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https://www.readbyqxmd.com/read/28752891/inhibition-of-nuclear-wnt-signaling-challenges-of-an-elusive-target-for-cancer-therapy
#1
REVIEW
Yung Lyou, Amber N Habowski, George T Chen, Marian L Waterman
The highly conserved Wnt signaling pathway plays an important role in embryonic development and disease pathogenesis, most notably cancer. The "canonical," or β-catenin-dependent Wnt signal initiates at the cell plasma membrane with the binding of Wnt proteins to Frizzled:LRP5/LRP6 receptor complexes, and is mediated by the translocation of the transcription co-activator protein, β-catenin, into the nucleus. β-catenin then forms a complex with TCF/LEF transcription factors to regulate multiple gene programs...
July 28, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28741966/the-connections-of-wnt-pathway-components-with-cell-cycle-and-centrosome-side-effects-or-a-hidden-logic
#2
Vítězslav Bryja, Igor Červenka, Lukáš Čajánek
Wnt signaling cascade has developed together with multicellularity to orchestrate the development and homeostasis of complex structures. Wnt pathway components - such as β-catenin, Dishevelled (DVL), Lrp6, and Axin-- are often dedicated proteins that emerged in evolution together with the Wnt signaling cascade and are believed to function primarily in the Wnt cascade. It is interesting to see that in recent literature many of these proteins are connected with cellular functions that are more ancient and not limited to multicellular organisms - such as cell cycle regulation, centrosome biology, or cell division...
July 25, 2017: Critical Reviews in Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/28723729/wnt-signaling-in-cardiovascular-disease-opportunities-and-challenges
#3
Austin Gay, Dwight A Towler
PURPOSE OF REVIEW: Cardiometabolic diseases increasingly afflict our aging, dysmetabolic population. Complex signals regulating low-density lipoprotein receptor-related protein (LRP) and frizzled protein family members - the plasma membrane receptors for the cadre of Wnt polypeptide morphogens - contribute to the control of cardiovascular homeostasis. RECENT FINDINGS: Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease...
July 18, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28697798/a-proteomic-analysis-of-lrrk2-binding-partners-reveals-interactions-with-multiple-signaling-components-of-the-wnt-pcp-pathway
#4
Alena Salašová, Chika Yokota, David Potěšil, Zbyněk Zdráhal, Vítězslav Bryja, Ernest Arenas
BACKGROUND: Autosomal-dominant mutations in the Park8 gene encoding Leucine-rich repeat kinase 2 (LRRK2) have been identified to cause up to 40% of the genetic forms of Parkinson's disease. However, the function and molecular pathways regulated by LRRK2 are largely unknown. It has been shown that LRRK2 serves as a scaffold during activation of WNT/β-catenin signaling via its interaction with the β-catenin destruction complex, DVL1-3 and LRP6. In this study, we examine whether LRRK2 also interacts with signaling components of the WNT/Planar Cell Polarity (WNT/PCP) pathway, which controls the maturation of substantia nigra dopaminergic neurons, the main cell type lost in Parkinson's disease patients...
July 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28696417/harnessing-low-density-lipoprotein-receptor-protein-6-lrp6-genetic-variation-and-wnt-signaling-for-innovative-diagnostics-in-complex-diseases
#5
REVIEW
Z-M Wang, J-Q Luo, L-Y Xu, H-H Zhou, W Zhang
Wnt signaling regulates a broad variety of processes in both embryonic development and various diseases. Recent studies indicated that some genetic variants in Wnt signaling pathway may serve as predictors of diseases. Low-density lipoprotein receptor protein 6 (LRP6) is a Wnt co-receptor with essential functions in the Wnt/β-catenin pathway, and mutations in LRP6 gene are linked to many complex human diseases, including metabolic syndrome, cancer, Alzheimer's disease and osteoporosis. Therefore, we focus on the role of LRP6 genetic polymorphisms and Wnt signaling in complex diseases, and the mechanisms from mouse models and cell lines...
July 11, 2017: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/28694256/multiple-modes-of-lrp4-function-in-modulation-of-wnt-%C3%AE-catenin-signaling-during-tooth-development
#6
Youngwook Ahn, Carrie Sims, Megan J Murray, Paige K Kuhlmann, Jesús Fuentes-Antrás, Scott D Weatherbee, Robb Krumlauf
During development and homeostasis, precise control of Wnt/β-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of Wnt co-receptors, Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/β-catenin signaling presumably through its ability to bind to the Wise (Sostdc1)/Sost (Sclerostin) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles...
July 10, 2017: Development
https://www.readbyqxmd.com/read/28679315/bone-marrow-mesenchymal-stem-cell-derived-cd63-exosomes-transport-wnt3a-exteriorly-and-enhance-dermal-fibroblast-proliferation-migration-and-angiogenesis-in-vitro
#7
Jeffrey D McBride, Luis Menocal-Rodriguez, Ambar Candanedo, Wellington Guzman, Marta Garcia-Contreras, Evangelos Van Badiavas
Wnts are secreted glycoproteins that regulate stem cell self-renewal, differentiation, and cell-to-cell communication during embryonic development and in adult tissues. Bone marrow mesenchymal stem cells (BM-MSCs) have been shown to stimulate dermis repair and regeneration; however, it is unclear how BM-MSCs may modulate downstream Wnt signaling. While recent reports implicate that Wnt ligands and Wnt messenger RNAs (such as Wnt4) exist within the interior compartment of exosomes, it has been debated whether or not Wnts exist on the exterior surface of exosomes to travel in the extracellular space...
July 5, 2017: Stem Cells and Development
https://www.readbyqxmd.com/read/28674183/n-terminal-part-of-dishevelled-dep-domain-is-required-for-wnt-%C3%AE-catenin-signaling-in-mammalian-cells
#8
Petra Paclíková, Ondřej Bernatík, Tomasz Witold Radaszkiewicz, Vítězslav Bryja
Dishevelled (DVL) proteins are key mediators of Wnt/β-catenin signaling pathway. All DVL proteins contain three conserved domains -- DIX, PDZ and DEP. There is a consensus in the field that DIX domain is critical for Wnt/β-catenin signaling but contradictory evidence exists regarding the function of the DEP domain. It has been difficult until recently to test the importance of the DEP domain rigorously because of the interference with endogenous DVL, expressed in all Wnt-responsive cell lines. In this study, we took advantage of DVL KO (DVL1/DVL2/DVL3-triple knockout) cells, fully deficient in Wnt3a-induced signaling events, and performed series of rescue experiments...
July 3, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28586911/serpina3k-ameliorates-the-corneal-oxidative-injury-induced-by-4-hydroxynonenal
#9
Xiling Zheng, Huixia Cui, Yuanyuan Yin, Yajing Zhang, Rongrong Zong, Xiaorui Bao, Jian-Xing Ma, Zuguo Liu, Yueping Zhou
Purpose: We previously demonstrated that SERPINA3K has anti-inflammatory, antiangiogenic, and antioxidant effects in corneas. Here we further investigated the effects of SERPINA3K on the corneal oxidant injury setting recently developed and induced by 4-hydroxynonenal (4-HNE). Methods: We applied the 4-HNE-induced corneal oxidant stress in cultured human corneal epithelial (HCE) cells in vitro and to the cornea of rats in vivo. The following experiments were conducted: cell counting kit 8 assay to detect cell viability; quantitative real-time PCR assay; Western blotting and immunofluorescent staining to measure gene expressions or protein levels of key reactive oxygen species (ROS)-associated factors (3-nitrotyrosine [3-NT]; nicotinamide adenine dinucleotide phosphate [NADPH]-oxidase 4 [NOX4]; superoxide dismutase [SOD]); catalase and nuclear factor [erythroid-derived 2]-like 2 [NRF2]); as well as main factors of the Wnt/β-catenin signaling pathway (p-LRP6, β-catenin and transcription factor 4 [TCF4]); histologic staining; and TUNEL staining to examine sections of rat corneas...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28569772/deficiency-of-pigment-epithelium-derived-factor-in-nasopharyngeal-carcinoma-cells-triggers-the-epithelial-mesenchymal-transition-and-metastasis
#10
Ting Zhang, Ping Yin, Zichen Zhang, Banglao Xu, Di Che, Zhiyu Dai, Chang Dong, Ping Jiang, Honghai Hong, Zhonghan Yang, Ti Zhou, Jianyong Shao, Zumin Xu, Xia Yang, Guoquan Gao
Distant metastasis is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure while epithelial-mesenchymal transition (EMT) is the critical process of NPC invasion and metastasis. However, tumor-suppressor genes involved in the EMT and metastasis of NPC have not been explored clearly compared with the oncogenes. In the present study, the expression of pigment epithelium-derived factor (PEDF), a potent endogenous antitumor factor, was diminished in human NPC tissues and associated with clinicopathological and EMT features...
June 1, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28549041/value-of-osteoblast-derived-exosomes-in-bone-diseases
#11
Min Ge, Yingzhi Wu, Ronghu Ke, Tianyi Cai, Junyi Yang, Xiongzheng Mu
PURPOSE: The authors' purpose is to reveal the value of osteoblast-derived exosomes in bone diseases. METHODS: Microvesicles from supernatants of mouse Mc3t3 were isolated by ultracentrifugation and then the authors presented the protein profile by proteomics analysis. RESULTS: The authors detected a total number of 1536 proteins by mass spectrometry and found 172 proteins overlap with bone database. The Ingenuity Pathway Analysis shows network of "Skeletal and Muscular System Development and Function, Developmental Disorder, Hereditary Disorder" and pathway about osteogenesis...
June 2017: Journal of Craniofacial Surgery
https://www.readbyqxmd.com/read/28532817/-pro-renin-receptor-as-a-therapeutic-target-for-the-treatment-of-cardiovascular-diseases
#12
REVIEW
Yuan Sun, A H Jan Danser, Xifeng Lu
The discovery of the (pro)renin receptor [(P)RR] 15years ago stimulated ideas on prorenin being more than renin's inactive precursor. Indeed, binding of prorenin to the (P)RR induces a conformational change in the prorenin molecule, allowing it to display angiotensin-generating activity, and additionally results in intracellular signaling in an angiotensin-independent manner. However, the prorenin levels required to observe these angiotensin-dependent and -independent effects of the (P)RR are many orders above its in vivo concentrations, both under normal and pathological conditions...
May 19, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28521288/hypermethylation-of-ndn-promotes-cell-proliferation-by-activating-the-wnt-signaling-pathway-in-colorectal-cancer
#13
Yu-Han Hu, Qing Chen, Yan-Xia Lu, Jian-Ming Zhang, Chun Lin, Fan Zhang, Wen-Juan Zhang, Xiao-Min Li, Wei Zhang, Xue-Nong Li
The progression of CRC is a multistep process involving several genetic changes or epigenetic modifications. NDN is a member of the MAGE family, encoding a protein that generally suppresses cell proliferation and acting as a transcriptional repressor. Immunohistochemical staining revealed that the expression of NDN was significantly down-regulated in CRC tissues compared with normal tissues and the down-regulation of NDN in CRC could reflect the hypermethylation of the NDN promoter. Treatment of the CRC cell line SW480 with the demethylating agent 5-Aza-CdR restored the NDN expression level...
July 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28515679/downregulation-of-the-repressor-element-1-silencing-transcription-factor-rest-is-associated-with-akt-mtor-and-wnt-%C3%AE-catenin-signaling-in-prion-diseases-models
#14
Zhiqi Song, Syed Z A Shah, Wei Yang, Haodi Dong, Lifeng Yang, Xiangmei Zhou, Deming Zhao
Prion diseases are a group of infectious diseases characterized by multiple neuropathological changes, yet the mechanisms that preserve function and protect against prion-associated neurodegeneration are still unclear. We previously reported that the repressor element 1-silencing transcription factor (REST) alleviates neurotoxic prion peptide (PrP106-126)-induced toxicity in primary neurons. Here we confirmed the findings of the in vitro model in 263K infected hamsters, an in vivo model of prion diseases and further showed the relationships between REST and related signaling pathways...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28514532/the-dickkopf1-ckap4-axis-creates-a-novel-signaling-pathway-and-may-represent-a-molecular-target-for-cancer-therapy
#15
REVIEW
Akira Kikuchi, Katsumi Fumoto, Hirokazu Kimura
Dickkopf 1 (DKK1) is a secretory protein and antagonizes oncogenic Wnt signaling by binding to the Wnt co-receptor low-density lipoprotein receptor-related proteins 6 (LRP6). DKK1 is also suggested to regulate its own signaling to associate with tumor aggressiveness. However, the underlying mechanism by which DKK1 promotes cancer cell proliferation has remained to be clarified for a long time. It has been recently found that cytoskeleton-associated protein 4 (CKAP4), which was originally reported as an endoplasmic reticulum membrane protein, acts as a novel DKK1 receptor...
May 17, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28513615/exome-sequencing-of-two-italian-pedigrees-with-non-isolated-chiari-malformation-type-i-reveals-candidate-genes-for-cranio-facial-development
#16
Elisa Merello, Lorenzo Tattini, Alberto Magi, Andrea Accogli, Gianluca Piatelli, Marco Pavanello, Domenico Tortora, Armando Cama, Zoha Kibar, Valeria Capra, Patrizia De Marco
Chiari malformation type I (CMI) is a congenital abnormality of the cranio-cerebral junction with an estimated incidence of 1 in 1280. CMI is characterized by underdevelopment of the occipital bone and posterior fossa (PF) and consequent cerebellar tonsil herniation. The presence for a genetic basis to CMI is supported by many lines of evidence. The cellular and molecular mechanisms leading to CM1 are poorly understood. The occipital bone formation is dependent on complex interactions between genes and molecules with pathologies resulting from disruption of this delicate process...
August 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/28484252/wnt-inhibitory-factor-1-wif1-methylation-and-its-association-with-clinical-prognosis-in-patients-with-chondrosarcoma
#17
Pei Liu, Jacson K Shen, Francis J Hornicek, Fuyun Liu, Zhenfeng Duan
Chondrosarcoma (CS) is a rare cancer, but it is the second most common primary malignant bone tumor and highly resistant to conventional chemotherapy and radiotherapy. Aberrant DNA methylation in the promoter CpG island of Wnt inhibitory factor 1 (WIF1) has been observed in different cancers. However, no studies have shown the relationship between WIF1 methylation and CS. In this study, we found promoter methylated WIF1 in both CS cell lines (CS-1 and SW1353) and tumor tissues. Western blot analysis confirmed loss WIF1 expression and activation of Wnt pathway proteins (Wnt5a/b, LRP6, and Dvl2)...
May 8, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28467820/non-equivalence-of-wnt-and-r-spondin-ligands-during-lgr5-intestinal-stem-cell-self-renewal
#18
Kelley S Yan, Claudia Y Janda, Junlei Chang, Grace X Y Zheng, Kathryn A Larkin, Vincent C Luca, Luis A Chia, Amanda T Mah, Arnold Han, Jessica M Terry, Akifumi Ootani, Kelly Roelf, Mark Lee, Jenny Yuan, Xiao Li, Christopher R Bolen, Julie Wilhelmy, Paige S Davies, Hiroo Ueno, Richard J von Furstenberg, Phillip Belgrader, Solongo B Ziraldo, Heather Ordonez, Susan J Henning, Melissa H Wong, Michael P Snyder, Irving L Weissman, Aaron J Hsueh, Tarjei S Mikkelsen, K Christopher Garcia, Calvin J Kuo
The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28467818/surrogate-wnt-agonists-that-phenocopy-canonical-wnt-and-%C3%AE-catenin-signalling
#19
Claudia Y Janda, Luke T Dang, Changjiang You, Junlei Chang, Wim de Lau, Zhendong A Zhong, Kelley S Yan, Owen Marecic, Dirk Siepe, Xingnan Li, James D Moody, Bart O Williams, Hans Clevers, Jacob Piehler, David Baker, Calvin J Kuo, K Christopher Garcia
Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors...
May 11, 2017: Nature
https://www.readbyqxmd.com/read/28456913/the-effect-and-osteoblast-signaling-response-of-trace-silicon-doping-hydroxyapatite
#20
Tian Sun, Ming Wang, Yiran Shao, Liping Wang, Yingchun Zhu
It is commonly accepted that silicon-doped hydroxyapatite (HAp) can achieve good repair effects for both spinal fusion and bone defect filling. However, the underlying mechanism by which silicon aids such beneficial effects is still not fully understood. Herein, we report on silicon-doped hydroxyapatites with excellent biocompatibility to osteoblast cells and suggest the signaling pathway involved. Non-doped HAp and trace Si-doped HAp (Si/HAp) with Si concentration close to and higher than natural bones were synthesized (i...
April 29, 2017: Biological Trace Element Research
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