Characterization of the Human Endothelial Nitric-oxide Synthase Promoter

Karantzoulis-Fegaras, Fotula; Antoniou, Hariclia; Lai, Sheue-Lim M.; Kulkarni, Gajanan; D'Abreo, Cheryl; Wong, Garrett B.; Miller, Tricia L.; Chan, Yvonne; Atkins, Judith; Wang, Yan; Marsden, Philip A.

doi:10.1074/jbc.274.5.3076

Cited by 183 publications

(196 citation statements)

References 89 publications

(104 reference statements)

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“…Similar to the human (Karantzoulis-Fegaras et al, 1999) and mouse (Gnanapandithen et al, 1996) NOS3 promoters, the sheep NOS3 promoter isolated herein lacks a TATA-box, but possesses proximal elements such as Sp-1 and GATA motifs that features the NOS3 gene typically as a constitutively expressed gene (Forstermann et al, 1998). This is best exemplified by the fact that NOS3 mRNA and protein expression can be detected in various endothelial cells in vivo and in vitro under non-stimulated or stimulated conditions regardless of the origin of the cells.…”

Section: Disscussionmentioning

confidence: 92%

“…In addition, a potential site for the binding of the NF-1 transcription factor (TGGNNNNNNNCCA), a sterol regulatory element (SRE-1, CACCCCAC), 3 acute-phase response (APR) elements (CTGGGA or TCCCAG), 3 shear stress-responsive element (SSRE, GGTCTC), 26 Ets (GGAA/T or A/ TTCC, not included) were also identified. Five Sp1 binding sites (GGGCGG or CCGCCC) were identified, 4 of which were present in the so-called "positive regulatory domain" (Karantzoulis-Fegaras et al, 1999;Wariishi et al, 1995;Zhang et al, 1995), which also contained a p53 half site (GGGCTAGTTC), a Ets/Elf site, 1 myc-associated zine-finger protein (MAZ, CCCTCCC), 1 Ying Yang (CCATT, YY1), one PAX (GTTCC), and a Ets family transcription factor PEA3 (CCCTTCCT) (Fleming and Busse, 2003;KarantzoulisFegaras et al, 1999). Of note, the AP-1 site was conserved in the NOS3 promoter of all species surveyed (Fig.…”

Section: Cloning and Analysis Of Sheep Nos3 Promoter Sequencementioning

confidence: 99%

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Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

Qian¹,

Mata‐Greenwood²,

Wu³

et al. 2007

Molecular and Cellular Endocrinology

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Despite extensive studies have shown that increased endothelial nitric oxide synthase (NOS3) expression in the uterine artery endothelial cells (UAEC) plays a key role in uterine vasodilatation, the molecular mechanism controlling NOS3 expression in UAEC is unknown. According to the sheep NOS3 promoter sequence isolated in our laboratory, we hypothesize that the activator protein-1 (AP-1) site in the proximal sheep NOS3 promoter (TGAGTCA, -682 to -676) is important for NOS3 expression. We developed a c-Jun adenoviral expression system to overexpress c-Jun protein into UAEC to investigate the effects of c-Jun/AP-1 on NOS3 expression. Basal levels of c-Jun protein and mRNA were detected in UAEC. C-Jun protein was overexpressed in a concentration and timedependent fashion in UAEC infected with sense c-Jun (S-c-Jun), but not sham and antisense c-Jun (A-c-Jun) adenoviruses. Infection with S-c-Jun adenovirus (25 MOI, multiplicity of infection) resulted in efficient c-Jun protein overexpression in UAEC up to 3 days. In S-c-Jun, but not sham and A-c-Jun adenovirus infected UAEC, NOS3 mRNA and protein levels were increased (P<0.05) compared to noninfected controls. Increased NOS3 expression was associated with increased total NOS activity. Transient transfections showed that c-Jun overexpression augmented the transactivation of the sheep NOS3 promoter-driven luciferase/reporter constructs with the AP-1 site but not of deletion constructs without the AP-1 site. When the AP-1 site was mutated, c-Jun failed to trans-activate the sheep NOS3 promoter. AP-1 DNA binding activity also increased in c-Jun overexpressed UAEC. Lastly, the pharmacological AP-1 activator phorbol myristate acetate increased AP-1 binding, trans-activated the wild-type but not the AP-1 mutant NOS3 promoter and dose-dependently stimulated UAEC NOS3 and c-Jun protein expression. Hence, our data show that c-Jun/AP-1 regulates NOS3 transcription involving the proximal AP-1 site in the 5′-regulatory region of the sheep NOS3 gene. Keywordsc-Jun/AP-1; endothelial nitric oxide synthase expression; uterine artery endothelial cells

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Section: Disscussionmentioning

confidence: 92%

Section: Cloning and Analysis Of Sheep Nos3 Promoter Sequencementioning

confidence: 99%

Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

Qian¹,

Mata‐Greenwood²,

Wu³

et al. 2007

Molecular and Cellular Endocrinology

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“…20 Briefly, cells were cultured in 60-mm dishes and transfected at 40 to 60% confluency using the lipofectin reagent and Opti-Mem I (Life Technologies, Inc., Gaithersburg, MD). Each 60-mm dish of cells was cotransfected with 1.0 g of promoter/reporter construct, 0.5 g of pRSV␤gal DNA, and 1.5 g of pBluescript II SK(Ϫ) DNA with a DNA/lipofectin ratio of 2:1 (mass: mass).…”

Section: In Vitro Promoter-reporter Studiesmentioning

confidence: 99%

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

Wang¹,

Newton²,

Miller³

et al. 2002

The American Journal of Pathology

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Neuronal nitric oxide synthase (nNOS) plays a modulatory role in the biology of a variety of neuroendocrine tissues and is especially relevant to gonadal function. We have previously reported the cloning and characterization of a variant of the nNOS protein, termed testis nNOS (TnNOS), the mRNA for which was restricted in expression to male gonadal tissues. To examine the cell-specificity of the testis-specific NOS regulatory regions we defined patterns of ␤-galactosidase expression of an insertional transgene in which the reporter gene lacZ was under the transcriptional control of the human TnNOS promoter. ␤-galactosidase activity was detected exclusively in the interstitial cells of the testis in transgenic mice. These cells also evidenced positive staining for nNOS protein and were identified as androgen-producing Leydig cells by staining with the Leydig cell marker, P 450 scc. Expression of the promoter was absent in cells of the seminiferous tubules, specifically germline cells of different stages and Sertoli cells. In contrast to the male gonad, ␤-galactosidase activity was not detected in ovaries of adult female mice. Activity was also not evident in organs known to express full-length nNOS, such as skeletal muscle, kidney, or cerebellum. The same pattern of ␤-galactosidase staining was observed in independent transgenic founders and was distinct from that observed for an endothelial NOS promoter/reporter transgene. In the testis of male adult eNOS promoter-reporter transgenic mice, ␤-galactosidase activity was expressed only in endothelial cells of large-and medium-sized arterial blood vessels. Transcriptional activity of the Of the three known human nitric oxide synthases (NOS) isoforms, the neuronal nitric oxide synthase (nNOS) has unique properties. The nNOS (NOS1) isoform is expressed from a very complex human genomic locus spanning 240 kb at 12q24.2.

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“…61 It can regulate the expression of numerous genes, such as c-myc, [61][62][63] genes for insulin I and II, 64 the gene for CD4, 65 the gene for the serotonin receptor, 57 and the gene for nitric oxide synthase. 60 The human telomerase promoter, a TATA-less promoter, possesses 2 Sp1 and 3 MAZ sites. 45 We examined the promoter to determine the mechanism by which HBx-1 suppressed it and found that HBx-1 did not affect binding of Sp1 to its consensus sequence (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…[56][57][58][59][60] Both Sp1 and MAZ may play an important role in initiating TATA-less gene transcription. 61 MAZ was initially identified as a transcription factor bound to a GA box (GGGAGGG) at the ME1a1 site of the c-myc promoter and to the CT element of the c-myc gene.…”

Section: Discussionmentioning

confidence: 99%

X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter

Su¹,

Lai

Lan

et al. 2007

Hepatology

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The X protein of hepatitis B virus (HBx) is essential for transactivation of hepatitis B viral and host cellular genes. It has been specifically implicated in the development of hepatocellular carcinoma; however, the molecular mechanism remains unknown. Telomeres, the DNA-protein complexes at the ends of eukaryotic chromosomes, protect chromosomes from degradation at the terminal regions, fusion with a broken DNA end, and inappropriate recombination. The shortening of telomeres that occurs during hepatocellular carcinogenesis has been well studied. In the present study, we isolated an HBx isoform that resulted in telomere shortening in hepatoma cell lines. We found that this HBx isoform down-regulated the expression of human telomerase by transcriptionally repressing its promoter. To further determine the molecular mechanism, we examined human telomerase promoter and identified myc-associated zinc finger protein (MAZ) as a transcriptional repressor of the promoter. We found that the HBx isoform achieved transcriptional suppression of human telomerase by enhancing MAZ binding to its consensus sequence in the promoter through physical association with MAZ. Conclusion: The data suggest that HBx can induce telomere shortening by acting as a transcriptional corepressor of MAZ on the human telomerase promoter. (HEPATOLOGY 2007;46:402-413.)

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Characterization of the Human Endothelial Nitric-oxide Synthase Promoter

Cited by 183 publications

References 89 publications

Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

Transcriptional regulation of endothelial nitric oxide synthase expression in uterine artery endothelial cells by c-Jun/AP-1

An Alternative Promoter of the Human Neuronal Nitric Oxide Synthase Gene Is Expressed Specifically in Leydig Cells

X protein of hepatitis B virus functions as a transcriptional corepressor on the human telomerase promoter

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