Regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper transcription factors

Sarraj, Jude Al; Vinson, Charles; Han, Jiahuai; Thiel, Gerald

doi:10.1002/jcb.20580

Cited by 29 publications

(25 citation statements)

References 46 publications

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“…Both the CRE and the CCAAT-box are required for maximum basal and cAMP-dependent transcription (27,28). Whereas the CRE sequence binds members of the basic leucine zipper family of transcription factors, including CREB, activating transcription factor-2 (ATF-2), c-Jun, and CAAT enhancer-binding protein ␤ (C/EBP␤), the CCAATbox binds the obligate heterotrimeric protein nuclear factor Y (NF-Y) (1,23,27,28). In our study, mutating the CRE site in the Ϫ146 promoter led to a loss in response to NO.…”

Section: Discussionmentioning

confidence: 99%

GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP

Kumar¹,

Sun²,

Sharma³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Our previous studies have demonstrated that nitric oxide (NO) leads to nitric oxide synthase (NOS) uncoupling and an increase in NOS-derived superoxide. However, the cause of this uncoupling has not been adequately resolved. The pteridine cofactor tetrahydrobiopterin (BH(4)) is a critical determinant of endothelial NOS (eNOS) activity and coupling, and GTP cyclohydrolase I (GCH1) is the rate-limiting enzyme in its generation. Thus the initial purpose of this study was to determine whether decreases in BH(4) could underlie, at least in part, the NO-mediated uncoupling of eNOS we have observed both in vitro and in vivo. Initially we evaluated the effect of inhaled NO levels on GCH1 expression and BH(4) levels in the intact lamb. Contrary to our hypothesis, we found that there was a significant increase in both plasma BH4 levels and peripheral lung GCH1 protein levels. Furthermore, in vitro, we found that exposure to the NO donor spermine NONOate (SPNONO) led to an increase in GCH1 protein and BH(4) levels in both COS-7 and pulmonary arterial endothelial cells. However, SPNONO treatment also caused a significant increase in phospho-cAMP response element binding protein (CREB) levels, as detected by Western blot analysis, and significantly increased cAMP levels, as detected by enzyme immunoassay. Furthermore, utilizing GCH1 promoter fragments fused to a luciferase reporter gene, we found that GCH1 promoter activity was enhanced by SPNONO in a CREB-dependent manner, and electromobility shift assays revealed an NO-dependent increase in the nuclear binding of CREB. These data suggest that NO increases BH(4) levels through a cAMP/CREB-mediated increase in GCH1 transcription and that the eNOS uncoupling associated with exogenous NO does not involved reduced BH(4) levels.

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Section: Discussionmentioning

confidence: 99%

GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP

Kumar¹,

Sun²,

Sharma³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Both cyclic adenosine monophosphatedependent protein kinase and stress-activated protein kinases are able to activate GTP cyclohydrolase gene transcription in normal conditions. 37 By contrast, glucocorticoids decrease GTPCH gene transcription, 38,39 and transforming growth factor beta (TGF-␤) has been shown to counterbalance the cytokine activation of nitric oxide synthase in endothelial cells by down-regulating GTPCH mRNA expression. [40][41][42] Because increased levels of TGF-␤ are present in cirrhosis, speculating that TGF-␤ could play a role in the decreased GTPCH expression found in cirrhosis is tempting.…”

Section: Discussionmentioning

confidence: 99%

The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis

et al. 2006

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In cirrhosis, intrahepatic endothelial dysfunction is one of the mechanisms involved in the increased resistance to portal blood flow and therefore in the development of portal hypertension. Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH 4 ) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis. Basal levels of tetrahydrobiopterin and guanosine triphosphate (GTP)-cyclohydrolase (BH 4 rate-limiting enzyme) expression and activity were determined in liver homogenates of control and rats with CCl 4 cirrhosis. Thereafter, rats were treated with tetrahydrobiopterin, and eNOS activity, NO bioavailability, assessed with a functional assay, and the vasodilator response to acetylcholine (endothelial function) were evaluated. Livers with cirrhosis showed reduced BH 4 levels and decreased GTPcyclohydrolase activity and expression, which were associated with impaired vasorelaxation to acetylcholine. Tetrahydrobiopterin supplementation increased BH 4 hepatic levels and eNOS activity and significantly improved the vasodilator response to acetylcholine in rats with cirrhosis. In conclusion, the impaired response to acetylcholine of livers with cirrhosis is modulated by a reduced availability of the eNOS cofactor, tetrahydrobiopterin. Tetrahydrobiopterin supplementation improved the endothelial dysfunction of cirrhotic livers. (HEPATOLOGY 2006;44:44-52.)

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“…To examine this putative interaction, Al Sarraj et al [45] used constitutively active and dominant-negative bZIP transcription factor mutants and measured transcriptional activation of a GCH1 promoter/luciferase reporter gene. Signalling pathways involving either PKA (cAMP-dependent protein kinase) or SAPKs (stress-activated protein kinases) converged to the GCH1 gene, indicating that enzymatic reactions requiring BH4 as a cofactor are indirectly controlled by signalling cascades involving the transcription factors CREB (CRE-binding protein), c-Jun and ATF2 (activating transcription factor 2) [45]. Insulin may also up-regulate GTPCH expression in endothelial cells via a PI3K (phosphoinositide 3-kinase)-dependent pathway [46].…”

Section: Synthetic Pathwaysmentioning

confidence: 99%

Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease

2007

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NO produced by eNOS (endothelial nitric oxide synthase) is a key mediator of vascular homoeostasis. NO bioavailability is reduced early in vascular disease states, such as hypercholesterolaemia, diabetes and hypertension, and throughout the progression of atherosclerosis. This is a result of both reduced NO synthesis and increased NO consumption by reactive oxygen species. eNOS enzymatic activity appears to be determined by the availability of its cofactor BH4 (tetrahydrobiopterin). When BH4 levels are adequate, eNOS produces NO; when BH4 levels are limiting, eNOS becomes enzymatically uncoupled and generates superoxide, contributing to vascular oxidative stress and endothelial dysfunction. BH4 bioavailability is determined by a balance of enzymatic de novo synthesis and recycling, versus oxidative degradation in dysfunctional endothelium. Augmenting vascular BH4 levels by pharmacological supplementation, by enhancing the rate of de novo biosynthesis or by measures to reduce BH4 oxidation have been shown in experimental studies to enhance NO bioavailability. Thus BH4 represents a potential therapeutic target for preserving eNOS function in vascular disease.

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Regulation of GTP cyclohydrolase I gene transcription by basic region leucine zipper transcription factors

Cited by 29 publications

References 46 publications

GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP

GTP cyclohydrolase I expression is regulated by nitric oxide: role of cyclic AMP

The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis

Mechanisms for the role of tetrahydrobiopterin in endothelial function and vascular disease

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