Complex Contribution of the 3′-Untranslated Region to the Expressional Regulation of the Human Inducible Nitric-oxide Synthase Gene

Rodrı́guez-Pascual, Fernando; Hausding, Michael; Ihrig-Biedert, Irmgard; Furneaux, Henry; Levy, Andrew P.; Förstermann, Ulrich; Kleinert, Hartmut

doi:10.1074/jbc.m910460199

Cited by 165 publications

(190 citation statements)

References 49 publications

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“…The results also suggest the possibility of posttranscriptional regulation because the magnitude of human iNOS protein and NO levels were much less than the fold increase in iNOS mRNA. Whereas others have shown direct posttranscriptional regulation of the human iNOS gene by RNA binding proteins (17), nothing is known about miRNA binding to the human iNOS mRNA 3′-UTR.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…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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“…HuR has been found to interact with several AREs in vitro and in cells, and its overexpression induced stabilization of mRNAs for vascular endothelial growth factor (23), nitric oxide synthase II (35), eotaxin (1), and different ARE-containing reporter RNAs (14,15,33). Furthermore, suppression of HuR amounts by antisense RNA or small interfering RNA approaches inhibited stabilization induced by hypoxia (23), cytokines (35), or UV light (43) or during cell cycle progression (42). Most recently, constitutively active MK2 (41), as well as stimuli known to activate the p38/MK2 pathway (H 2 O 2 [41] and TNF-␣ [1]), was found to induce cytoplasmic accumulation of HuR.…”

Section: Discussionmentioning

confidence: 99%

“…HuR is a ubiquitously expressed member of the human ELAV family of RNA binding proteins (24) whose functional role in the stabilization of several ARE-containing mRNAs has been established (15,23,33,35,42,43). It also plays a role in the nuclear export of mRNA (17) and in control of translation (20,26).…”

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confidence: 99%

Distinct Domains of AU-Rich Elements Exert Different Functions in mRNA Destabilization and Stabilization by p38 Mitogen-Activated Protein Kinase or HuR

Winzen¹,

Gowrishankar²,

Bollig

et al. 2004

Molecular and Cellular Biology

116

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“…Beyond this, the regulation of mRNA and protein iNOS stability also represents an important mechanism by which iNOS levels and activity may be regulated and may explain some of the differences in iNOS induction observed between different species. For example, the 3'-UTR region of the human iNOS mRNA contains several AU-rich elements that have been shown to destabilize reporter mRNAs [129]. Recent advances also indicate that epigenetic factors including DNA methylation and histone H3 lysine 9 methylation silence or repress human iNOS expression in human endothelial and smooth muscle cell cultures [21].…”

Section: Regulation Of Inos Activity and Expressionmentioning

confidence: 99%

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

Ginnan

Guikema

Halligan

et al. 2008

Free Radical Biology and Medicine

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Inflammation plays a critical role in promoting smooth muscle migration and proliferation during vascular diseases such as post-angioplasty restenosis and atherosclerosis. Another common feature of many vascular diseases is the contribution of reactive oxygen (ROS) and nitrogen (RNS) species to vascular injury. Primary sources of ROS and RNS in smooth muscle are several isoforms of NADPH oxidase (Nox) and the cytokine-regulated inducible nitric oxide (NO) synthase (iNOS). One important example of the interaction between NO and ROS is the reaction of NO with superoxide to yield peroxynitrite, which may contribute to the pathogenesis of hypertension. In this review, we discuss the literature that supports an alternate possibility: Nox-derived ROS modulate NO bioavailability by altering the expression of iNOS. We highlight data showing co-expression of iNOS and Nox in vascular smooth muscle and demonstrating the functional consequences of iNOS and Nox during vascular injury. We describe the relevant literature demonstrating that the mitogen activated protein kinases (MAP kinases) are important modulators of pro-inflammatory cytokinedependent expression of iNOS. A central hypothesis discussed is that ROS-dependent regulation of the serine/threonine kinase protein kinase Cδ (PKCδ) is essential to understanding how Nox may regulate signaling pathways leading to iNOS expression. Overall, the integration of non-phagocytic NADPHoxidase with cytokine signaling in general and in vascular smooth muscle in particular is poorly understood and merit further investigation.

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Complex Contribution of the 3′-Untranslated Region to the Expressional Regulation of the Human Inducible Nitric-oxide Synthase Gene

Cited by 165 publications

References 49 publications

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

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

Distinct Domains of AU-Rich Elements Exert Different Functions in mRNA Destabilization and Stabilization by p38 Mitogen-Activated Protein Kinase or HuR

Regulation of smooth muscle by inducible nitric oxide synthase and NADPH oxidase in vascular proliferative diseases

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