The Experts below are selected from a list of 21149322 Experts worldwide ranked by ideXlab platform
Claire Lugnier - One of the best experts on this subject based on the ideXlab platform.
-
cyclic nucleotide phosphodiesterase pde isozymes as targets of the intracellular signalling network benefits of pde inhibitors in various diseases and perspectives for future therapeutic developments
British Journal of Pharmacology, 2012Co-Authors: Thérèse Keravis, Claire LugnierAbstract:Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene-related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies. This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments.
-
Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigenetic integrator UHRF1.
Molecular Nutrition & Food Research, 2011Co-Authors: Abdurazzag Abusnina, Thérèse Keravis, Issaka Yougbaré, Christian Bronner, Claire LugnierAbstract:Scope Curcumin inhibits proliferation of many cancer cells. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) and/or cyclic guanosine-3',5'-monophosphate (cGMP), play a pivotal role in signalling pathways involved in cell proliferation. Therefore, this study investigated PDE1-5 participations in the anti-proliferative properties of curcumin in B16F10 murine melanoma cells. Methods and results We report that curcumin inhibits PDE1-5 activities (IC(50) ≅10(-5) M), indicating that curcumin acts as a non-selective PDE inhibitor. In melanoma cells, PDE4 and PDE1 represent the major cAMP-PDEs and cGMP-PDEs activities, respectively. Curcumin treatment decreased PDE1 and PDE4 activities and dose dependently increased intracellular cGMP levels, whereas cAMP levels were unchanged. Curcumin inhibited cell proliferation and cell cycle progression by accumulating cells in the S- and G2/M-phases with enhanced expressions of cyclin-dependent kinase inhibitors. In contrast, expressions of PDE1A, cyclin A and the epigenetic integrator ubiquitin-like containing PHD and Ring Finger domains 1 (UHRF1) and DNA methyltransferase 1 (DNMT1) were decreased by curcumin. Interestingly, PDE1A overexpression increased UHRF1 and DNMT1 expressions and rescued the B16F10 cells from curcumin anti-proliferative effects. Nimodipine, a PDE1 inhibitor, mimicked the curcumin effects. Conclusion Curcumin exerts its anti-cancer property by targeting PDE1 that inhibits melanoma cell proliferation via UHRF1, DNMT1, cyclin A, p21 and p27 regulations. This suggests that natural PDE1 inhibitors present in food might be effective in preventing cancer.
-
Down-regulation of cyclic nucleotide phosphodiesterase PDE1A is the key event of p73 and UHRF1 deregulation in thymoquinone-induced acute lymphoblastic leukemia cell apoptosis.
Cellular signalling, 2010Co-Authors: Abdurazzag Abusnina, Thérèse Keravis, Christian Bronner, Mahmoud Alhosin, Guy Fuhrmann, Christian D. Muller, Claire LugnierAbstract:Thymoquinone (TQ), the active principle of Nigella sativa black seeds, has anti-proliferative properties on numerous cancer cell types. Others and we have previously reported that TQ acts as agent that triggers cell cycle arrest and apoptosis through either a p53- or p73-dependent pathway. However, the immediate targets recruited upon TQ-induced cytotoxicity have not yet been clearly identified. We therefore asked whether cyclic nucleotide phosphodiesterases (PDEs) could be involved in TQ-triggered pro-apoptotic reactivity; PDEs are regulators of intracellular levels of cyclic nucleotides and therefore can modulate cAMP and cGMP-dependent cell death pathways. Our results showed that TQ specifically repressed PDE1A expression in the acute lymphoblastic leukemia Jurkat cell line. This effect is concomitant with the previously described sequential deregulation of the expression of the tumor suppressor protein p73 and the epigenetic integrator UHRF1 (Ubiquitin-like, PHD Ring Finger 1). Interestingly, RNA-interference knock-down of PDE1A expression as well as decreased PDE1A expression induced growth inhibition of Jurkat cells, cell cycle arrest and apoptosis through an activation of p73 and a repression of UHRF1. Conversely, PDE1A re-expression counteracted the cellular pro-apoptotic effects of TQ in association with a p73 repression and UHRF1 re-expression. Altogether, our results show that TQ induced an initial down-regulation of PDE1A with a subsequent down-regulation of UHRF1 via a p73-dependent mechanism. This study further proposes that PDE1A might be involved in the epigenetic code inheritance by regulating, via p73, the epigenetic integrator UHRF1. Our findings also suggest that a forced inhibition of PDE1A expression might be a new therapeutic strategy for the management of acute lymphoblastic leukemia.
-
cyclic nucleotide phosphodiesterases pde and peptide motifs
Current Pharmaceutical Design, 2010Co-Authors: Thérèse Keravis, Claire LugnierAbstract:Abstract Cyclic nucleotide phosphodiesterase (PDE), that is a multigenic enzyme superfamily ubiquitously distributed in mammalians, mainly contributes to intracellular signaling regulation. Its various isozymes specifically control in a spatio-temporal manner intracellular levels of cAMP and cGMP downstream receptor activation and nearby functional proteins. The PDE superfamily is constituted by 11 gene families (PDE1-PDE11), comprising 21 genes represented by more than 100 mRNA products due to alternative splicing. Among them, PDE3, PDE4 and PDE5 were viewed as therapeutic targets and therefore, due to the successful development of Viagra (sildenafil, potent selective PDE5 inhibitor), the knowledge in PDE field burst out with the help of academic/pharmaceutical collaborations. Organic medicinal chemistry, using crystallographic and docking approaches, has focused its search on the catalytic pocket of PDEs, leaving aside the development of variant subtype specific PDE inhibitors and activators. This review firstly describes the various properties of each PDE isozyme, focusing particularly on their regulatory domains, mainly located in the N-terminus. Thereafter, we review the possible peptidic regulations of PDE activity itself, then the PDE anchoring in macromolecular complexes and finally the direct interaction of PDE with some critical intracellular proteins, such as beta-arrestin, immunophilin and proteins containing SH3-domain. Altogether, it appears that a peptidic approach would be helpful to study the intrinsic PDE regulation of each subfamily, and thereafter the PDE peptidic motifs implicated as well as PDE location in signaling cascades. Taking in account the various regulatory PDE domains could lead to design new peptides to conceive variant specific inhibitors as well as activators in a therapeutical goal.
-
cyclic nucleotide phosphodiesterase pde superfamily a new target for the development of specific therapeutic agents
Pharmacology & Therapeutics, 2006Co-Authors: Claire LugnierAbstract:Cyclic nucleotide phosphodiesterases (PDEs), which are ubiquitously distributed in mammalian tissues, play a major role in cell signaling by hydrolyzing cAMP and cGMP. Due to their diversity, which allows specific distribution at cellular and subcellular levels, PDEs can selectively regulate various cellular functions. Their critical role in intracellular signaling has recently designated them as new therapeutic targets for inflammation. The PDE superfamily represents 11 gene families (PDE1 to PDE11). Each family encompasses 1 to 4 distinct genes, to give more than 20 genes in mammals encoding the more than 50 different PDE proteins probably produced in mammalian cells. Although PDE1 to PDE6 were the first well-characterized isoforms because of their predominance in various tissues and cells, their specific contribution to tissue function and their regulation in pathophysiology remain open research fields. This concerns particularly the newly discovered families, PDE7 to PDE11, for which roles are not yet established. In many pathologies, such as inflammation, neurodegeneration, and cancer, alterations in intracellular signaling related to PDE deregulation may explain the difficulties observed in the prevention and treatment of these pathologies. By inhibiting specifically the up-regulated PDE isozyme(s) with newly synthesized potent and isozyme-selective PDE inhibitors, it may be potentially possible to restore normal intracellular signaling selectively, providing therapy with reduced adverse effects.
Chen Yan - One of the best experts on this subject based on the ideXlab platform.
-
Cyclic nucleotide phosphodiesterase 1A: A key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res. Cardiol
2016Co-Authors: Chen YanAbstract:VSMCs (vascular smooth muscle cells) play critical roles in arterial remodelling with aging, hypertension and atherosclerosis. VSMCs exist in diverse phenotypes and exhibit phenotypic plasticity, e.g. changing from a quiescent/contractile phenotype to an active myofibroblast-like, often called ‘synthetic’, phenotype. Synthetic VSMCs are able to proliferate, migrate and secrete ECM (extracellular matrix) proteinases and ECM proteins. In addition, they produce pro-inflammatory molecules, providing an inflammatory microenvironment for leucocyte penetration, accumulation and activation. The aging VSMCs have also shown changes in cellular phenotype, responsiveness to contracting and relaxing mediators, replicating potential, matrix synthesis, inflammatory mediators and intracellular signalling. VSMC dysfunction plays a key role in age-associated vascular remodelling. Cyclic nucleotide PDEs (phosphodiesterases), by catalysing cyclic nucleotide hydrolysis, play a critical role in regulating the amplitude, duration and compartmentalization of cyclic nucleotide signalling. Abnormal alterations of PDEs and subsequent changes in cyclic nucleotide homoeostasis have been implicated in a number of different diseases. In the study published in the latest issue of Clinical Science, Bautista Niño and colleagues have shown that, in cultured senescent human VSMCs, PDE1A and PDE1C mRNA levels are significantly up-regulated and inhibition of PDE1 activity with vinpocetine reduced cellular senescent makers in senescent VSMCs. Moreover, i
-
Role of cAMP-Phosphodiesterase 1C Signaling in Regulating Growth Factor Receptor Stability, Vascular Smooth Muscle Cell Growth, Migration, and Neointimal Hyperplasia
Circulation Research, 2015Co-Authors: Yu-jun Cai, Haiqing Zhao, David J. Nagel, Peter A. Knight, Qian Zhou, Katherine D. Cygnar, Chen YanAbstract:Rationale:Neointimal hyperplasia characterized by abnormal accumulation of vascular smooth muscle cells (SMCs) is a hallmark of occlusive disorders such as atherosclerosis, postangioplasty restenosis, vein graft stenosis, and allograft vasculopathy. Cyclic nucleotides are vital in SMC proliferation and migration, which are regulated by cyclic nucleotide phosphodiesterases (PDEs). Objective:Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases. Methods and Results:We performed screening for genes differentially expressed in normal contractile versus proliferating synthetic SMCs. We observed that PDE1C expression was low in contractile SMCs but drastically elevated in synthetic SMCs in vitro and in various mouse vascular injury models in vivo. In addition, PDE1C was highly induced in neointimal SMCs of human coronary arteries. More importantly, injury-induced neointimal formation was significantly attenuated by PDE1C deficiency or PDE1 inhibition in vivo. PDE...
-
ca2 calmodulin stimulated pde1 regulates the beta catenin tcf signaling through pp2a b56 gamma subunit in proliferating vascular smooth muscle cells
FEBS Journal, 2010Co-Authors: Kye-im Jeon, Pingjin Gao, Hirofumi Jono, Clint L. Miller, Yu-jun Cai, Soyeon Lim, Xuan Liu, Jun Ichi Abe, Chen YanAbstract:The phenotypic change of vascular smooth muscle cells (VSMCs), from a ‘contractile’ phenotype to a ‘synthetic’ phenotype, is crucial for pathogenic vascular remodeling in vascular diseases such as atherosclerosis and restenosis. Ca2+/calmodulin-stimulated phosphodiesterase 1 (PDE1) isozymes, including PDE1A and PDE1C, play integral roles in regulating the proliferation of synthetic VSMCs. However, the underlying molecular mechanism(s) remain unknown. In this study, we explore the role and mechanism of PDE1 isoforms in regulating β-catenin/T-cell factor (TCF) signaling in VSMCs, a pathway important for vascular remodeling through promoting VSMC growth and survival. We found that inhibition of PDE1 activity markedly attenuated β-catenin/TCF signaling by downregulating β-catenin protein. The effect of PDE1 inhibition on β-catenin protein reduction is exerted via promoting glycogen synthase kinase 3 (GSK3)β activation, β-catenin phosphorylation and subsequent β-catenin protein degradation. Moreover, PDE1 inhibition specifically upregulated phosphatase protein phosphatase 2A (PP2A) B56γ subunit gene expression, which is responsible for the effects of PDE1 inhibition on GSK3β and β-catenin/TCF signaling. Furthermore, the effect of PDE1 inhibition on β-catenin was specifically mediated by PDE1A but not PDE1C isozyme. Interestingly, in synthetic VSMCs, PP2A B56γ, phospho-GSK3β and phospho-β-catenin were all found in the nucleus, suggesting that PDE1A regulates nuclear β-catenin protein stability through the nuclear PP2A–GSK3β–β-catenin signaling axis. Taken together, these findings provide direct evidence for the first time that PP2A B56γ is a critical mediator for PDE1A in the regulation of β-catenin signaling in proliferating VSMCs.
-
Cyclic GMP Phosphodiesterases and Regulation of Smooth Muscle Function
Circulation Research, 2003Co-Authors: Sergei D. Rybalkin, Chen Yan, Karin E. Bornfeldt, Joseph A. BeavoAbstract:Cyclic GMP (cGMP) made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an important regulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals. The ability of smooth muscle cells (SMCs) to utilize different combinations of phosphodiesterase (PDE) isozymes allows cGMP to mediate these multiple processes. For example, PDE5 as a major cGMP-hydrolyzing PDE effectively controls the development of smooth muscle relaxation. In order for contraction to occur, PDE5 is activated and cGMP falls. Conversely, blockade of PDE5 activity allows the relaxation cycle to be prolonged and enhanced. A recently shown direct activation of PDE5 by cGMP binding to the GAF A domain suggests that this regulatory site might be a target for new drug development. The calcium surge associated with vasoconstrictor initiated contraction also activates a calcium/calmodulin-dependent PDE (PDE1A). Together, PDE5 and PDE1A lower cGMP sufficiently to allow contraction. Longer term, both PDE5 and PDE1A mRNA are induced by chronic stimulation of guanylyl cyclase. This induction is a major cause of the tolerance that develops to NO-releasing drugs. Finally, high levels of cGMP or cAMP also act as a brake to attenuate the proliferative response of SMCs to many mitogens. After vessel damage, in order for SMC proliferation to occur, the levels of cGMP and cAMP must be decreased. In humans, this decrease is caused in large part by induction of another Ca2+/calmodulin-dependent PDE (PDE1C) that allows the brake to be released and proliferation to start.
Clint L. Miller - One of the best experts on this subject based on the ideXlab platform.
-
cyclic nucleotide phosphodiesterase 1a a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart
Basic Research in Cardiology, 2011Co-Authors: Clint L. Miller, Masayoshi Oikawa, Tamlyn Thomas, Wolfgang R Dostmann, Manuela Zaccolo, Keigi FujiwaraAbstract:Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca2+/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.
-
ca2 calmodulin stimulated pde1 regulates the beta catenin tcf signaling through pp2a b56 gamma subunit in proliferating vascular smooth muscle cells
FEBS Journal, 2010Co-Authors: Kye-im Jeon, Pingjin Gao, Hirofumi Jono, Clint L. Miller, Yu-jun Cai, Soyeon Lim, Xuan Liu, Jun Ichi Abe, Chen YanAbstract:The phenotypic change of vascular smooth muscle cells (VSMCs), from a ‘contractile’ phenotype to a ‘synthetic’ phenotype, is crucial for pathogenic vascular remodeling in vascular diseases such as atherosclerosis and restenosis. Ca2+/calmodulin-stimulated phosphodiesterase 1 (PDE1) isozymes, including PDE1A and PDE1C, play integral roles in regulating the proliferation of synthetic VSMCs. However, the underlying molecular mechanism(s) remain unknown. In this study, we explore the role and mechanism of PDE1 isoforms in regulating β-catenin/T-cell factor (TCF) signaling in VSMCs, a pathway important for vascular remodeling through promoting VSMC growth and survival. We found that inhibition of PDE1 activity markedly attenuated β-catenin/TCF signaling by downregulating β-catenin protein. The effect of PDE1 inhibition on β-catenin protein reduction is exerted via promoting glycogen synthase kinase 3 (GSK3)β activation, β-catenin phosphorylation and subsequent β-catenin protein degradation. Moreover, PDE1 inhibition specifically upregulated phosphatase protein phosphatase 2A (PP2A) B56γ subunit gene expression, which is responsible for the effects of PDE1 inhibition on GSK3β and β-catenin/TCF signaling. Furthermore, the effect of PDE1 inhibition on β-catenin was specifically mediated by PDE1A but not PDE1C isozyme. Interestingly, in synthetic VSMCs, PP2A B56γ, phospho-GSK3β and phospho-β-catenin were all found in the nucleus, suggesting that PDE1A regulates nuclear β-catenin protein stability through the nuclear PP2A–GSK3β–β-catenin signaling axis. Taken together, these findings provide direct evidence for the first time that PP2A B56γ is a critical mediator for PDE1A in the regulation of β-catenin signaling in proliferating VSMCs.
-
role of ca2 calmodulin stimulated cyclic nucleotide phosphodiesterase 1 in mediating cardiomyocyte hypertrophy
Circulation Research, 2009Co-Authors: Clint L. Miller, Joseph A. Beavo, Yu-jun Cai, Masayoshi Oikawa, David J. Nagel, Sergei D. Rybalkin, Andrew P Wojtovich, Vince Florio, Yiu Fai Chen, Burns C BlaxallAbstract:Rationale: Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca2+/calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca2+/CaM and cGMP signaling; however, its function in cardiomyocytes is unknown. Objective: Herein, we investigate the role of Ca2+/CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo. Methods and Results: Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human h...
Thérèse Keravis - One of the best experts on this subject based on the ideXlab platform.
-
cyclic nucleotide phosphodiesterase pde isozymes as targets of the intracellular signalling network benefits of pde inhibitors in various diseases and perspectives for future therapeutic developments
British Journal of Pharmacology, 2012Co-Authors: Thérèse Keravis, Claire LugnierAbstract:Cyclic nucleotide phosphodiesterases (PDEs) that specifically inactivate the intracellular messengers cAMP and cGMP in a compartmentalized manner represent an important enzyme class constituted by 11 gene-related families of isozymes (PDE1 to PDE11). Downstream receptors, PDEs play a major role in controlling the signalosome at various levels of phosphorylations and protein/protein interactions. Due to the multiplicity of isozymes, their various intracellular regulations and their different cellular and subcellular distributions, PDEs represent interesting targets in intracellular pathways. Therefore, the investigation of PDE isozyme alterations related to various pathologies and the design of specific PDE inhibitors might lead to the development of new specific therapeutic strategies in numerous pathologies. This manuscript (i) overviews the different PDEs including their endogenous regulations and their specific inhibitors; (ii) analyses the intracellular implications of PDEs in regulating signalling cascades in pathogenesis, exemplified by two diseases affecting cell cycle and proliferation; and (iii) discusses perspectives for future therapeutic developments.
-
Anti-proliferative effect of curcumin on melanoma cells is mediated by PDE1A inhibition that regulates the epigenetic integrator UHRF1.
Molecular Nutrition & Food Research, 2011Co-Authors: Abdurazzag Abusnina, Thérèse Keravis, Issaka Yougbaré, Christian Bronner, Claire LugnierAbstract:Scope Curcumin inhibits proliferation of many cancer cells. Cyclic nucleotide phosphodiesterases (PDEs), by hydrolyzing intracellular cyclic adenosine-3',5'-monophosphate (cAMP) and/or cyclic guanosine-3',5'-monophosphate (cGMP), play a pivotal role in signalling pathways involved in cell proliferation. Therefore, this study investigated PDE1-5 participations in the anti-proliferative properties of curcumin in B16F10 murine melanoma cells. Methods and results We report that curcumin inhibits PDE1-5 activities (IC(50) ≅10(-5) M), indicating that curcumin acts as a non-selective PDE inhibitor. In melanoma cells, PDE4 and PDE1 represent the major cAMP-PDEs and cGMP-PDEs activities, respectively. Curcumin treatment decreased PDE1 and PDE4 activities and dose dependently increased intracellular cGMP levels, whereas cAMP levels were unchanged. Curcumin inhibited cell proliferation and cell cycle progression by accumulating cells in the S- and G2/M-phases with enhanced expressions of cyclin-dependent kinase inhibitors. In contrast, expressions of PDE1A, cyclin A and the epigenetic integrator ubiquitin-like containing PHD and Ring Finger domains 1 (UHRF1) and DNA methyltransferase 1 (DNMT1) were decreased by curcumin. Interestingly, PDE1A overexpression increased UHRF1 and DNMT1 expressions and rescued the B16F10 cells from curcumin anti-proliferative effects. Nimodipine, a PDE1 inhibitor, mimicked the curcumin effects. Conclusion Curcumin exerts its anti-cancer property by targeting PDE1 that inhibits melanoma cell proliferation via UHRF1, DNMT1, cyclin A, p21 and p27 regulations. This suggests that natural PDE1 inhibitors present in food might be effective in preventing cancer.
-
Down-regulation of cyclic nucleotide phosphodiesterase PDE1A is the key event of p73 and UHRF1 deregulation in thymoquinone-induced acute lymphoblastic leukemia cell apoptosis.
Cellular signalling, 2010Co-Authors: Abdurazzag Abusnina, Thérèse Keravis, Christian Bronner, Mahmoud Alhosin, Guy Fuhrmann, Christian D. Muller, Claire LugnierAbstract:Thymoquinone (TQ), the active principle of Nigella sativa black seeds, has anti-proliferative properties on numerous cancer cell types. Others and we have previously reported that TQ acts as agent that triggers cell cycle arrest and apoptosis through either a p53- or p73-dependent pathway. However, the immediate targets recruited upon TQ-induced cytotoxicity have not yet been clearly identified. We therefore asked whether cyclic nucleotide phosphodiesterases (PDEs) could be involved in TQ-triggered pro-apoptotic reactivity; PDEs are regulators of intracellular levels of cyclic nucleotides and therefore can modulate cAMP and cGMP-dependent cell death pathways. Our results showed that TQ specifically repressed PDE1A expression in the acute lymphoblastic leukemia Jurkat cell line. This effect is concomitant with the previously described sequential deregulation of the expression of the tumor suppressor protein p73 and the epigenetic integrator UHRF1 (Ubiquitin-like, PHD Ring Finger 1). Interestingly, RNA-interference knock-down of PDE1A expression as well as decreased PDE1A expression induced growth inhibition of Jurkat cells, cell cycle arrest and apoptosis through an activation of p73 and a repression of UHRF1. Conversely, PDE1A re-expression counteracted the cellular pro-apoptotic effects of TQ in association with a p73 repression and UHRF1 re-expression. Altogether, our results show that TQ induced an initial down-regulation of PDE1A with a subsequent down-regulation of UHRF1 via a p73-dependent mechanism. This study further proposes that PDE1A might be involved in the epigenetic code inheritance by regulating, via p73, the epigenetic integrator UHRF1. Our findings also suggest that a forced inhibition of PDE1A expression might be a new therapeutic strategy for the management of acute lymphoblastic leukemia.
-
cyclic nucleotide phosphodiesterases pde and peptide motifs
Current Pharmaceutical Design, 2010Co-Authors: Thérèse Keravis, Claire LugnierAbstract:Abstract Cyclic nucleotide phosphodiesterase (PDE), that is a multigenic enzyme superfamily ubiquitously distributed in mammalians, mainly contributes to intracellular signaling regulation. Its various isozymes specifically control in a spatio-temporal manner intracellular levels of cAMP and cGMP downstream receptor activation and nearby functional proteins. The PDE superfamily is constituted by 11 gene families (PDE1-PDE11), comprising 21 genes represented by more than 100 mRNA products due to alternative splicing. Among them, PDE3, PDE4 and PDE5 were viewed as therapeutic targets and therefore, due to the successful development of Viagra (sildenafil, potent selective PDE5 inhibitor), the knowledge in PDE field burst out with the help of academic/pharmaceutical collaborations. Organic medicinal chemistry, using crystallographic and docking approaches, has focused its search on the catalytic pocket of PDEs, leaving aside the development of variant subtype specific PDE inhibitors and activators. This review firstly describes the various properties of each PDE isozyme, focusing particularly on their regulatory domains, mainly located in the N-terminus. Thereafter, we review the possible peptidic regulations of PDE activity itself, then the PDE anchoring in macromolecular complexes and finally the direct interaction of PDE with some critical intracellular proteins, such as beta-arrestin, immunophilin and proteins containing SH3-domain. Altogether, it appears that a peptidic approach would be helpful to study the intrinsic PDE regulation of each subfamily, and thereafter the PDE peptidic motifs implicated as well as PDE location in signaling cascades. Taking in account the various regulatory PDE domains could lead to design new peptides to conceive variant specific inhibitors as well as activators in a therapeutical goal.
Nikolai O Artemyev - One of the best experts on this subject based on the ideXlab platform.
-
luteinizing hormone causes phosphorylation and activation of the cgmp phosphodiesterase pde5 in rat ovarian follicles contributing together with pde1 activity to the resumption of meiosis
Biology of Reproduction, 2016Co-Authors: Jeremy R Egbert, Robin J. Kleiman, Tracy F Uliasz, Leia C Shuhaibar, Andreas Geerts, Frank Wunder, John M Humphrey, Paul D Lampe, Nikolai O Artemyev, Sergei D. RybalkinAbstract:The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism.
-
exchange of cone for rod phosphodiesterase 6 catalytic subunits in rod photoreceptors mimics in part features of light adaptation
The Journal of Neuroscience, 2015Co-Authors: Anurima Majumder, Johan Pahlberg, Alapakkam P Sampath, Nikolai O ArtemyevAbstract:Despite the expression of homologous phototransduction components, the molecular basis for differences in light-evoked responses between rod and cone photoreceptors remains unclear. We examined the role of cGMP phosphodiesterase (PDE6) in this difference by expressing cone PDE6 (PDE6C) in rd1/rd1 rods lacking rod PDE6 (PDE6AB) using transgenic mice. The expression of PDE6C rescues retinal degeneration observed in rd1/rd1 rods. Double-transgenic rods (PDE6C++) were compared with rd1/+ rods based on similar PDE6 expression. PDE6C increased the basal PDE activity and speeded the rate-limiting step for phototransduction deactivation, causing rod photoresponses to appear light adapted, with reduced dark current and sensitivity and faster response kinetics. When PDE6C++ and rd1/+ rods were exposed to similar background light, rd1/+ rods displayed greater desensitization. These results indicate an increased spontaneous activity and faster deactivation of PDE6C compared with PDE6AB in darkness, but that background light increases steady PDE6C activity to a lesser extent. In addition to accelerating the recovery of the photoresponse, faster PDE6C deactivation may blunt the rise in background-induced steady PDE6C activity. Therefore, higher basal PDE6C activity and faster deactivation together partially account for faster and less sensitive cone photoresponses in darkness, whereas a reduced rise of steady PDE6C activity in background light may allow cones to avoid saturation. Significance Statement Cones are the primary photoreceptors responsible for most of our visual experience. Cone light responses are less sensitive and display speeded responses compared with rods. Despite the fact that rods and cones use a G-protein signaling cascade with similar organization, the mechanistic basis for these differences remains unclear. Here, we examined the role of distinct isoforms of PDE6, the effector enzyme in phototransduction, in these differences. We developed a transgenic mouse model that expresses cone PDE6 in rods and show that the cone PDE6 isoform is partially responsible for the difference in sensitivity and response kinetics between rods and cones.
-
rod phosphodiesterase 6 pde6a and pde6b subunits are enzymatically equivalent
Journal of Biological Chemistry, 2010Co-Authors: Nikolai O ArtemyevAbstract:Phosphodiesterase-6 (PDE6) is the key effector enzyme of the phototransduction cascade in rods and cones. The catalytic core of rod PDE6 is a unique heterodimer of PDE6A and PDE6B catalytic subunits. The functional significance of rod PDE6 heterodimerization and conserved differences between PDE6AB and cone PDE6C and the individual properties of PDE6A and PDE6B are unknown. To address these outstanding questions, we expressed chimeric homodimeric enzymes, enhanced GFP (EGFP)-PDE6C-A and EGFP-PDE6C-B, containing the PDE6A and PDE6B catalytic domains, respectively, in transgenic Xenopus laevis. Similar to EGFP-PDE6C, EGFP-PDE6C-A and EGFP-PDE6C-B were targeted to the rod outer segments and concentrated at the disc rims. PDE6C, PDE6C-A, and PDE6C-B were isolated following selective immunoprecipitation of the EGFP fusion proteins. All three enzymes, PDE6C, PDE6C-A, and PDE6C-B, hydrolyzed cGMP with similar Km (20–23 μm) and kcat (4200–5100 s−1) values. Likewise, the Ki values for PDE6C, PDE6C-A, and PDE6C-B inhibition by the cone- and rod-specific PDE6 γ-subunits (Pγ) were comparable. Recombinant cone transducin-α (Gαt2) and native rod Gαt1 fully and potently activated PDE6C, PDE6C-A, and PDE6C-B. In contrast, the half-maximal activation of bovine rod PDE6 required markedly higher concentrations of Gαt2 or Gαt1. Our results suggest that PDE6A and PDE6B are enzymatically equivalent. Furthermore, PDE6A and PDE6B are similar to PDE6C with respect to catalytic properties and the interaction with Pγ but differ in the interaction with transducin. This study significantly limits the range of mechanisms by which conserved differences between PDE6A, PDE6B, and PDE6C may contribute to remarkable differences in rod and cone physiology.