The Experts below are selected from a list of 135 Experts worldwide ranked by ideXlab platform
Cristóbal De Los Ríos - One of the best experts on this subject based on the ideXlab platform.
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An okadaic acid fragment analogue prevents nicotine-induced resistance to cisplatin by recovering PP2A activity in non-small cell lung cancer cells
Bioorganic chemistry, 2020Co-Authors: Raquel L. Arribas, Anna Bordas, Judit Domènech Omella, José Luis Cedillo, Veerle Janssens, Carmen Montiel, Cristóbal De Los RíosAbstract:We herein report the design, synthesis, and functional impact of an okadaic acid (OA) small analogue, ITH12680, which restores the activity of Phosphoprotein Phosphatase 2A (PP2A), whose deficient activity has been implicated in nicotine-mediated tumor progression and chemoresistance in non-small cell lung cancer (NSCLC). For its design, we paid attention to the structure of the PP2A-OA complex, where the C16-C38 OA fragment confers PP2A affinity and selectivity, but it is not involved in the inhibitory effect. Confirming this hypothesis, PP2A activity was not inhibited by ITH12680. By contrast, the compound partially restored OA-exerted PP2A inhibition in vitro. Moreover, flow cytometry and immunoblotting experiments revealed that ITH12680 reversed nicotine-induced cisplatin resistance in NSCLC cells, as it prevented nicotine-induced reduction of Bax expression and inhibited nicotine-mediated activation of cell survival and proliferation kinases, Akt and ERK1/2. Our findings suggest that the rescue of nicotine-inhibited PP2A activity could diminish the resistance to cisplatin treatment observed in NSCLC patients who continue smoking.
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ITH12410/SC058: A New Neuroprotective Compound with Potential in the Treatment of Alzheimer's Disease
ACS chemical neuroscience, 2014Co-Authors: Alejandro Romero, Javier Egea, Gema C. González-muñoz, María Dolores Martín De Saavedra, Laura Del Barrio, María Isabel Rodríguez-franco, Santiago Conde, Manuela G. López, Mercedes Villarroya, Cristóbal De Los RíosAbstract:The neuroprotective profile of the dibenzothiadiazepine ITH12410/SC058 (2-chloro-5,6-dihydro-5,6-diacetyldibenzo[b,f][1,4,5]thiadiazepine) against several neurotoxicity models related to neurodegenerative diseases is herein described. ITH12410/SC058 protected SH-SY5Y cells against the loss of cell viability elicited by amyloid beta peptide and okadaic acid, a selective inhibitor of Phosphoprotein Phosphatase 2A that induces neurofibrillary tangle formation. Furthermore, ITH12410/SC058 is neuroprotective against several in vitro models of oxidative stress, that is, H2O2 exposure or incubation with rotenone plus oligomycin A in SH-SY5Y cells, and oxygen and glucose deprivation followed by reoxygenation in rat hippocampal slices. By contrast, ITH12410/SC058 was unable to significantly protect SH-SY5Y neuroblastoma cells against the toxicity elicited by Ca2+ overload. Our results confirm the hypothesis that the dibenzothiadiazepine ITH12410/SC058 features its neuroprotective actions in a multitarget fashion, ...
Craig C Malbon - One of the best experts on this subject based on the ideXlab platform.
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Phosphoprotein Phosphatase-2A docks to Dishevelled and counterregulates Wnt3a/β-catenin signaling
Journal of Molecular Signaling, 2007Co-Authors: Noriko Yokoyama, Craig C MalbonAbstract:Background Wnt3a stimulates cellular trafficking of key signaling elements ( e.g ., Axin, Dishevelled-2, β-catenin, and glycogen synthase kinase-3β) and primitive endoderm formation in mouse F9 embryonic teratocarcinoma cells. Results The role of Phosphoprotein Phosphatase-2A in signaling of the Wnt/β-catenin/Lef-Tcf-sensitive gene activation pathway was investigated. Wnt3a action attenuates Phosphoprotein Phosphatase-2A activity and stimulates the Lef/Tcf-sensitive gene transcription. Inhibiting Phosphoprotein Phosphatase-2A by okadaic acid, by treatment with siRNA (targeting the C-subunit of the enzyme), or by expression of SV40 small t antigen mimics Wnt3a action, increasing the cellular abundance of Axin and phospho-glycogen synthase kinase-3β as well as the trafficking of signaling elements in the Wnt/β-catenin pathway. Although mimicking effects of Wnt3a on the cellular abundance and trafficking of key signaling elements in the Wnt canonical pathway, suppression of Phosphatase-2A alone did not provoke activation of the Lef/Tcf-sensitive transcriptional response, but did potentiate its activation by Wnt3a. Phosphoprotein Phosphatase-2A and the scaffold Phosphoprotein Dishevelled-2 display similarities in cellular trafficking in response to either Wnt3a or suppression of the Phosphatase. A docking site for Phosphoprotein Phosphatase-2A in the DEP domain of Dishevelled-2 was identified. Conclusion In current study, we showed new roles of Phosphoprotein Phosphatase-2A in Wnt/β-catenin signaling pathway: effect on protein expression, effect on protein trafficking, retention of molecules in subcellular compartments, and regulation of enzymatic activity of several key players. Docking of Phosphoprotein Phosphatase-2A by Dishevelled-2 suppresses Phosphatase activity and explains in part the central role of this Phosphatase in the counterregulation of the Wnt/β-catenin signaling pathway.
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Phosphoprotein Phosphatase 2A docks to dishevelled and counterregulates wnt3a β catenin signaling
Journal of Molecular Signaling, 2007Co-Authors: Noriko Yokoyama, Craig C MalbonAbstract:Background: Wnt3a stimulates cellular trafficking of key signaling elements (e.g., Axin, Dishevelled-2, β-catenin, and glycogen synthase kinase-3β) and primitive endoderm formation in mouse F9 embryonic teratocarcinoma cells. Results: The role of Phosphoprotein Phosphatase-2A in signaling of the Wnt/β-catenin/Lef-Tcfsensitive gene activation pathway was investigated. Wnt3a action attenuates Phosphoprotein Phosphatase-2A activity and stimulates the Lef/Tcf-sensitive gene transcription. Inhibiting Phosphoprotein Phosphatase-2A by okadaic acid, by treatment with siRNA (targeting the Csubunit of the enzyme), or by expression of SV40 small t antigen mimics Wnt3a action, increasing the cellular abundance of Axin and phospho-glycogen synthase kinase-3β as well as the trafficking of signaling elements in the Wnt/β-catenin pathway. Although mimicking effects of Wnt3a on the cellular abundance and trafficking of key signaling elements in the Wnt canonical pathway, suppression of Phosphatase-2A alone did not provoke activation of the Lef/Tcf-sensitive transcriptional response, but did potentiate its activation by Wnt3a. Phosphoprotein Phosphatase- 2A and the scaffold Phosphoprotein Dishevelled-2 display similarities in cellular trafficking in response to either Wnt3a or suppression of the Phosphatase. A docking site for Phosphoprotein Phosphatase-2A in the DEP domain of Dishevelled-2 was identified. Conclusion: In current study, we showed new roles of Phosphoprotein Phosphatase-2A in Wnt/ β-catenin signaling pathway: effect on protein expression, effect on protein trafficking, retention of molecules in subcellular compartments, and regulation of enzymatic activity of several key players. Docking of Phosphoprotein Phosphatase-2A by Dishevelled-2 suppresses Phosphatase activity and explains in part the central role of this Phosphatase in the counterregulation of the Wnt/β-catenin signaling pathway.
Yi-fang Tsai - One of the best experts on this subject based on the ideXlab platform.
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overexpression of Phosphoprotein Phosphatase 2A predicts worse prognosis in patients with breast cancer a 15 year follow up
Human Pathology, 2017Co-Authors: Po-ming Chen, Pei-yi Chu, Shiao-lin Tung, Chun-yu Liu, Yi-fang TsaiAbstract:Breast cancer subtypes can be stratified by IHC expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2). The signaling pathways mediated by these receptors are the dominant drivers of cell proliferation and survival in most human breast cancers. One of the most frequently overactivated pathways in breast cancer is the AKT signaling cascade. Protein Phosphatase 2A (PP2A) acts as a switch to turn off signal transduction in the AKT pathway; however, it is frequently inactivated in many cancers by phosphorylation of Tyr-307 to form Phosphoprotein Phosphatase 2A (p-PP2A). This study aimed to investigate the clinical significance of p-PP2A and phospho-AKT (p-AKT) expression in 672 patients with breast cancer during a 15-year follow-up. The breast tissue microarray was evaluated for p-PP2A and p-AKT expression using IHC staining and scores. Analysis of IHC staining results revealed that p-PP2A expression was positively correlated with HER2, Ki-67, and p-AKT overexpression (P<.001, P=.003, and P=.001, respectively). At the time of diagnosis, breast cancer patients with higher p-PP2A expression had significantly shorter 15-year OS than patients with lower p-PP2A expression did (P=.017). Multivariate Cox regression analysis revealed that high p-PP2A expression was an independent prognostic factor for shorter OS (hazard ratio, 1.741; P=.012). Our data revealed that high p-PP2A expression is positively associated with HER2, Ki-67, and p-AKT expression. High p-PP2A expression correlates with poor clinical outcomes in breast cancer, especially in patients with TNBC.
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Overexpression of Phosphoprotein Phosphatase 2A predicts worse prognosis in patients with breast cancer: a 15-year follow-up.
Human pathology, 2017Co-Authors: Po-ming Chen, Pei-yi Chu, Shiao-lin Tung, Chun-yu Liu, Yi-fang Tsai, Yen-shu Lin, Wan-lun Wang, Yu-ling Wang, Pei-ju Lien, Ta-chung ChaoAbstract:Breast cancer subtypes can be stratified by IHC expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2). The signaling pathways mediated by these receptors are the dominant drivers of cell proliferation and survival in most human breast cancers. One of the most frequently overactivated pathways in breast cancer is the AKT signaling cascade. Protein Phosphatase 2A (PP2A) acts as a switch to turn off signal transduction in the AKT pathway; however, it is frequently inactivated in many cancers by phosphorylation of Tyr-307 to form Phosphoprotein Phosphatase 2A (p-PP2A). This study aimed to investigate the clinical significance of p-PP2A and phospho-AKT (p-AKT) expression in 672 patients with breast cancer during a 15-year follow-up. The breast tissue microarray was evaluated for p-PP2A and p-AKT expression using IHC staining and scores. Analysis of IHC staining results revealed that p-PP2A expression was positively correlated with HER2, Ki-67, and p-AKT overexpression (P
Jeffry B. Stock - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic benefits of a component of coffee in a rat model of Alzheimer's disease
Neurobiology of aging, 2014Co-Authors: Gustavo Basurto-islas, Michael Voronkov, Jeffry B. Stock, Julie Blanchard, Yunn Chyn Tung, José R. Fernández, Maxwell Stock, Sherry Zhang, Khalid IqbalAbstract:A minor component of coffee unrelated to caffeine, eicosanoyl-5-hydroxytryptamide (EHT), provides protection in a rat model for Alzheimer’s disease (AD). In this model, viral expression of the Phosphoprotein Phosphatase 2A (PP2A) endogenous inhibitor, the I PP2A , or SET protein in the brains of rats leads to several characteristic features of AD including cognitive impairment, tau hyperphosphorylation, and elevated levels of cytoplasmic amyloid-b protein. Dietary supplementation with EHT for 6e12 months resulted in substantial amelioration of all these defects. The beneficial effects of EHT could be associated with its ability to increase PP2A activity by inhibiting the demethylation of its catalytic subunit PP2Ac. These findings raise the possibility that EHT may make a substantial contribution to the apparent neuroprotective benefits associated with coffee consumption as evidenced by numerous epidemiologic studies indicating that coffee drinkers have substantially lowered risk of developing AD.
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Phosphoprotein Phosphatase 2A a novel druggable target for alzheimer s disease
Future Medicinal Chemistry, 2011Co-Authors: Michael Voronkov, Steven P. Braithwaite, Jeffry B. StockAbstract:Tau hyperphosphorylation is thought to play an important role in the etiology of Alzheimer's disease by facilitating the formation of neurofibrillary tangles. Reducing phosphorylation through kinase inhibition has therefore emerged as a target for drug development, but despite considerable efforts to develop therapeutic kinase inhibitors, success has been limited. An alternative approach is to develop pharmaceuticals to enhance the activity of the principal phospho-tau Phosphatase, Phosphoprotein Phosphatase 2A (PP2A). In this article we review evidence that this mechanism is pharmacologically achievable and has promise for delivering the next generation of Alzheimer's disease therapeutics. A number of different chemotypes have been reported to lead to enhanced PP2A activity through a range of proposed mechanisms. Some of these compounds appear to act directly as allosteric activators of PP2A, while others act indirectly by inhibiting the binding of PP2A inhibitors or by altering post-translational modifications that act in turn to regulate PP2A activity towards phospho-tau. These results indicate that PP2A may provide a useful target that can be safely, selectively and effectively modulated through pharmaceutical intervention to treat Alzheimer's disease.
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Phosphoprotein Phosphatase 2A: a novel druggable target for Alzheimer’s disease
Future medicinal chemistry, 2011Co-Authors: Michael Voronkov, Steven P. Braithwaite, Jeffry B. StockAbstract:Tau hyperphosphorylation is thought to play an important role in the etiology of Alzheimer's disease by facilitating the formation of neurofibrillary tangles. Reducing phosphorylation through kinase inhibition has therefore emerged as a target for drug development, but despite considerable efforts to develop therapeutic kinase inhibitors, success has been limited. An alternative approach is to develop pharmaceuticals to enhance the activity of the principal phospho-tau Phosphatase, Phosphoprotein Phosphatase 2A (PP2A). In this article we review evidence that this mechanism is pharmacologically achievable and has promise for delivering the next generation of Alzheimer's disease therapeutics. A number of different chemotypes have been reported to lead to enhanced PP2A activity through a range of proposed mechanisms. Some of these compounds appear to act directly as allosteric activators of PP2A, while others act indirectly by inhibiting the binding of PP2A inhibitors or by altering post-translational modifications that act in turn to regulate PP2A activity towards phospho-tau. These results indicate that PP2A may provide a useful target that can be safely, selectively and effectively modulated through pharmaceutical intervention to treat Alzheimer's disease.
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Carboxyl methylation regulates Phosphoprotein Phosphatase 2A by controlling the association of regulatory B subunits.
The EMBO journal, 2000Co-Authors: Tatiana Tolstykh, Jookyung Lee, Scott Bradley Vafai, Jeffry B. StockAbstract:Phosphoprotein Phosphatase 2A (PP2A) is a major phosphoserine/threonine protein Phosphatase in all eukaryotes. It has been isolated as a heterotrimeric holoenzyme composed of a 65 kDa A subunit, which serves as a scaffold for the association of the 36 kDa catalytic C subunit, and a variety of B subunits that control Phosphatase specificity. The C subunit is reversibly methyl esterified by specific methyltransferase and methylesterase enzymes at a completely conserved C-terminal leucine residue. Here we show that methylation plays an essential role in promoting PP2A holoenzyme assembly and that demethylation has an opposing effect. Changes in methylation indirectly regulate PP2A Phosphatase activity by controlling the binding of regulatory B subunits to AC dimers.
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Carboxyl methylation of the Phosphoprotein Phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo.
The EMBO journal, 2000Co-Authors: Tatiana Tolstykh, Jeffry B. Stock, Jookyung Lee, Kimberly Boyd, James R. BroachAbstract:The Phosphoprotein Phosphatase 2A (PP2A) catalytic subunit contains a methyl ester on its C-terminus, which in mammalian cells is added by a specific carboxyl methyltransferase and removed by a specific carboxyl methylesterase. We have identified genes in yeast that show significant homology to human carboxyl methyltransferase and methylesterase. Extracts of wild-type yeast cells contain carboxyl methyltransferase activity, while extracts of strains deleted for one of the methyltransferase genes, PPM1, lack all activity. Mutation of PPM1 partially disrupts the PP2A holoenzyme in vivo and ppm1 mutations exhibit synthetic lethality with mutations in genes encoding the B or B′ regulatory subunit. Inactivation of PPM1 or overexpression of PPE1, the yeast gene homologous to bovine methylesterase, yields phenotypes similar to those observed after inactivation of either regulatory subunit. These phenotypes can be reversed by overexpression of the B regulatory subunit. These results demonstrate that Ppm1 is the sole PP2A methyltransferase in yeast and that its activity is required for the integrity of the PP2A holoenzyme.
Pei-yi Chu - One of the best experts on this subject based on the ideXlab platform.
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overexpression of Phosphoprotein Phosphatase 2A predicts worse prognosis in patients with breast cancer a 15 year follow up
Human Pathology, 2017Co-Authors: Po-ming Chen, Pei-yi Chu, Shiao-lin Tung, Chun-yu Liu, Yi-fang TsaiAbstract:Breast cancer subtypes can be stratified by IHC expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2). The signaling pathways mediated by these receptors are the dominant drivers of cell proliferation and survival in most human breast cancers. One of the most frequently overactivated pathways in breast cancer is the AKT signaling cascade. Protein Phosphatase 2A (PP2A) acts as a switch to turn off signal transduction in the AKT pathway; however, it is frequently inactivated in many cancers by phosphorylation of Tyr-307 to form Phosphoprotein Phosphatase 2A (p-PP2A). This study aimed to investigate the clinical significance of p-PP2A and phospho-AKT (p-AKT) expression in 672 patients with breast cancer during a 15-year follow-up. The breast tissue microarray was evaluated for p-PP2A and p-AKT expression using IHC staining and scores. Analysis of IHC staining results revealed that p-PP2A expression was positively correlated with HER2, Ki-67, and p-AKT overexpression (P<.001, P=.003, and P=.001, respectively). At the time of diagnosis, breast cancer patients with higher p-PP2A expression had significantly shorter 15-year OS than patients with lower p-PP2A expression did (P=.017). Multivariate Cox regression analysis revealed that high p-PP2A expression was an independent prognostic factor for shorter OS (hazard ratio, 1.741; P=.012). Our data revealed that high p-PP2A expression is positively associated with HER2, Ki-67, and p-AKT expression. High p-PP2A expression correlates with poor clinical outcomes in breast cancer, especially in patients with TNBC.
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Overexpression of Phosphoprotein Phosphatase 2A predicts worse prognosis in patients with breast cancer: a 15-year follow-up.
Human pathology, 2017Co-Authors: Po-ming Chen, Pei-yi Chu, Shiao-lin Tung, Chun-yu Liu, Yi-fang Tsai, Yen-shu Lin, Wan-lun Wang, Yu-ling Wang, Pei-ju Lien, Ta-chung ChaoAbstract:Breast cancer subtypes can be stratified by IHC expression of estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2). The signaling pathways mediated by these receptors are the dominant drivers of cell proliferation and survival in most human breast cancers. One of the most frequently overactivated pathways in breast cancer is the AKT signaling cascade. Protein Phosphatase 2A (PP2A) acts as a switch to turn off signal transduction in the AKT pathway; however, it is frequently inactivated in many cancers by phosphorylation of Tyr-307 to form Phosphoprotein Phosphatase 2A (p-PP2A). This study aimed to investigate the clinical significance of p-PP2A and phospho-AKT (p-AKT) expression in 672 patients with breast cancer during a 15-year follow-up. The breast tissue microarray was evaluated for p-PP2A and p-AKT expression using IHC staining and scores. Analysis of IHC staining results revealed that p-PP2A expression was positively correlated with HER2, Ki-67, and p-AKT overexpression (P