Analysis of the Cytokine-Stimulated Human Inducible Nitric Oxide Synthase (iNOS) Gene: Characterization of Differences between Human and Mouse iNOS Promoters

Chu, Shan C.; Marks-Kończalik, Joanna; Wu, Haiping; Banks, Tazewell; Moss, Joel

doi:10.1006/bbrc.1998.9062

Cited by 157 publications

(133 citation statements)

References 40 publications

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“…Together, these studies establish the notion that MTA1 is an essential mediator of HBx transactivation of iNOS activities. (17,18) suggests that an NF-B protein complex was recruited to the NF-B response elements located in the iNOS gene promoter. To gain a detailed insight into the mechanism by which HBx regulates iNOS via MTA1, we analyzed the upstream 8.5-kb region of the putative iNOS promoter for the presence of binding motifs of NF-B.…”

Section: Hbx Targets Mir-661 To Up-regulate Mta1 Expression-mentioning

confidence: 99%

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Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

Bui-Nguyen

Pakala

Sirigiri

et al. 2010

Journal of Biological Chemistry

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Nitric oxide has been implicated in the pathogenesis of inflammatory disorders, including hepatitis B virus-associated hepatocellular carcinoma. Transactivator protein HBx, a major regulator of cellular responses of hepatitis B virus, is known to induce the expression of MTA1 (metastasis-associated protein 1) coregulator via NF-B signaling in hepatic cells. However, the underlying mechanism of HBx regulation of the inducible nitric-oxide synthase (iNOS) pathway remains unknown. Here we provide evidence that MTA1 is a positive regulator of iNOS transcription and plays a mechanistic role in HBx stimulation of iNOS expression and activity. We found that the HBx-MTA1 complexisrecruitedontothehumaniNOSpromoterinanNF-Bdependent manner. Pharmacological inhibition of the NF-B signaling prevented the ability of HBx to stimulate the transcription, the expression, and the activity of iNOS; nevertheless, these effects could be substantially rescued by MTA1 dysregulation. We further discovered that HBx-mediated stimulation of MTA1 is paralleled by the suppression of miR-661, a member of the small noncoding RNAs, recently shown to target MTA1. We observed that miR-661 controls of MTA1 expression contributed to the expression and activity of iNOS in HBx-expressing HepG2 cells. Accordingly, depletion of MTA1 by either miR-661 or siRNA in HBx-expressing cells severely impaired the ability of HBx to modulate the endogenous levels of iNOS and nitrite production. Together, these findings reveal an inherent role of MTA1 in HBx regulation of iNOS expression and consequently its function in the liver cancer cells.

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Section: Hbx Targets Mir-661 To Up-regulate Mta1 Expression-mentioning

confidence: 99%

“…Specifically, HBx activates NF-B signaling (12,13) and enhances the expression of its downstream inflammatory targets, including inducible nitric-oxide synthase (iNOS) (9, 14 -16). Inducible NOS is both an NF-B-responsive (17)(18)(19)(20) and an HBx-regulated gene (14). Inducible NOS generates nitric oxide (NO) from L-arginine.…”

mentioning

confidence: 99%

Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

Bui-Nguyen

Pakala

Sirigiri

et al. 2010

Journal of Biological Chemistry

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“…18 Promoter activity involves the 5Ј UTR spanning up to 16 kb upstream from the transcription start site, 19 with important cytokine responsive elements located −3.7 kb to −5.6 kb upstream of the transcription initiation start site. 20 In the human NOS2 promoter region three different polymorphisms have been identified in the −0.7 to −2.6 kb region: a single nucleotide polymorphism (G/C) causing a restriction enzyme site (Bsal) 21 and two microsatellites: a biallelic tetranucleotide repeat sequence (TAAA) n , 22 and a highly polymorphic (nine alleles) pentanucleotide repeat sequence (CCTTT) n . 23 The G/C has been associated with protection from all forms of severe malaria, 21 and the pentanucleotide repeat sequence have been functionally characterised in a promoter reporter assay.…”

Section: Introductionmentioning

confidence: 99%

No evidence for linkage in the promoter region of the inducible nitric oxide synthase gene (NOS2) in a Danish type 1 diabetes population

et al. 2000

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Exposure of human pancreatic islets to a mixture of cytokines induces expression of inducible nitric oxide synthase (iNOS), impairs beta-cell function and induces apoptosis. Exposing human islets to high amounts of NO from chemical NO-donors causes DNA strand breaks and mitochondrial damage, suggesting that NO is deleterious to human beta-cells. Hence, we consider the gene encoding iNOS in beta-cells, NOS2, a candidate gene for type 1 diabetes in humans. In the present study we have tested three identified polymorphisms within the promoter sequence of the human NOS2 gene in a type 1 diabetic family material comprising 154 affected sib-pair families and 103 affected simplex families (1143 individuals in total). PCR-based amplification of the polymorphic loci were established. Linkage analysis was performed using the extended transmission disequilibrium testing (ETDT). A Bsal RFLP was found not to be polymorphic in 20 type 1 diabetic patients and 14 healthy control subjects and was not analysed further. In affected cases a nine allele CCTTT repeat and a bi-allelic TAAA repeat revealed allelewise P etdt of 0.52 and 0.60, respectively. ETDT applied to {(TAAA)n; (CCTTT)n} haplotypes demonstrated random transmission from heterozygous parents to affected offspring. In conclusion, the tested polymorphisms within the NOS2 gene promoter did not show evidence for linkage to type 1 diabetes in a Danish family material. Genes and Immunity (2000) 1, 362-366.

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“…During inflammatory conditions, the rodent (4-6) and human inducible nitric oxide synthase (hiNOS) genes (7,8) are activated by LPS and cytokines. Transcriptional regulation of the hiNOS gene involves transcription factors NF-κB, Stat-1, AP-1, C/EBPβ, KLF6, and NRF (9)(10)(11)(12)(13)(14)(15)(16). Important posttranscriptional mechanisms also regulate hiNOS mRNA stability through RNA binding proteins HuR, TTP, and KSRP (17)(18)(19)(20).…”

mentioning

confidence: 99%

miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes

Guo¹,

Shao²,

Zheng

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Human inducible nitric oxide synthase (hiNOS) gene expression is regulated by transcriptional and posttranscriptional mechanisms. The purpose of this study was to determine whether specific microRNA (miRNA) directly regulate hiNOS gene expression. Sequence analysis of the 496-bp hiNOS 3′-untranslated region (3′-UTR) revealed five putative miR-939 binding sites. The hiNOS 3′-UTR conferred significant posttranscriptional blockade of luciferase activity in human A549, HCT8, and HeLa cells. The hiNOS 3′-UTR also exerted basal and cytokine-stimulated posttranscriptional repression in an orientation-dependent manner. Functional studies demonstrated that transfection of miR-939 into primary human hepatocytes (HCs) significantly inhibited cytokine-induced NO synthesis in a dose-dependent manner that was abrogated by a specific miR-939 inhibitor. MiR-939 (but not other miRNAs) abolished cytokine-stimulated hiNOS protein in human HC, but had no effect on hiNOS mRNA levels. Site-directed mutagenesis of miR-939 bindings sites at +99 or +112 bp in the hiNOS 3′-UTR increased reporter gene expression. Furthermore, intact miR-939 binding sites at +99 or +112 positions were required for posttranscriptional suppression by miR-939. Cytokine stimulation directly increased miR-939 levels in human HC. Transfection of miR-939 inhibitor (antisense miR-939) enhanced cytokine-induced hiNOS protein and increased NO synthesis in vitro in human HC. Finally, cytokine or LPS injection in vivo in mice increased hepatic miR-939 levels. Taken together, these data identify that miR-939 directly regulates hiNOS gene expression by binding in the 3′-UTR to produce a translational blockade. These findings suggest dual regulation of iNOS gene expression where cytokines induce iNOS transcription and also increase miR-939, leading to translational inhibition in a checkand-balance system. nitric oxide | miRNA regulation

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Analysis of the Cytokine-Stimulated Human Inducible Nitric Oxide Synthase (iNOS) Gene: Characterization of Differences between Human and Mouse iNOS Promoters

Cited by 157 publications

References 40 publications

Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

No evidence for linkage in the promoter region of the inducible nitric oxide synthase gene (NOS2) in a Danish type 1 diabetes population

miRNA-939 regulates human inducible nitric oxide synthase posttranscriptional gene expression in human hepatocytes

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