共查询到20条相似文献,搜索用时 31 毫秒
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Prostaglandin E2 promotes MYCN non‐amplified neuroblastoma cell survival via β‐catenin stabilization
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Sepp R. Jansen Rian Holman Ilja Hedemann Ewoud Frankes Carolina R. S. Elzinga Wim Timens Reinoud Gosens Eveline S. de Bont Martina Schmidt 《Journal of cellular and molecular medicine》2015,19(1):210-226
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Dharshini Gopal Aditi G Muddebihalkar Akshay Uttarkar C Prinith Kaveramma Ulluvangada Praveen 《Journal of biomolecular structure & dynamics》2020,38(15):4584-4599
AbstractCandida albicans, fungal yeast causes several lethal infections in immune-suppressed patients and recently emerged as drug-resistant pathogens worldwide. The present study aimed to screen putative drug targets of Candia albicans and to study the binding potential of novel natural lead compounds towards these targets by computational virtual screening and molecular dynamic (MD) simulation. Through extensive analysis of mitogen-activated protein kinase (MAPK) signalling pathways, mitogen-activated protein kinase-1 (HOG1) and cell division control protein-42 (CDC42) genes were prioritized as putative targets based on their virulent functions. The three-dimensional structures of these genes, not available in their native forms, were computationally modeled and validated. 76 lead molecules from various natural sources were screened and their drug likeliness and pharmacokinetic features were predicted. Among these ligands, two lead molecules that demonstrated ideal drug-likeliness and pharmacokinetic features were docked against HOG1 and CDC42 and their binding potential was compared with the binding of conventional drug Fluconazole with their usual target. The prediction was computationally validated by MD simulation. The current study revealed that Cudraxanthone-S present in Cudrania cochinchinensis and Scutifoliamide-B present in Piper scutifolium exhibited ideal drug likeliness, pharmacokinetics and binding potential to the prioritized targets in comparison with the binding of Fluconazole and their usual target. MD simulation showed that CDC42-Cudraxanthone-S and HOG1-Scutifoliamide-B complexes were exhibited stability throughout MD simulation. Thus, the study provides significant insight into employing HOG1 and CDC42 of MAPK as putative drug targets of C. albicans and Cudraxanthone-S and Scutifoliamide-B as potential inhibitors for drug discovery.Communicated by Ramaswamy H. Sarma 相似文献
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Transcriptional memory of cells of origin overrides β‐catenin requirement of MLL cancer stem cells
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Magdalena Zarowiecki Tsz Kan Fung Maria Mallardo Chiou‐Tsun Tsai Priscilla Nga Ieng Lau Quoc Chinh Hoang Pedro Veiga Jo Barnes Claire Lynn Amanda Wilson Boris Lenhard Chi Wai Eric So 《The EMBO journal》2017,36(21):3139-3155
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Cui Q Sulea T Schrag JD Munger C Hung MN Naïm M Cygler M Purisima EO 《Journal of molecular biology》2008,379(4):787-802
Using the MP1-p14 scaffolding complex from the mitogen-activated protein kinase signaling pathway as model system, we explored a structure-based computational protocol to probe and characterize binding affinity hot spots at protein-protein interfaces. Hot spots are located by virtual alanine-scanning consensus predictions over three different energy functions and two different single-structure representations of the complex. Refined binding affinity predictions for select hot-spot mutations are carried out by applying first-principle methods such as the molecular mechanics generalized Born surface area (MM-GBSA) and solvated interaction energy (SIE) to the molecular dynamics (MD) trajectories for mutated and wild-type complexes. Here, predicted hot-spot residues were actually mutated to alanine, and crystal structures of the mutated complexes were determined. Two mutated MP1-p14 complexes were investigated, the p14(Y56A)-mutated complex and the MP1(L63A,L65A)-mutated complex. Alternative ways to generate MD ensembles for mutant complexes, not relying on crystal structures for mutated complexes, were also investigated. The SIE function, fitted on protein-ligand binding affinities, gave absolute binding affinity predictions in excellent agreement with experiment and outperformed standard MM-GBSA predictions when tested on the MD ensembles of Ras-Raf and Ras-RalGDS protein-protein complexes. For wild-type and mutant MP1-p14 complexes, SIE predictions of relative binding affinities were supported by a yeast two-hybrid assay that provided semiquantitative relative interaction strengths. Results on the MP1-mutated complex suggested that SIE predictions deteriorate if mutant MD ensembles are approximated by just mutating the wild-type MD trajectory. The SIE data on the p14-mutated complex indicated feasibility for generating mutant MD ensembles from mutated wild-type crystal structure, despite local structural differences observed upon mutation. For energetic considerations, this would circumvent costly needs to produce and crystallize mutated complexes. The sensitized protein-protein interface afforded by the p14(Y56A) mutation identified here has practical applications in screening-based discovery of first-generation small-molecule hits for further development into specific modulators of the mitogen-activated protein kinase signaling pathway. 相似文献
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François Fagotto 《EMBO reports》2013,14(5):422-433
After two decades of stardom, one would think that β‐catenin has revealed all of its most intimate details. Yet the essence of its duality has remained mysterious—how can a single protein both be the core link between cadherins and the cytoskeleton, and the nuclear messenger for Wnt signalling? On the basis of the available evidence and on molecular and evolutionary considerations, I propose that β‐catenin was a born nuclear transport receptor, which by interacting with adhesion molecules acquired the property to coordinate nuclear functions with cell–cell adhesion. While Wnt signalling diverted this activity, the original pathway might still function in modern eukaryotes. 相似文献
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Can Wang Zengxia Li Zhaohua Yang Hongbo Zhao Yong Yang Kangli Chen Xiumei Cai Liying Wang Yinghong Shi Shuangjian Qiu Jia Fan Xiliang Zha 《Journal of cellular biochemistry》2010,109(1):113-123
N‐acetylglucosaminyltransferase V (GnT‐V) has been reported to be positively associated with tumor progression, but its mechanism still remains unknown. In the present study, we found that GnT‐V overexpression not only changed the glycosylation of receptor protein tyrosine phosphatase kappa (RPTPκ) but also decreased its protein level. Moreover, GnT‐V overexpression decreased cell calcium‐independent adhesion and increased the tyrosine phosphorylation level of β‐catenin, in which RPTPκ played an important role. Since RPTPκ has an RXKR motif, which is a favored cleavage site for furin, we used furin inhibitor to further explore the effect of RPTPκ on the change of cell adhesion and β‐catenin signaling induced by GnT‐V. Our results showed that preventing RPTPκ cleavage rescued the above effects of GnT‐V, suggesting that furin cleavage could be one of the factors for RPTPκ to regulate cell adhesion and β‐catenin signaling in GnT‐V overexpression cell lines. In addition, the increased tyrosine phosphorylation level of β‐catenin was associated with the increased nuclear level of β‐catenin and downstream signaling molecules such as c‐myc and cyclin D1 that were associated with cell proliferation. Our results suggest that GnT‐V could decrease human hepatoma SMMC‐7721 cell adhesion and promote cell proliferation partially through RPTPκ. J. Cell. Biochem. 109: 113–123, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
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LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose‐induced podocyte injury via its interplay with β‐catenin
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Mengsi Hu Rong Wang Xiaobing Li Minghua Fan Jiangong Lin Junhui Zhen Liqun Chen Zhimei Lv 《Journal of cellular and molecular medicine》2017,21(11):2732-2747
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Ming Zhang Ying Yan Yong‐bin Lim Dezhi Tang Rong Xie Ann Chen Peter Tai Stephen E. Harris Lianping Xing Yi‐Xian Qin Di Chen 《Journal of cellular biochemistry》2009,108(4):896-905
Canonical BMP and Wnt signaling pathways play critical roles in regulation of osteoblast function and bone formation. Recent studies demonstrate that BMP‐2 acts synergistically with β‐catenin to promote osteoblast differentiation. To determine the molecular mechanisms of the signaling cross‐talk between canonical BMP and Wnt signaling pathways, we have used primary osteoblasts and osteoblast precursor cell lines 2T3 and MC3T3‐E1 cells to investigate the effect of BMP‐2 on β‐catenin signaling. We found that BMP‐2 stimulates Lrp5 expression and inhibits the expression of β‐TrCP, the F‐box E3 ligase responsible for β‐catenin degradation and subsequently increases β‐catenin protein levels in osteoblasts. In vitro deletion of the β‐catenin gene inhibits osteoblast proliferation and alters osteoblast differentiation and reduces the responsiveness of osteoblasts to the BMP‐2 treatment. These findings suggest that BMP‐2 may regulate osteoblast function in part through modulation of the β‐catenin signaling. J. Cell. Biochem. 108: 896–905, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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