Identification and Characterization of Basal and Cyclic AMP Response Elements in the Promoter of the Rat GTP Cyclohydrolase I Gene

Kapatos, Gregory; Stegenga, Susan L.; Hirayama, Kei

doi:10.1074/jbc.275.8.5947

Cited by 56 publications

(99 citation statements)

References 56 publications

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“…This intermediate is then converted to BH 4 in two subsequent reactions catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase, respectively, neither of which are rate-limiting. The signal transduction pathways that regulate induction of GTPCH are not well understood, although transcription factors such as NF-␤ and AP-1 are required for GTPCH mRNA expression (10) and recently, 5.8 kb of the rat GTPCH promoter have been cloned and found to contain a number of potential cytokine responsive elements (11). Although it is well established that iNOS induction is dependent on the redox-sensitive transcription factor NF-B, we previously showed that NF-␤ was not required for induction of GTPCH in rat C6 glioma cells, a convenient astrocyte model, when stimulated with combinations of proinflammatory cytokines (12).…”

Section: (R)-5678-tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

Involvement of Sphingosine Kinase in TNF-α-stimulated Tetrahydrobiopterin Biosynthesis in C6 Glioma Cells

Vann

Payne

Edsall

et al. 2002

Journal of Biological Chemistry

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In C6 glioma cells, the sphingolipid second messenger ceramide potentiates expression of inducible nitric-oxide synthase (iNOS) induced by tumor necrosis factor ␣ (TNF-␣) without affecting GTP cyclohydrolase I (GT-PCH), the rate-limiting enzyme in the biosynthesis of 6(R)-5,6,7,8-tetrahydrobiopterin (BH 4 ), a cofactor required for iNOS activity. TNF-␣ also stimulates sphingosine kinase, the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (SPP), a further metabolite of ceramide. Several clones of C6 cells, expressing widely varying levels of sphingosine kinase, were used to examine the role of SPP in regulation of GTPCH and BH 4 biosynthesis. Overexpression of sphingosine kinase, with concomitant increased endogenous SPP levels, potentiated the effect of TNF-␣ on GTPCH expression and activity and BH 4 biosynthesis. In contrast, enforced expression of sphingosine kinase had no effect on iNOS expression or NO formation. Furthermore, N,N-dimethylsphingosine, a potent sphingosine kinase inhibitor, completely eliminated the increased GTPCH activity and expression induced by TNF-␣. Surprisingly, we found that, although C6 cells can secrete SPP, which is enhanced by TNF-␣, treatment of C6 cells with exogenous SPP or dihydro-SPP had no affect on BH 4 biosynthesis. However, both SPP and dihydro-SPP markedly stimulated ERK 1/2 in C6 cells, which express cell surface SPP receptors. Interestingly, although this ERK activation was blocked by PD98059, which also reduced cellular proliferation induced by enforced expression of sphingosine kinase, PD98059 had no effect on GTPCH activity. Collectively, these results suggest that only intracellularly generated SPP plays a role in regulation of GTPCH and BH 4 levels. 5,6,7, 1 is the obligate cofactor for the aromatic L-amino hydroxylases and is also required for activity of all nitric-oxide synthase isoforms (reviewed in Ref. 1). It has been proposed that BH 4 may also have cofactorindependent roles (2), including inhibition of cytokine-induced apoptosis (3) and stimulation of dopamine release (4). Cellular levels of BH 4 are regulated by the activity of GTP cyclohydrolase I (GTPCH), the first and rate-limiting enzyme in the BH 4 biosynthetic pathway (5). Its expression is increased by proinflammatory cytokines, such as IFN-␥ and TNF-␣, and is coordinately regulated with cytokine-inducible nitric-oxide synthase (iNOS) (6). BH 4 binds to NOS monomers, promoting their dimerization and subsequent activation (7), and recent crystallographic analysis suggests that it may play a direct role in the NOS reaction in a radical form (8). 6(R)-GTPCH, a homodecamer of 30-kDa subunits arranged as two pentamers facing one another (9), catalyzes the rearrangement of GTP to dihydroneopterin triphosphate. This intermediate is then converted to BH 4 in two subsequent reactions catalyzed by 6-pyruvoyltetrahydropterin synthase and sepiapterin reductase, respectively, neither of which are rate-limiting. The signal transduction pathways that regulate induction of GTPCH are not wel...

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Section: (R)-5678-tetrahydrobiopterin (Bh 4 )mentioning

confidence: 99%

Involvement of Sphingosine Kinase in TNF-α-stimulated Tetrahydrobiopterin Biosynthesis in C6 Glioma Cells

Vann

Payne

Edsall

et al. 2002

Journal of Biological Chemistry

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“…In our previous study, we showed increased promoter activity of the GCH gene in the V-1 clones (52) as we did for that of the TH gene in this report. Recently, ϳ150 bp of the 5Ј-promoter region of the GCH gene was identified as the region contributing to basal and cyclic AMP-induced transcriptional activity and containing a non-canonical CRE (28,53), and we showed that this region was sufficient for the increased activity of the GCH promoter in the V-1 clones (52). Hirayama et al (53) reported that the proximal promoter region could recruit ATF-2.…”

Section: Discussionmentioning

confidence: 99%

Identification of ATF-2 as a Transcriptional Regulator for the Tyrosine Hydroxylase Gene

Suzuki

Yamakuni

Hagiwara

et al. 2002

Journal of Biological Chemistry

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Transcriptional regulation of catecholamine-synthesizing genes is important for the determination of neurotransmitters during brain development. We found that three catecholamine-synthesizing genes were transcriptionally up-regulated in cloned PC12D cells overexpressing V-1, a protein that is highly expressed during postnatal brain development (1). To reveal the molecular mechanism to regulate the expression of tyrosine hydroxylase (TH), which is the rate-limiting enzyme for catecholamine biosynthesis, we analyzed the transcription factors responsible for TH induction in the V-1 clonal cells. First, by using reporter constructs, we found that the transcription mediated by cAMP-responsive element (CRE) was selectively enhanced in the V-1 cells, and TH promoter activity was totally dependent on the CRE in the promoter region of the TH gene. Next, immunoblot analyses and a transactivation assay using a GAL4 reporter system revealed that ATF-2, but not cAMP-responsive element-binding protein (CREB), was highly phosphorylated and activated in the V-1 cells, while both CREB and ATF-2 were bound to the TH-CRE. Finally, the enhanced TH promoter activity was competitively attenuated by expression of a plasmid containing the ATF-2 transactivation domain. These data demonstrated that activation of ATF-2 resulted in the increased transcription of the TH gene and suggest that ATF-2 may be deeply involved in the transcriptional regulation of catecholamine-synthesizing genes during neural development.Catecholamines are synthesized from L-tyrosine by the sequential action of four enzymes: tyrosine is converted to DOPA by tyrosine hydroxylase (TH), 1 DOPA to dopamine by aromatic L-amino acid decarboxylase (AADC), dopamine to norepinephrine by dopamine ␤-hydroxylase (DBH), and norepinephrine to epinephrine by phenylethanolamine N-methyltransferase. The regulation of the gene expression of these enzymes is important for the determination of the expression of neurotransmitters during brain development as well as for brain function under physiological and pathological conditions. TH is the rate-limiting enzyme for catecholamine biosynthesis. The transcriptional regulation of the TH gene has been extensively studied, and many transcription factors were suggested to regulate TH gene expression. CREB, ATF-1, and CREM were shown to recognize the cAMP-responsive element (CRE) located at position Ϫ45/Ϫ38 in the TH promoter (2-6). CREB was reported to mediate basal and cAMP-induced TH transcription in various cultured cells including PC12 cells by the use of dominant-negative CREB protein and antisense RNA against CREB (7-10). CREB is activated by phosphorylation on Ser 133 (11,12). The activation of CREB by phosphorylation has been shown to mediate PKA-dependent (7, 13-15) and -independent (13, 14) induction of TH transcription. Functional and physiological roles of ATF-1 and CREM for TH transcription remained unclear. AP-1 transcription factors bound to the TPA-responsive element located at Ϫ205/Ϫ199 in the TH promoter, which also plays ...

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“…A labeled probe (50,000 cpm) was then used in EMSA as previously described (19). Briefly, the probe was incubated with or without 1 to 10 g whole cell extracts at 4°C for 20 min in a reaction mixture that contained 12.5 mM HEPES, pH 7.9, 100 mM KCl, 1 mM EDTA, 1 mM DTT, 1 g poly dI-dC, and 10% glycerol.…”

Section: Methodsmentioning

confidence: 99%

AVP-induced VIT32 gene expression in collecting duct cells occurs via trans-activation of a CRE in the 5′-flanking region of the VIT32 gene

Thomas

Loftus

Liu

2004

American Journal of Physiology-Renal Physiology

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. AVP-induced VIT32 gene expression in collecting duct cells occurs via trans-activation of a CRE in the 5Ј-flanking region of the VIT32 gene. Am J Physiol Renal Physiol 287: F460 -F468, 2004. First published May 12, 2004 10.1152/ajprenal.00107.2004.-VIT32, a vasopressin-induced transcript, inhibits Na ϩ transport when coexpressed with the epithelial sodium channel in Xenopus laevis oocytes (EMBO J 21: 5109 -5117, 2002). To understand the mechanism of VIT32 gene regulation, we examined the effect of DDAVP and cAMP stimulation on VIT32 expression in M-1 mouse collecting duct cells and in H441 human airway epithelial cells. Elevation of cAMP with forskolin and IBMX increased VIT32 gene expression with a peak effect at 2 h. The increase in gene expression was abolished by H89 and by actinomycin D, suggesting that cAMP stimulates VIT32 mRNA expression by a PKA-mediated increase in gene transcription. An ϳ1.5-kb fragment of the 5Ј-flanking region of VIT32 was cloned and was able to confer cAMP-stimulated reporter gene activity when transfected into M-1 and H441 cells. By deletion analysis and sitedirected mutagenesis, a cAMP response element (CRE) was identified within the proximal promoter region that was sufficient to account for the increase in VIT32 gene expression seen with DDAVP and elevation of cAMP. Furthermore, DDAVP-stimulated VIT32 promoterreporter activity was inhibited by H89 and by a dominant negative CREB construct. Finally, we were able to identify CREB as a nuclear protein that bound to the VIT32 CRE in gel mobility shift assays. In summary, DDAVP stimulates transcription of VIT32 via a CRE within the proximal promoter region of the VIT32 gene.PP5395; epithelial sodium channel; sodium transport; airway epithelia; adenosine 3Ј,5Ј-cyclic monophosphate response element binding protein IN THE COLLECTING duct, AVP binds the V2 receptor and regulates water homeostasis by activation of the water channel, aquaporin-2 (34). AVP also regulates Na ϩ handling in the distal nephron by its effects on Na ϩ transporters (30). The principal effect is a stimulation of benzamil-sensitive Na ϩ transport, which has been noted in the toad bladder, in the isolated rat cortical collecting duct, in primary cultures of collecting duct cells, and in many distal nephron cell lines. The early effects of AVP may be mediated by cAMP and result in an increase in surface expression of the epithelial Na ϩ channel (ENaC) (24,31,35). Others have reported an increase in Na ϩ -K ϩ -ATPase activity in microdissected mouse and rat collecting ducts and in a mouse collecting duct cell line, mpkCCD14 (6,8,13). In A6 cells, an amphibian cell line used as a model of collecting duct epithelia, the early effects of AVP effect on Na ϩ transport appear to require phosphatidylinositol-3 kinase and be mediated by the regulatory kinase sgk1 (2,11,12).Although the earliest effects of AVP on Na ϩ transport are independent of transcription, chronic effects are likely to require the transcription of target genes (18). DDAVP, a selective V2 receptor agoni...

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Identification and Characterization of Basal and Cyclic AMP Response Elements in the Promoter of the Rat GTP Cyclohydrolase I Gene

Cited by 56 publications

References 56 publications

Involvement of Sphingosine Kinase in TNF-α-stimulated Tetrahydrobiopterin Biosynthesis in C6 Glioma Cells

Involvement of Sphingosine Kinase in TNF-α-stimulated Tetrahydrobiopterin Biosynthesis in C6 Glioma Cells

Identification of ATF-2 as a Transcriptional Regulator for the Tyrosine Hydroxylase Gene

AVP-induced VIT32 gene expression in collecting duct cells occurs via trans-activation of a CRE in the 5′-flanking region of the VIT32 gene

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