The untranslated region of exon 2 of the human neuronal nitric oxide synthase (NOS1) gene exerts regulatory activity

Bros, Matthias; Boissel, J. P.; Gödtel-Armbrust, Ute; Förstermann, Ulrich

doi:10.1016/j.gene.2007.08.018

Cited by 10 publications

(11 citation statements)

References 52 publications

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“…In addition to the broadly expressed 12 different first exon nNOS mRNA forms, Wang and colleagues (54,55) showed expression of testisspecific nNOS variants in vitro and in vivo. Recently, it was also demonstrated that the 5Ј-untranslated region of human nNOS exon 2 and its 5Ј-flanking sequence exerts promoter activity (13,57). However, in TGW-nu-I cells, we were not able to detect nNOS exon 2 mRNA variants and observed only a ϳ2-fold induction of the Ϫ10110/exon2nNOS-Luc reporter gene construct due to RA treatment.…”

Section: Discussioncontrasting

confidence: 57%

“…2A, RA stimulation does not alter nNOS mRNA degradation in actinomycin D-treated cells compared with controls. To examine RA-induced transactivation of the different nNOS promoters, we used luciferase reporter gene plasmids containing the investigated first nNOS exons and their promoter regions as well as exon 2 and its recently characterized 5Ј-regulatory region (13,57). In contrast to the strong induction of nNOS mRNA expression, nNOS luciferase reporter gene expression was only marginally upregulated by RA using various different nNOS promoter constructs (Fig.…”

Section: Ra Induces Nnos Transcription In Tgw-nu-i Cellsmentioning

confidence: 99%

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Retinoic acid-induced nNOS expression depends on a novel PI3K/Akt/DAX1 pathway in human TGW-nu-I neuroblastoma cells

Nagl¹,

Schönhofer²,

Seidler³

et al. 2009

American Journal of Physiology-Cell Physiology

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Neuronal nitric oxide synthase (nNOS)-derived nitric oxide (NO) acts as a neurotransmitter and intracellular signaling molecule in the central and peripheral nervous system. NO regulates multiple processes like neuronal development, plasticity, and differentiation and is a mediator of neurotoxicity. The nNOS gene is highly complex with 12 alternative first exons, exon 1a-1l, transcribed from distinct promoters, leading to nNOS variants with different 5'-untranslated regions. Transcriptional control of the nNOS gene is not understood in detail. To investigate regulation of nNOS gene expression by retinoic acid (RA), we used the human neuroblastoma cell line TGW-nu-I as a model system. We show that RA induces nNOS transcription in a protein synthesis-dependent fashion. We identify the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and the atypical orphan nuclear receptor DAX1 (NR0B1) as critical mediators involved in RA-induced nNOS gene transcription. RA treatment increases DAX1 expression via PI3K/Akt signaling. Upregulation of DAX1 expression in turn induces nNOS transcription in response to RA. These results identify nNOS as a target gene of a novel RA/PI3K/Akt/DAX1-dependent pathway in human neuroblastoma cells and stress the functional importance of the transcriptional regulator DAX1 for nNOS gene expression in response to RA treatment.

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Section: Discussioncontrasting

confidence: 57%

Section: Ra Induces Nnos Transcription In Tgw-nu-i Cellsmentioning

confidence: 99%

Retinoic acid-induced nNOS expression depends on a novel PI3K/Akt/DAX1 pathway in human TGW-nu-I neuroblastoma cells

Nagl¹,

Schönhofer²,

Seidler³

et al. 2009

American Journal of Physiology-Cell Physiology

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“…This regulation includes regulatory sites in intron 1 and inhibitory elements within exon 2 (Jaffrey and Snyder, 1996) that are located firmly within the region of interest identified by this study (Figure 1 insert), suggesting that the observed inversion of effect could be because of a disruption in the regulation of the gene. Exon 2 also contains an N-terminal PDZ domain, which allows NOS1 isoforms containing exon 2 to bind to the plasma membrane and a number of different proteins (Bros et al, 2007). This includes the NMDA receptor, where it acts as a second messenger for the NMDA pathway (Weber et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Nitric Oxide Synthase (NOS1) Polymorphisms Interact with Financial Hardship to Affect Depression Risk

Sarginson

Deakin

Anderson

et al. 2014

Neuropsychopharmacol

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There is increasing evidence that genetic factors have a role in differential susceptibility to depression in response to severe or chronic adversity. Studies in animals suggest that nitric oxide (NO) signalling has a key role in depression-like behavioural responses to stress. This study investigated whether genetic variation in the brain-expressed nitric oxide synthase gene NOS1 modifies the relationship between psychosocial stress and current depression score. We recruited a population sample of 1222 individuals who provided DNA and questionnaire data on symptoms and stress. Scores on the List of Life-Threatening Experiences (LTE) questionnaire for the last year and self-rated current financial hardship were used as measures of recent/ongoing psychosocial stress. Twenty SNPs were genotyped. Significant associations between eight NOS1 SNPs, comprising two regional haplotypes, and current depression score were identified that survived correction for multiple testing when current financial hardship was used as the interaction term. A smaller three-SNP haplotypes (rs10507279, rs1004356 and rs3782218) located in a regulatory region of NOS1 showed one of the strongest effects, with the A-C-T haplotype associating with higher depression scores at low adversity levels but lower depression scores at higher adversity levels (p ¼ 2.3E-05). These results suggest that NOS1 SNPs interact with exposure to economic and psychosocial stressors to alter individual's susceptibility to depression.

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“…Exon 2 UTR itself constitutes a promoter, which enables self-expression, while the exon 2 upstream flanking genomic region displays inhibitory activity in a cell type-specific manner [36] . Mutational analysis has revealed that promoter activity of the human exon 2 UTR relies largely on 2 conserved cAMP response element-binding protein (CREB)/activator protein 1 (AP-1)-binding sites which mask activity of other cis-acting elements located within the first 345 bp of the exon 2 UTR.…”

Section: Regulation Of Nnos Expressionmentioning

confidence: 99%

“…Expression of the human nNOS gene can be stimulated by various cAMP-activating agents due to increased transcription of either exon 1f or exon 1g [6,39] . by db-cAMP is protein kinase A (PKA)-dependent [36] . In cortical neurons, nNOS exon 2 contains the regulatory sequences that respond to Ca 2+ .…”

Section: Regulation Of Nnos Expressionmentioning

confidence: 99%

Research progress on neurobiology of neuronal nitric oxide synthase

Luo

Zhu

2011

Neurosci. Bull.

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Neuronal nitric oxide synthase (nNOS) is mainly expressed in neurons, to some extent in astrocytes and neuronal stem cells. The alternative splicing of nNOS mRNA generates 5 isoforms of nNOS, including nNOS-α, nNOS-β, nNOS-µ, nNOS-γ and nNOS-2. Monomer of nNOS is inactive, and dimer is the active form. Dimerization requires tetrahydrobiopterin (BH4), heme and L-arginine binding. Regulation of nNOS expression relies largely on cAMP response element-binding protein (CREB) activity, and nNOS activity is regulated by heat shock protein 90 (HSP90)/HSP70, calmodulin (CaM), phosphorylation and dephosphorylation at Ser847 and Ser1412, and the protein inhibitor of nNOS (PIN). There are primarily 9 nNOS-interacting proteins, including post-synaptic density protein 95 (PSD95), clathrin assembly lymphoid leukemia (CALM), calcium/calmodulin-dependent protein kinase II alpha (CAMKIIA), Disks large homolog 4 (DLG4), DLG2, 6-phosphofructokinase, muscle type (PFK-M), carboxy-terminal PDZ ligand of nNOS (CAPON) protein, syntrophin and dynein light chain (LC). Among them, PSD95, CAPON and PFK-M are important nNOS adapter proteins in neurons. The interaction of PSD95 with nNOS controls synapse formation and is implicated in N-methyl-D-aspartic acid-induced neuronal death. nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states, and negatively regulates neurogenesis under physiological and pathological conditions.

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The untranslated region of exon 2 of the human neuronal nitric oxide synthase (NOS1) gene exerts regulatory activity

Cited by 10 publications

References 52 publications

Retinoic acid-induced nNOS expression depends on a novel PI3K/Akt/DAX1 pathway in human TGW-nu-I neuroblastoma cells

Retinoic acid-induced nNOS expression depends on a novel PI3K/Akt/DAX1 pathway in human TGW-nu-I neuroblastoma cells

Neuronal Nitric Oxide Synthase (NOS1) Polymorphisms Interact with Financial Hardship to Affect Depression Risk

Research progress on neurobiology of neuronal nitric oxide synthase

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