Tissue-specific Regulation of the Ecto-5′-nucleotidase Promoter

Spychała, Józef; Zimmermann, Albert; Mitchell, Beverly S.

doi:10.1074/jbc.274.32.22705

Cited by 53 publications

(16 citation statements)

References 51 publications

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“…This hypothesis is supported by studies in mammalian cells, in which mutation of these two nucleotides in the ATF cis-acting element abrogates the activation of the ecto-5Ј-nucleotidase promoter by phorbol 12-myristate 13-acetate (25). Thus, our findings support other reports that describe the ATF cis-acting site as a phorbol 12-myristate 13-acetate/DAG responsive element (22,23,25).…”

Section: App1 Transcription Is Regulated By Atf and Ap-2 Cis-actingsupporting

confidence: 82%

APP1 Transcription Is Regulated by Inositol-phosphorylceramide Synthase 1-Diacylglycerol Pathway and Is Controlled by ATF2 Transcription Factor in Cryptococcus neoformans

Mare

Iatta

Montagna

et al. 2005

Journal of Biological Chemistry

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Inositol-phosphorylceramide synthase 1 (Ipc1) is a fungal-specific enzyme that regulates the level of two bioactive molecules, phytoceramide and diacylglycerol (DAG). In previous studies, we demonstrated that Ipc1 regulates the expression of the antiphagocytic protein 1 (App1), a novel fungal factor involved in pathogenicity of Cryptococcus neoformans. Here, we investigated the molecular mechanism by which Ipc1 regulates App1. To this end, the APP1 promoter was fused to the firefly luciferase gene in the C. neoformans GAL7:IPC1 strain, in which the Ipc1 expression can be modulated, and found that the luciferase activity was indeed regulated when Ipc1 was modulated. Next, using the luciferase reporter assay in both C. neoformans wild-type and GAL7:IPC1 strains, we investigated the role of DAG and sphingolipids in the activation of the APP1 promoter and found that treatment with 1,2-dioctanoylglycerol does increase APP1 transcription, whereas treatment with phytosphingosine or ceramides does not. Two putative consensus sequences were found in the APP1 promoter for ATF and AP-2 transcription factors. Mutagenesis analysis of these sequences revealed that they play a key role in the regulation of APP1 transcription: ATF is an activator, whereas AP-2 in a negative regulator. Finally, we identified a putative Atf2 transcription factor, which is required for APP1 transcription and under the control of Ipc1-DAG pathway. These studies provide novel regulatory mechanisms of the sphingolipid pathway involved in the regulation of gene transcription of C. neoformans. Inositol-phosphorylceramide synthase 1 (Ipc1)3 is a fungal-specific enzyme of the sphingolipid pathway ( Fig. 1) that regulates the level of phytoceramide and diacylglycerol (DAG), two well established bioactive molecules in mammalian cells, which regulate key cellular functions such as cell growth and viability (1-6). On the other hand, the role of these lipids in signaling in yeast cells is poorly understood.Although the presence of sphingolipid enzymes has been demonstrated in Saccharomyces cerevisiae (7), and in pathogenic fungi, such as Aspergillus fumigatus (8), Candida albicans, and Cryptococcus neoformans (9), studies of sphingolipid-mediated signaling transduction in pathogenic fungi are in their infancy. Studies in S. cerevisiae showed that Ipc1 modulates the level of phytoceramide and DAG (10) but whether these lipids regulate signaling in this microorganism has yet to be elucidated. Whereas in mammalian cells DAG is a well known activator of protein kinase C (PKC), DAG does not activate the fungal homolog Pkc1 in S. cerevisiae (11, 12) or in C. albicans (13). Thus, if DAG regulates signaling in S. cerevisiae or C. albicans this regulation would be exerted through proteins other than Pkc1.On the other hand, C. neoformans Pkc1 contains a putative DAGbinding domain, or C1 domain, which is highly homologous to the C1 domain of DAG-dependent mammalian PKCs (14). In recent studies, we showed that Ipc1 activates Pkc1 in C. neoformans through a DAGdependent m...

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Section: App1 Transcription Is Regulated By Atf and Ap-2 Cis-actingsupporting

confidence: 82%

APP1 Transcription Is Regulated by Inositol-phosphorylceramide Synthase 1-Diacylglycerol Pathway and Is Controlled by ATF2 Transcription Factor in Cryptococcus neoformans

Mare

Iatta

Montagna

et al. 2005

Journal of Biological Chemistry

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“…20) were because of this phenomenon (21). Although eN has broad substrate specificity, AMP is considered to be the major physiological substrate (for review, see (25,26).…”

Section: Properties Detection and Inhibition Of 5-nucleotidasesmentioning

confidence: 99%

“…24). The proximal promoter region of the gene contains a number of tissue-specific elements (25,26).…”

Section: Properties Detection and Inhibition Of 5-nucleotidasesmentioning

confidence: 99%

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Mammalian 5′-Nucleotidases

Bianchi

Spychała

2003

Journal of Biological Chemistry

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192

184

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Nucleoside monophosphate phosphohydrolases or 5Ј-nucleotidases (members of EC 3.1.3.5 and EC 3.1.3.6) dephosphorylate non-cyclic nucleoside monophosphates to nucleosides and inorganic phosphate. Seven human 5Ј-nucleotidases with different subcellular localization have been cloned (Table I). Sequence comparisons show high homology only between cytosolic 5Ј-nucleotidase IA (cN-IA) 1 and B and between cytosolic 5Ј(3Ј)-deoxynucleotidase (cdN) and mitochondrial 5Ј(3Ј)-deoxynucleotidase (mdN). However, the existence of common motifs suggests a common catalytic mechanism for all intracellular 5Ј-nucleotidases. Some 5Ј-nucleotidases are ubiquitous (ecto-5Ј-nucleotidase (eN), cN-II, cdN, and mdN); others display tissue-specific expression (cN-I and cN-III).Here we summarize recent advances on the structure and cellular functions of the cloned 5Ј-nucleotidases. We also propose a revised nomenclature, agreed upon with other colleagues active in the nucleotidase field. Catalytic MechanismCrystal structures are known for human mdN (10) and cdN 2 and for Escherichia coli periplasmic 5Ј-nucleotidase (11), a homologue of eN. All intracellular nucleotidases share a DX-DX(V/T) motif critical for catalysis and show structural similarity to the haloacid dehalogenase superfamily of enzymes (10). eN belongs to a separate family that includes also 2Ј,3Ј-cyclic phosphodiesterases and apyrases (11).The crystal structure of mdN and work on the active site of cN-II form the basis for a reaction mechanism of intracellular 5Ј-nucleotidases (10, 12). The reaction creates a phosphoenzyme intermediate involving the first aspartate in the DX-DX(V/T) motif (12). A detailed scheme of the catalytic process derived from the crystal structure of mdN (10) involved both aspartates in the above motif (Fig. 1). The first (Asp-41) generates a pentacovalent phosphorus intermediate with similar basic organization as the intermediate detected in the structure of ␤-phosphoglucomutase (13). The x-ray structure of cdN suggests a catalytic mechanism identical with that of mdN. Differences within the active sites account for differences in substrate specificity (10).2 Using the structurally important residues the best alignment was between the two deoxynucleotidases and cN-III (10). Two 5Ј-nucleotidases, cN-II and cN-III, exhibit phosphotransferase activity (for reviews see Refs. 14 and 15) possibly because of higher stability of the phosphoenzyme intermediate or faster exchange of the nucleoside product with the nucleoside acceptor. The active site of E. coli 5Ј-nucleotidase, the paradigm for eN, contains two zinc ions and the catalytic dyad . No phosphoenzyme intermediate is formed during catalysis, but a water molecule performs the nucleophilic attack on the phosphate (16). Properties, Detection, and Inhibition of 5-NucleotidasesAll 5Ј-nucleotidases have relatively broad substrate specificities. In agreement with the structural information on the active sites (10, 11), all family members except eN are absolutely dependent on magnesium for activity. Table II s...

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“…The regulation of E5NT by EsRα has been suggested to involve either a genomic mechanism, regulating the expression of this enzyme, or the interaction between EsRα and E5NT, directly or through second messengers. In the first case, transcription factors such as AP-1 and Sp1, which are active at the E5NT gene promoter 10, 56 , are regulated by activation of EsRα 28, 59, 60 . Of note, this interaction has been observed in hippocampal neurons, and associated to differences in neuroplasticity between the sexes 40 .…”

Section: Figmentioning

confidence: 99%

Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor α in the Rat

Ferrari

Araldi

Levine

2017

The Journal of Pain

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Hyperalgesic priming, a sexually dimorphic model of transition to chronic pain, is expressed as prolongation of prostaglandin E2 (PGE2)-induced hyperalgesia by the activation of an additional pathway including an autocrine mechanism at the plasma membrane. The autocrine mechanism involves the transport of cAMP to the extracellular space, and its conversion to AMP and adenosine, by ecto-5′phosphodiesterase and ecto-5′nucleotidase, respectively. The end product, adenosine, activates A1 receptors, producing delayed onset prolongation of PGE2 hyperalgesia. We tested the hypothesis that the previously reported, estrogen-dependent, sexual dimorphism observed in the induction of priming is present in the mechanisms involved in its expression, as a regulatory effect on ecto-5′nucleotidase by estrogen receptor alpha (EsRα), in female rats. In the primed paw AMP hyperalgesia was dependent on conversion to adenosine, being prevented by ecto-5′nucleotidase inhibitor AMPCP and A1 receptor antagonist DPCPX. To investigate an interaction between EsRα and ecto-5′nucleotidase, we treated primed female rats with ODN antisense or mismatch against EsRα mRNA. While in rats treated with antisense AMP-induced hyperalgesia was abolished, the A1 receptor agonist N6-cyclopentiladenosine (CPA) still produced hyperalgesia. Thus, EsRα interacts with this autocrine pathway at the level of ecto-5′nucleotidase. These results demonstrate a sexually dimorphic mechanism for the expression of priming. Perspective This study presents evidence of an estrogen-dependent mechanism of expression of chronic pain in females, supporting the suggestion that differential targets must be considered when establishing protocols for the treatment of painful conditions in males and females.

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Tissue-specific Regulation of the Ecto-5′-nucleotidase Promoter

Cited by 53 publications

References 51 publications

APP1 Transcription Is Regulated by Inositol-phosphorylceramide Synthase 1-Diacylglycerol Pathway and Is Controlled by ATF2 Transcription Factor in Cryptococcus neoformans

APP1 Transcription Is Regulated by Inositol-phosphorylceramide Synthase 1-Diacylglycerol Pathway and Is Controlled by ATF2 Transcription Factor in Cryptococcus neoformans

Mammalian 5′-Nucleotidases

Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor α in the Rat

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