derived TAR binding protein (HTBP). Gel retardation assays using synthetic oligonucleotide probes carrying different mutations in the TAR region and competition DNA mobility-shift experiments using these oligonucleotides revealed the binding site encompassing between +7 and +13 nucleotides (5'-TCTGGTT-3') in the HIV-1 LTR. An in vivo CAT competition assay using -65HIV-1 LTR CAT as a reporter plasmid and various competitor plasmids containing these mutated oligonucleotides also demonstrated that HTBP can influence the HIV-1 LTR-directed CAT gene expression in HepG2 cells by interaction with a specific sequence in the TAR region.

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“…The nuclear transcription factor (NFjB) can transcriptionally regulate both IL-8 and TNF-␣ [37]. It has been shown to bind to regulatory elements in the promoter region of IL-8 following H 2 O 2 exposure in lung epithelial cells [38].…”

Section: Discussionmentioning

confidence: 99%

Identification of a possible association between carbon tetrachloride-induced hepatotoxicity and interleukin-8 expression

Holden¹,

James²,

Brooks³

et al. 2000

J. Biochem. Mol. Toxicol.

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Hepatotoxicants can elicit liver damage by various mechanisms that can result in cell necrosis and death. The changes induced by these compounds can vary from gross alterations in DNA repair mechanisms, protein synthesis, and apoptosis, to more discrete changes in oxidative damage and lipid peroxidation. However, little is known of the changes in gene expression that are fundamental to the mechanisms of hepatotoxicity. We have used DNA microarray technology to identify gene transcription associated with the toxicity caused by the hepatotoxicant carbon tetrachloride. Labeled poly A+ RNA from cultured human hepatoma cells (HepG2) exposed to carbon tetrachloride for 8 hours was hybridized to a human microarray filter. We found that 47 different genes were either upregulated or downregulated more than 2‐fold by the hepatotoxicant compared with dimethyl formamide, a chemical that does not cause liver cell damage. The proinflammatory cytokine interleukin‐8 (IL‐8) was upregulated over 7‐fold compared with control on the array, and this was subsequently confirmed at 1 hour and 8 hours by Northern blot analyses. We also found that carbon tetrachloride caused a time‐dependent increase in interleukin‐8 protein release in HepG2 cells, which was paralleled by a decrease in cell viability. These data demonstrate that carbon tetrachloride causes a rapid increase in IL‐8 mRNA expression in HepG2 cells and that this increase correlates with a later and significant increase in the levels of interleukin‐8 protein. These results illustrate the potential of microarray technology in the identification of novel gene changes associated with toxic processes. © 2000 John Wiley & Sons, Inc. J Biochem Toxicol 14:283–290, 2000

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Tumor Necrosis Factor–α Induces A K B Sequence–Specific Dna–Binding Protein in Human Hepatoblastoma Hepg2 Cells

Cited by 26 publications

References 47 publications

Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.

Endotoxin downregulates rat hepatic ntcp gene expression via decreased activity of critical transcription factors.

Identification of a Human Immunodeficiency Virus Type 1 TAR Binding Protein in Human Hepatoblastoma HepG2 Cells ThatTrans-Activates HIV-1 LTR-Directed Gene Expression

Identification of a possible association between carbon tetrachloride-induced hepatotoxicity and interleukin-8 expression

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