Mapping of the Genes Encoding Human Inducible and Endothelial Nitric Oxide Synthase (NOS2 and NOS3) to the Pericentric Region of Chromosome 17 and to Chromosome 7, Respectively

doi:10.1006/geno.1994.1286

Genomics

Volume 21, Issue 2, 15 May 1994, Pages 419-422

https://doi.org/10.1006/geno.1994.1286 Get rights and content

Abstract

Nitric oxide (NO) is an important molecular messenger regulating the functions of a wide variety of cells and tissues. NO is synthesized from l -arginine by a variety of isoforms of the enzyme nitric oxide synthase (NOS). We have used Southern blotting analysis on DNAs obtained from a panel of human-rodent hybrid cell lines to map the gene encoding the inducible NOS (NOS2) to chromosome 17cen-17q11 and the gene encoding the endothelial form of NOS (NOS3) to chromosome 7. Fluorescence in situ hybridization using a NOS2 probe gave several signals in the 17p11-q11 pericentromeric region.

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In mammals, three different forms of iNOS are reported, two isoforms are expressed in neurons and endothelium and third isoform is induced by cytokines (Ghosh et al., 1999). The isoform iNOS is homodimer in nature and iNOS gene has been located on chromosome 17 (Michal, 1999; Xu et al., 1994). NO production was regulated by iNOS during translation and transcription process, the active iNOS produces unrestricted biosynthesis of NO until the available substrate completely depleted (Hickey et al., 2001).
Nitric oxide (NO) is one of the major signalling molecules in the mammalian body playing critical role in regulation of blood pressure, cardiovascular disease including stroke, immune activation, neuronal and cell communication. Moreover, hyper production of NO by the activity of nitric oxide synthase (NOS) involved in neuropathic pain, neurodegenerative disorders and stroke. Hence, the search on small molecules from the natural sources for the inhibition of NOS is desirable in therapeutic point of view. The elevated level of NO caused by NOS enzyme become a novel target in finding new inhibitors from natural sources as antistroke agents. The present study focuses on the molecular docking of quercetin and its analogues against NOS. The active site of the enzyme was docked with the ligand and pharmacological properties were analysed. From this result, we suggest the therapeutic property of quercetin and its analogues against NOS.
Abeta, oxidative stress in Alzheimer disease: Evidence based on proteomics studies
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A free radical in its natural form, NO is synthesized from l-arginine by endothelial, neuronal, or inducible nitric oxide synthases (NOS). NO has beneficial effects such as a biological mediator in several processes including neurotransmission, vascular smooth muscle relaxation as well as having antitumor, and antimicrobial activities [40,41] but becomes toxic at high concentrations [42]. NO and O2− exert more damaging effects when they react to form ONOO− [13].
The initiation and progression of Alzheimer disease (AD) is a complex process not yet fully understood. While many hypotheses have been provided as to the cause of the disease, the exact mechanisms remain elusive and difficult to verify. Proteomic applications in disease models of AD have provided valuable insights into the molecular basis of this disorder, demonstrating that on a protein level, disease progression impacts numerous cellular processes such as energy production, cellular structure, signal transduction, synaptic function, mitochondrial function, cell cycle progression, and proteasome function. Each of these cellular functions contributes to the overall health of the cell, and the dysregulation of one or more could contribute to the pathology and clinical presentation in AD. In this review, foci reside primarily on the amyloid β-peptide (Aβ) induced oxidative stress hypothesis and the proteomic studies that have been conducted by our laboratory and others that contribute to the overall understanding of this devastating neurodegenerative disease. This article is part of a Special Issue entitled: Misfolded Proteins, Mitochondrial Dysfunction, and Neurodegenerative Diseases.
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Polymorphisms of the Nos3 gene and unexplained late intrauterine fetal death
2005, European Journal of Obstetrics and Gynecology and Reproductive Biology
Genetic polymorphisms associated with vascular diseases have been proposed to be involved in the pathogenesis of late unexplained intrauterine fetal death (IUFD). The Nos3 gene is known to regulate vascular tone via the endothelial nitric oxide synthase/nitric oxide pathway.
In a multicenter case-control study, we evaluated two Nos3 polymorphisms (exon 7 Glu298Asp and a 27 bp-repeat in intron 4) in 92 women with IUFD and 92 healthy control women.
The investigated Nos3 polymorphisms were not associated with the occurrence of IUFD. In the subgroup of pregnancies affected by IUFD, women with at least one mutant allele of the Nos3 intron 4 polymorphism were diagnosed with IUFD at a significantly earlier gestational age (31.8 [standard deviation (S.D.) = 4.9] weeks versus 34.6 [S.D. = 4.8] weeks, p = 0.02) and showed a significantly reduced birth weight (2113 g [S.D. = 1028] versus 1571 g [S.D. = 568], p = 0.03).
We are the first to report on Nos3 polymorphisms and IUFD. While not being associated with the incidence of IUFD overall, the intron 4 Nos3 polymorphism might modulate the timing of IUFD in affected pregnancies.
Inducible nitric oxide synthase (iNOS) in tumor biology: The two sides of the same coin
2005, Seminars in Cancer Biology
Inducible nitric oxide synthase (iNOS) is one of three key enzymes generating nitric oxide (NO) from the amino acid l-arginine. iNOS-derived NO plays an important role in numerous physiological (e.g. blood pressure regulation, wound repair and host defence mechanisms) and pathophysiological (inflammation, infection, neoplastic diseases, liver cirrhosis, diabetes) conditions.
iNOS is the synthase isoform most commonly associated with malignant disease. Nevertheless, the role of iNOS during tumor development is highly complex, and incompletely understood. Both promoting and deterring actions have been described, presumably depending upon the local concentration of iNOS within the tumor microenvironment. In particular, pivotal effects such as malingnant transformation, angiogenesis, and metastasis are modulated by iNOS. On the other hand, NO derived from macrophages has a potentially cytotoxic/cytostatic effect upon tumor cells. Hence, therapeutical interference with iNOS activity is of considerable interest, especially in tumors where metastatic activity, host defence mechanisms and the level of differentiation seem to be correlated to iNOS expression.
This review will aim to summarize the dual actions of iNOS as simultaneous tumor promoter and suppressor.
The basics about nitric oxide
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Although these names are often used, there are objections to this nomenclature as cells often express more than one isoform. The genes for these isoforms are found on different chromosomes the loci of which are known (Xu et al., 1994; Alderton et al., 2001). The genomic structure is similar indicating a common ancestral NOS gene.
Nitric oxide is a gas and a free radical which is now recognised to have very important physiological roles. It is synthesised enzymatically from the amino acid l-arginine in a number of tissues using the three isoforms of nitric oxide synthase, one of which is inducible and can form much large amounts of NO. NO is important in the endothelium-dependent regulation of blood flow and pressure as well as inhibiting the activation of blood platelets. NO is recognised as a neurotransmitter at least in certain types of nerves. Along with other free radicals, NO is also important in the primary defence mechanisms against attack by micro-organisms. NO has a close interaction with iron-containing proteins and binds to haem. By this process NO activates a haem-containing enzyme called soluble guanylyl cyclase which is activated a thousand fold to produce the signalling molecule cyclic GMP. This has many effects at the molecular level to set in train the pathways which propagate the diverse physiological actions of NO.
Although this pathway through cyclic GMP is important, this is by no means the only mechanism by which NO influences the activities of the cell. These alternative pathways depend on modification of the structure of enzymes and structural proteins in several different ways. Most of these modifications result from the actions of NO with other free radicals such as oxygen and superoxide anions to produce reactive oxidants. The oxidants modify the proteins by, among others, nitrosation and nitration of proteins of thiol groups and aromatic amino acids respectively. These changes introduce potential new subtleties to the effects on NO on cellular function which are only now being explored. Protein modifications by NO are even more evident in many inflammatory disorders and may account, at least to some extent, to the pathology seen in these conditions.

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Short CommunicationMapping of the Genes Encoding Human Inducible and Endothelial Nitric Oxide Synthase (NOS2 and NOS3) to the Pericentric Region of Chromosome 17 and to Chromosome 7, Respectively

Abstract

Short Communication
Mapping of the Genes Encoding Human Inducible and Endothelial Nitric Oxide Synthase (NOS2 and NOS3) to the Pericentric Region of Chromosome 17 and to Chromosome 7, Respectively