Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) enhances prolactin-stimulated DNA synthesis and inhibits prolactin-induced differentiation in mouse mammary epithelium. The molecular pathways used by NO were determined by employing specific inhibitors of the transducers utilized by NO. Inhibitors of the Jun N-terminal kinase (JNK) blocked the effect of NO on DNA synthesis, although this appeared to involve a protein kinase G (PKG)-independent pathway. In contrast, inhibitors of the extracellular signal-regulated kinase (ERK) prevented NO from suppressing alpha-lactalbumin accumulation and this effect was PKG-dependent. NO can also elevate cAMP through the inhibition of phosphodiesterase 3 and cAMP mimicks the actions of NO on both DNA synthesis and differentiation. However, suppression of cAMP levels did not prevent the effects of NO. Therefore, NO uses two separate pathways to affect mammary epithelium: it stimulates growth via JNK and inhibits differentiation through ERK.
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PMID:The mechanisms by which nitric oxide affects mammary epithelial growth and differentiation. 1271 33

Inhibitors of regeneration in myelin, such as myelin-associated glycoprotein (MAG), play an important role in preventing regeneration after CNS injury. Elevation of cAMP, either with dibutyryl-cAMP (db-cAMP) or by priming with a variety of neurotrophins, overcomes inhibition by MAG and myelin. However, activation of cAMP is not generally regarded as a signaling pathway for neurotrophins. Here we show that the NGF-like neurotrophins overcome inhibition by MAG by activating tyrosine kinase receptors. We also show that activation of extracellular signal-regulated kinase (Erk) by BDNF is required to overcome inhibition by MAG, and that activated Erk transiently inhibits phosphodiesterase 4 (PDE4), the enzyme that hydrolyzes cAMP. Inhibition of PDE4 then allows cAMP to increase and so initiates the pathway to overcome inhibition. Furthermore, we also show that basal levels of Erk activation and basal cAMP levels contribute to the effects of db-cAMP by pushing the combined levels of cAMP above a threshold required to overcome inhibition. Together, these results not only show how NGF-like neurotrophins can elevate cAMP and overcome inhibition but also point to a novel mechanism of cross talk in neurons from the Erk to the cAMP signaling pathways.
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PMID:Neurotrophins elevate cAMP to reach a threshold required to overcome inhibition by MAG through extracellular signal-regulated kinase-dependent inhibition of phosphodiesterase. 1468 79

In vitro, cAMP elevation alters neuronal responsiveness to diffusible growth factors and overcomes myelin-associated inhibitory molecules. Significant advances have been made recently in understanding the role of increases in cAMP in promoting axonal growth. Importantly, it has now been shown that cAMP elevation can promote axonal regeneration and functional recovery after central nervous system injury. Elevation of cAMP can be achieved via either direct application of cAMP analogs or an inhibitor of the enzyme phosphodiesterase that degrades cAMP in vivo. Current information points to a number of protein kinase A-mediated pathways (mitogen-activated protein kinase/extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/akt pathway activation and Rho inactivation) underlying cAMP elevation-induced neuronal survival and axonal regeneration.
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PMID:Involvement of cAMP in neuronal survival and axonal regeneration. 1563 59

PDE4B and PDE4D provide >90% of PDE4 cAMP phosphodiesterase activity in human embryonic kidney (HEK293B2) cells. Their selective small interference RNA (siRNA)-mediated knockdown potentiates isoprenaline-stimulated protein kinase A (PKA) activation. Whereas endogenous PDE4D co-immunoprecipitates with beta arrestin, endogenous PDE4B does not, even upon PDE4D knockdown. Ectopic overexpression of PDE4B2 confers co-immunoprecipitation with beta arrestin. Knockdown of PDE4D, but not PDE4B, amplifies isoprenaline-stimulated phosphorylation of the beta2-adrenergic receptor (beta2-AR) by PKA and activation of extracellular signal-regulated kinase (ERK) through G(i). Isoform-selective knockdown identifies PDE4D5 as the functionally important species regulating isoprenaline stimulation of both these processes. Ht31-mediated disruption of the tethering of PKA to AKAP scaffold proteins attenuates isoprenaline activation of ERK, even upon PDE4D knockdown. Selective siRNA-mediated knockdown identifies AKAP79, which is constitutively associated with the beta2-AR, rather than isoprenaline-recruited gravin, as being the functionally relevant AKAP in this process. Isoprenaline-stimulated membrane recruitment of PDE4D is ablated upon beta arrestin knockdown. A mutation that compromises interactions with beta arrestin prevents catalytically inactive PDE4D5 from performing a dominant negative role in potentiating isoprenaline-stimulated ERK activation. Beta arrestin-recruited PDE4D5 desensitizes isoprenaline-stimulated PKA phosphorylation of the beta2-AR and the consequential switching of its signaling to ERK. The ability to observe a cellular phenotype upon PDE4D5 knockdown demonstrates that other PDE4 isoforms, expressed at endogenous levels, are unable to afford rescue in HEK293B2 cells.
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PMID:RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. 1603 21

Compartmentation of cAMP signaling been demonstrated to be attributable to the structural association of protein kinase A (PKA) (via association with A-kinase anchoring proteins [AKAPs]) with phosphodiesterase and AKAP-dependent effector molecules. However, other mechanisms contributing to compartmentalization have not been rigorously explored, including the possibility that different isoforms of adenylyl cyclase (AC) may be functionally "compartmentalized" because of differential association with tethering or signaling molecules. To this end, we examined the effect of adenoviral transduction of representative AC isoforms (AC1, AC2, AC5, and AC6) on cellular cAMP production, PKA activation, extracellular signal-regulated kinase (ERK) activation, cell doubling and proliferation, as well as arborization responses (an index of cAMP-mediated cytoskeletal re-organization) in vascular smooth muscle cells. When isoforms were expressed at levels to achieve comparable forskolin-stimulated AC activity, only gene transfer of AC6 significantly enhanced PKA-dependent vasodilator-stimulated phosphoprotein (VASP) phosphorylation and arborization responses. Treatment of control cells, which express AC6 endogenously, as well as vascular smooth overexpressing the AC6 isoform with small interfering RNA directed against AC6, significantly suppressed both isoproterenol-stimulated cAMP accumulation and arborization. Notably, the selective effects of AC6 expression were abrogated in the presence of phosphodiesterase suppression. In contrast, only the expression of AC1 enhanced forskolin-stimulated association of ERK with AC, demonstrated by coimmuno-isolation of ERK with Flag-tagged AC1, but not with Flag-tagged AC6. To determine whether these isoform-selective effects of AC were unique to differentiated and morphologically compartmentalized vascular smooth muscle cells or were a general property of these isoforms, we examined the consequence of expression of these various isoforms in human embryonic kidney (HEK) cells. Indeed, we observed similar isoform-dependent association of AC1 with ERK, activation of ERK by stimulation of AC1 with forskolin, and AC1-dependent lengthening of doubling time, indicating that these properties of AC1 are cell autologous and likely result from AC1-dependent protein-protein interactions. In aggregate, these findings suggest that isoform-selective signaling complexes likely contribute to various functional consequences of cAMP elevation in vascular smooth muscle cells.
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PMID:Adenylyl cyclase isoform-selective regulation of vascular smooth muscle proliferation and cytoskeletal reorganization. 1703 46

Cyclic AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) controlled both the magnitude and the duration of its influence. Recent evidence shows that PDEs also act as coincident detectors linking cyclic-nucleotide- and non-cyclic-nucleotide-based cellular signaling processes and are tethered with great selectively to defined intracellular structures, thereby integrating and spatially restricting their cellular effects in time and space. Although 11 distinct families of PDEs have been defined, and cells invariably express numerous individual PDE enzymes, a large measure of our increased appreciation of the roles of these enzymes in regulating cyclic nucleotide signaling has come from studies on the PDE4 family. Four PDE4 genes encode more than 20 isoforms. Alternative mRNA splicing and the use of different promoters allows cells the possibility of expressing numerous PDE4 enzymes, each with unique amino-terminal-targeting and/or regulatory sequences. Dominant negative and small interfering RNA-mediated knockdown strategies have proven that particular isoforms can uniquely control specific cellular functions. Thus the protein kinase A phosphorylation status of the beta(2) adrenoceptor and, thereby, its ability to switch its signaling to extracellular signal-regulated kinase activation, is uniquely regulated by PDE4D5 in cardiomyocytes. We describe how cardiomyocytes and vascular smooth muscle cells selectively vary both the expression and the catalytic activities of PDE4 isoforms to regulate their various functions and how altered regulation of these processes can influence the development, or resolution, of cardiovascular pathologies, such as heart failure, as well as various vasculopathies.
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PMID:cAMP-Specific phosphodiesterase-4 enzymes in the cardiovascular system: a molecular toolbox for generating compartmentalized cAMP signaling. 1743 Nov 97

Fibrotic alterations are part of the airway re-modelling processes observed in asthma and chronic obstructive pulmonary disease. There is increasing evidence that in addition to acute bronchodilatory effects, classical anti-obstructive drugs such as muscarinic antagonists and beta-adrenoceptor agonists may also modulate long-term re-modelling processes. The present review aims to summarise muscarinic and beta-adrenergic effects on pulmonary fibroblasts. Recent experimental evidence demonstrated muscarinic stimulatory effects on pulmonary fibroblasts, and long-term blockade of these pro-fibrotic effects may contribute to the beneficial effects of muscarinic antagonists, as observed particularly for the long-acting muscarinic antagonist tiotropium. On the other hand, beta-adrenoceptor agonists, via activation of adenylyl cyclase, can also exert various inhibitory effects on pulmonary fibroblasts, and these anti-fibrotic effects are mimicked by other agents that cause an increase in intracellular cyclic adenosine monophosphate (cAMP), such as phosphodiesterase inhibitors or EP2 prostanoid receptor agonists. In addition, the role of the extracellular signal-regulated kinase-mitogen-activated protein kinase pathway, protein kinase A and exchange protein activated by cAMP (Epac) and potential interactions between these cellular signalling pathways are discussed.
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PMID:Pulmonary fibroblasts, an emerging target for anti-obstructive drugs. 1827 Jun 87

Protein kinase A (PKA) is an important mediator of many signal transduction pathways that occur in eukaryotic cells, and it has been implicated as a regulator of stage differentiation in Trypanosoma cruzi. To evaluate the importance of the PKA catalytic subunit of T. cruzi (TcPKAc), a gene encoding a PKA inhibitor (PKI) containing a specific PKA pseudosubstrate, R-R-N-A, was subcloned into a pTREX vector and introduced into epimastigotes by electroporation. Expression of PKI has a lethal effect in this parasite. Similarly, a pharmacological inhibitor, H89, killed epimastigotes at a concentration of 10 muM. To understand the biology of PKA, identification of the particular substrates of this enzyme is essential. Using a yeast two-hybrid system, 38 candidates interacting with TcPKAc were identified. Eighteen of these were hypothetical proteins with unknown functions, while the others had putative or known functions. The entire open reading frames of eight genes presumably important in regulating T. cruzi growth, adaptation, and differentiation, including a type III PI3 kinase (Vps34), a putative PI3 kinase, a putative mitogen-activated extracellular signal-regulated kinase, a cyclic AMP (cAMP)-specific phosphodiesterase (PDEC2), a hexokinase, a putative ATPase, a DNA excision repair protein, and an aquaporin were confirmed to interact with TcPKAc in the yeast Saccharomyces cerevisiae under the highest stringency selection conditions, and PKA phosphorylated the recombinant proteins of these genes. Taken together, these findings demonstrate the importance of cAMP-PKA signaling in this organism.
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PMID:Role of protein kinase A in Trypanosoma cruzi. 1869 66

The mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway is important for both long-term survival and timing of the progression of oligodendrocyte differentiation. Oligodendroglial cells treated with MEK inhibitor were distinguished by using stage specific markers: NG2 proteoglycan, A2B5, 2'3'nucleotide-cyclic 3'phosphodiesterase (CNPase) and myelin basic protein (MBP), and classified according to their morphology into different developmental stages. Treatment significantly increased the number of cells with more immature morphologies and decreased the number of mature cells. Furthermore, it increased the number of rounded cells that could not be classified into any of the oligodendroglial developmental stages. The strongest effects were usually observed shortly after treatment. Rounded cells were CNPase/MBP positive and they were not stained by anti-NG2 or A2B5, indicating that they were mature cells unable either to extend and/or to maintain their processes. These data showed an effect of the MAPK/ERK pathway on oligodendroglial branching, with possible consequences for the formation of the myelin sheath.
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PMID:A role for the MAPK/ERK pathway in oligodendroglial differentiation in vitro: stage specific effects on cell branching. 1972 58

Epithelial-mesenchymal transition (EMT) has emerged as a critical event in the pathogenesis of organ fibrosis and cancer and is typically induced by the multifunctional cytokine transforming growth factor (TGF)-beta1. The present study was undertaken to evaluate the potential role of phosphodiesterases (PDEs) in TGF-beta1-induced EMT in the human alveolar epithelial type II cell line A549. Stimulation of A549 with TGF-beta1 induced EMT by morphological alterations and by expression changes of the epithelial phenotype markers E-cadherin, cytokeratin-18, zona occludens-1, and the mesenchymal phenotype markers, collagen I, fibronectin, and alpha-smooth muscle actin. Interestingly, TGF-beta1 stimulation caused twofold increase in total cAMP-PDE activity, contributed mostly by PDE4. Furthermore, mRNA and protein expression demonstrated up-regulation of PDE4A and PDE4D isoforms in TGF-beta1-stimulated cells. Most importantly, treatment of TGF-beta1 stimulated epithelial cells with the PDE4-selective inhibitor rolipram or PDE4 small interfering RNA potently inhibited EMT changes in a Smad-independent manner by decreasing reactive oxygen species, p38, and extracellular signal-regulated kinase phosphorylation. In contrast, the ectopic overexpression of PDE4A and/or PDE4D resulted in a significant loss of epithelial marker E-cadherin but did not result in changes of mesenchymal markers. In addition, Rho kinase signaling activated by TGF-beta1 during EMT demonstrated to be a positive regulator of PDE4. Collectively, the findings presented herein suggest that TGF-beta1 mediated up-regulation of PDE4 promotes EMT in alveolar epithelial cells. Thus, targeting PDE4 isoforms may be a novel approach to attenuate EMT-associated lung diseases such as pulmonary fibrosis and lung cancer.
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PMID:Expression and activity of phosphodiesterase isoforms during epithelial mesenchymal transition: the role of phosphodiesterase 4. 1975 79


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