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https://www.readbyqxmd.com/read/28546513/the-siah-e3-ubiquitin-ligases-promote-wnt-%C3%AE-catenin-signaling-through-mediating-wnt-induced-axin-degradation
#1
Lei Ji, Bo Jiang, Xiaomo Jiang, Olga Charlat, Amy Chen, Craig Mickanin, Andreas Bauer, Wenqing Xu, Xiaoxue Yan, Feng Cong
The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin...
May 25, 2017: Genes & Development
https://www.readbyqxmd.com/read/28546512/wnt5a-promotes-frizzled-4-signalosome-assembly-by-stabilizing-cysteine-rich-domain-dimerization
#2
Zachary J DeBruine, Jiyuan Ke, Kaleeckal G Harikumar, Xin Gu, Peter Borowsky, Bart O Williams, Wenqing Xu, Laurence J Miller, H Eric Xu, Karsten Melcher
Wnt/β-catenin signaling is activated when extracellular Wnt ligands bind Frizzled (FZD) receptors at the cell membrane. Wnts bind FZD cysteine-rich domains (CRDs) with high affinity through a palmitoylated N-terminal "thumb" and a disulfide-stabilized C-terminal "index finger," yet how these binding events trigger receptor activation and intracellular signaling remains unclear. Here we report the crystal structure of the Frizzled-4 (FZD4) CRD in complex with palmitoleic acid, which reveals a CRD tetramer consisting of two cross-braced CRD dimers...
May 25, 2017: Genes & Development
https://www.readbyqxmd.com/read/28532855/long-term-influence-of-prenatal-high-sucrose-intake-on-learning-and-memory-of-aged-rat-offspring-with-oxidative-stress-and-disruptions-in-nmdars-wnt-signaling-in-hippocampus
#3
Axin He, Yingying Zhang, Lingjun Li, Xueqin Feng, Bin Wei, Di Zhu, Yanping Liu, Lei Wu, Lubo Zhang, Zhice Xu, Miao Sun
Maternal over-nutrition may increase risks of various diseases in the offspring. Our recent work demonstrated that prenatal high sucrose (HS) could impair spatial acquisitionin the adolescentoffspringrats. This study investigated whether prenatal HS has a long-term impact on cognitive capabilities in the aged offspring rats. The aged HS offspring showed impaired glucose tolerance, significantly increased fasting insulin and insulin resistance index, with unchanged plasma glucose. In the navigation test, the aged HS offspring exhibited longer escape latency and longer swimming path length to the platform...
May 19, 2017: Brain Research
https://www.readbyqxmd.com/read/28515221/regulation-of-cerebral-arterial-bkca-channels-by-angiotensin-ii-signaling-in-adult-offspring-exposed-to-prenatal-high-sucrose-diets
#4
Xiuxia Gu, Axin He, Xiaorong Fan, Ruixiu Shi, Xueqin Feng, Le Bo, Lin Jiang, Na Li, Jue Wu, Yuxian Yang, Qinqin Gao, Zhice Xu
Prenatal insults have been shown to affect vascular functions, leading to increased risks of cardiovascular diseases in offspring. The present study determined whether high sucrose intake in pregnancy affected central vascular functions in middle cerebral artery (MCA) of offspring. Sprague-Dawley rats were fed a standard food and tap water with normal or high (20%) sucrose content during pregnancy. Offspring were maintained with normal diets and tap water. Central vascular functions and related ion channels were assessed in male offspring at 5 months old...
May 17, 2017: Bioscience Reports
https://www.readbyqxmd.com/read/28499884/inhibition-of-ubiquitin-specific-protease-34-usp34-induces-epithelial-mesenchymal-transition-and-promotes-stemness-in-mammary-epithelial-cells
#5
Eunhye Oh, Ji Young Kim, Daeil Sung, Youngkwan Cho, Nahyun Lee, Hyunsook An, Yoon-Jae Kim, Tae-Min Cho, Jae Hong Seo
Ubiquitin-specific protease 34 (USP34) is a deubiquitinating enzyme that regulates Axin stability and plays a critical role in Wnt/β-catenin signaling. We sought to investigate the role of USP34 on epithelial-mesenchymal (EMT) induction and its effects on mammary epithelial stem cells. USP34 expression levels were relatively lower in MDA-MB-231 and 4T1 mesenchymal-like cells when compared to epithelial-like cells. Inhibition of USP34 in NMuMG cells induced EMT, as evidenced by the upregulation of EMT markers including N-cadherin, phospho-Smad3, Snail and active-β-catenin, as well as the downregulation of Axin 1 and E-cadherin...
May 10, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28498832/prenatal-exposure-to-the-great-chinese-famine-and-mid-age-hypertension
#6
Lei Wu, Xueqin Feng, Axin He, Yi Ding, Xiuwen Zhou, Zhice Xu
BACKGROUND: One of the most terrible famines last century was Great Chinese Famine (GCF) in 1959~1961 when millions of people died from starving. Under-nutrition during famine between the Western and Eastern (Dutch Hungry vs. GCF) was similar, while cardiovascular consequences might not be the same. Addressing such questions may gain new insight into prevention of cardiovascular diseases. METHODS: A retrospective cohort of 18,593 participants aged 43-49 years of old, was from Suzhou, China...
2017: PloS One
https://www.readbyqxmd.com/read/28493029/age-and-sex-differences-in-human-skeletal-muscle-fibrosis-markers-and-transforming-growth-factor-%C3%AE-signaling
#7
Lewan Parker, Marissa K Caldow, Rani Watts, Pazit Levinger, David Cameron-Smith, Itamar Levinger
PURPOSE: The aim of the study was to determine whether higher fibrosis markers in skeletal muscle of older adults are accompanied by increased expression of components of the canonical TGF-β signal transduction pathway. METHODS: Fourteen healthy young (21-35 years; 9 males and 5 females) and seventeen older (55-75 years; 9 males and 8 females) participants underwent vastus lateralis biopsies to determine intramuscular mRNA and protein expression of fibrogenic markers and TGF-β signaling molecules related to TGF-β1 and myostatin...
May 10, 2017: European Journal of Applied Physiology
https://www.readbyqxmd.com/read/28468239/choline-other-methyl-donors-and-epigenetics
#8
Steven Zeisel
Choline dietary intake varies such that many people do not achieve adequate intakes. Diet intake of choline can modulate methylation because, via betaine homocysteine methyltransferase (BHMT), this nutrient (and its metabolite, betaine) regulate the concentrations of S-adenosylhomocysteine and S-adenosylmethionine. Some of the epigenetic mechanisms that modify gene expression without modifying the genetic code depend on the methylation of DNA or of histones; and diet availability of choline and other methyl-group donors influences both of these methylations...
April 29, 2017: Nutrients
https://www.readbyqxmd.com/read/28431932/the-lncrna-zbed3-as1-induces-chondrogenesis-of-human-synovial-fluid-mesenchymal-stem-cells
#9
Farong Ou, Kai Su, Jiadong Sun, Wenting Liao, Yu Yao, Youhua Zheng, Zhiguang Zhang
Human synovial fluid-derived mesenchymal stem cells (SFMSCs) have great potential for cartilage induction and are promising for cell-based strategies for articular cartilage repair. Many long non-coding RNAs (lncRNAs) regulate chondrogenesis of MSCs. We hypothesized that the divergent lncRNA ZBED3-AS1, which binds locally to chromatin, could promote the expression of zbed3, a novel Axin-interacting protein that activates Wnt/β-catenin signaling, involved in chondrogenesis. However, the function of ZBED3-AS1 in SFMSCs is unclear...
April 18, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28430866/maternal-high-sucrose-diets-altered-vascular-large-conductance-ca2-activated-k-channels-via-reactive-oxygen-species-in-offspring-rats%C3%A2
#10
Xueqin Feng, Xiuwen Zhou, Wenna Zhang, Xiang Li, Axin He, Bailin Liu, Ruixiu Shi, Lei Wu, Jue Wu, Di Zhu, Na Li, Miao Sun, Zhice Xu
Overnutrition during pregnancy could increase risks of cardiovascular diseases in late life. This study investigated whether and how reactive oxygen species (ROS) may influence functions of large-conductance Ca2+-activated K+ channels (BKCa) in the offspring exposed to prenatal high-sucrose (HS). We found that prenatal high-sucrose diets significantly increased phenylephrine (PE)-induced vessel contractions in mesenteric arteries of the adult offspring. Pretreatment with iberiotoxin (BKCa blocker, IBTX) significantly increased PE-mediated vascular contractions in the control, not in the HS group...
April 18, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/28430656/thyroid-cancer-1-c8orf4-shows-high-expression-no-mutation-and-reduced-methylation-level-in-lung-cancers-and-its-expression-correlates-with-%C3%AE-catenin-and-dnmt1-expression-and-poor-prognosis
#11
Yi-Wen Zheng, Li Zhang, Yuan Wang, Song-Yan Chen, Lei Lei, Na Tang, Da-Lei Yang, Lin-Lin Bai, Xiu-Peng Zhang, Gui-Yang Jiang, Lian-He Yang, Hong-Tao Xu, Qing-Chang Li, Xue-Shan Qiu, En-Hua Wang
Thyroid cancer 1 (TC1, C8orf4) plays important roles in tumors. The aim of this study was to examine the protein expression levels, methylation status, and mutational status of TC1 (C8orf4) in lung cancers, and investigate the correlation between TC1, other members of the Wnt signaling pathway, and lung cancer. TC1 expression levels were assessed via immunohistochemical staining in 179 cases of lung cancer. β-catenin, TCF4, Axin, Disabled-2, Chibby, and DNA methyltransferase-1 (DNMT1) expressions were also examined...
April 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28430615/a-novel-mechanism-of-angiotensin-ii-regulated-placental-vascular-tone-in-the-development-of-hypertension-in-preeclampsia
#12
Qinqin Gao, Jiaqi Tang, Na Li, Xiuwen Zhou, Yongmei Li, Yanping Liu, Jue Wu, Yuxian Yang, Ruixiu Shi, Axin He, Xiang Li, Yingying Zhang, Jie Chen, Lubo Zhang, Miao Sun, Zhice Xu
The present study tested the hypothesis that angiotensin II plays a role in the regulation of placental vascular tone, which contributes to hypertension in preeclampsia. Functional and molecular assays were performed in large and micro placental and non-placental vessels from humans and animals. In human placental vessels, angiotensin II induced vasoconstrictions in 78.7% vessels in 155 tests, as referenced to KCl-induced contractions. In contrast, phenylephrine only produced contractions in 3.0% of 133 tests...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28429652/atypical-regulators-of-wnt-%C3%AE-catenin-signaling-as-potential-therapeutic-targets-in-hepatocellular-carcinoma
#13
Jianxiang Chen, Muthukumar Rajasekaran, Kam M Hui
Hepatocellular carcinoma is one of the most common causes of cancer-related death worldwide. Hepatocellular carcinoma development depends on the inhibition and activation of multiple vital pathways, including the Wnt signaling pathway. The Wnt/β-catenin pathway lies at the center of various signaling pathways that regulate embryonic development, tissue homeostasis and cancers. Activation of the Wnt/β-catenin pathway has been observed frequently in hepatocellular carcinoma. However, activating mutations in β-catenin, Axin and Adenomatous Polyposis Coli only contribute to a portion of the Wnt signaling hyper-activation observed in hepatocellular carcinoma...
January 1, 2017: Experimental Biology and Medicine
https://www.readbyqxmd.com/read/28418865/anti-helminthic-niclosamide-inhibits-ras-driven-oncogenic-transformation-via-activation-of-gsk-3
#14
Sung Yong Ahn, Ji Hye Yang, Nam Hee Kim, Kyungro Lee, Yong Hoon Cha, Jun Seop Yun, Hee Eun Kang, Yoonmi Lee, Jiwon Choi, Hyun Sil Kim, Jong In Yook
Despite the importance of Ras oncogenes as a therapeutic target in human cancer, their 'undruggable' tertiary structures limit the effectiveness of anti-Ras drugs. Canonical Wnt signaling contributes to Ras activity by glycogen synthase kinase 3 (GSK-3)-dependent phosphorylation at the C-terminus and subsequent degradation. In the accompanying report, we show that the anti-helminthic niclosamide directly binds to GSK-3 and inhibits Axin functions in colon cancer cells, with reversion of Snail-mediated epithelial-mesenchymal transition...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418862/niclosamide-is-a-potential-therapeutic-for-familial-adenomatosis-polyposis-by-disrupting-axin-gsk3-interaction
#15
Sung Yong Ahn, Nam Hee Kim, Kyungro Lee, Yong Hoon Cha, Ji Hye Yang, So Young Cha, Eunae Sandra Cho, Yoonmi Lee, Jeong Seok Cha, Hyun Soo Cho, Yoon Jeon, Young-Su Yuk, Suebean Cho, Kyoung Tai No, Hyun Sil Kim, Ho Lee, Jiwon Choi, Jong In Yook
The epithelial-mesenchymal transition (EMT) is implicated in tumorigenesis and cancer progression, and canonical Wnt signaling tightly controls Snail, a key transcriptional repressor of EMT. While the suppression of canonical Wnt signaling and EMT comprises an attractive therapeutic strategy, molecular targets for small molecules reverting Wnt and EMT have not been widely studied. Meanwhile, the anti-helminthic niclosamide has been identified as a potent inhibitor of many oncogenic signaling pathways although its molecular targets have not yet been clearly identified...
May 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28418856/low-density-lipoprotein-receptor-related-protein-6-is-a-novel-coreceptor-of-protease-activated-receptor-2-in-the-dynamics-of-cancer-associated-%C3%AE-catenin-stabilization
#16
Jeetendra Kumar Nag, Arun Kancharla, Myriam Maoz, Hagit Turm, Daniel Agranovich, Chhedi Lal Gupta, Beatrice Uziely, Rachel Bar-Shavit
Protease-activated receptor-2 (PAR2) plays a central role in cancer; however, the molecular machinery of PAR2-instigated tumors remains to be elucidated. We show that PAR2 is a potent inducer of β-catenin stabilization, a core process in cancer biology, leading to its transcriptional activity. Novel association of low-density lipoprotein-related protein 6 (LRP6), a known coreceptor of Frizzleds (Fz), with PAR2 takes place following PAR2 activation. The association between PAR2 and LRP6 was demonstrated employing co-immunoprecipitation, bioluminescence resonance energy transfer (BRET), and confocal microscopy analysis...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28408316/down-regulation-of-lrp1b-in-colon-cancer-promoted-the-growth-and-migration-of-cancer-cells
#17
Zhiqiang Wang, Peng Sun, Chun Gao, Ji Chen, Jun Li, Zhonghao Chen, Ming Xu, Jun Shao, Yunpeng Zhang, Jiang Xie
Aberrant activation of beta-catenin/TCF signaling is one of the hallmarks of colon cancer. It is of great interest to study the mechanism for the regulation of beta-catenin/TCF signaling. In this study, it was found that LRP1B was down-regulated in colon cancer tissues and inhibited the growth, migration and metastasis of colon cancer cells. The molecular mechanism study revealed that LRP1B interacted with DVL2, inhibited the interaction between DVL2 and Axin, and negatively regulated beta-catenin/TCF signaling...
April 10, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28371398/targeting-tankyrase-to-fight-wnt-dependent-tumours
#18
Tor Espen Thorvaldsen
Aberrant WNT signalling activity is linked to various diseases due to the WNT dependency of fundamental processes during development and in adult tissue homeostasis. Mutations in components of the multiprotein β-catenin destruction complex promote excessive amounts of the main transcriptional activator β-catenin and are particularly common in colorectal cancer (CRC). The tankyrase enzymes were recently implicated as negative regulators of destruction complex activity by mediating degradation of the scaffolding protein AXIN...
April 2, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28355271/transient-helicity-in-intrinsically-disordered-axin-1-studied-by-nmr-spectroscopy-and-molecular-dynamics-simulations
#19
Rainer Bomblies, Manuel Patrick Luitz, Sandra Scanu, Tobias Madl, Martin Zacharias
Many natural proteins are, as a whole or in part, intrinsically disordered. Frequently, such intrinsically disordered regions (IDRs) undergo a transition to a defined and often helical conformation upon binding to partner molecules. The intrinsic propensity of an IDR sequence to fold into a helical conformation already in the absence of a binding partner can have a decisive influence on the binding process and affinity. Using a combination of NMR spectroscopy and molecular dynamics (MD) simulations we have investigated the tendency of regions of Axin-1, an intrinsically disordered scaffolding protein of the WNT signaling pathway, to form helices in segments interacting with binding partners...
2017: PloS One
https://www.readbyqxmd.com/read/28292937/disruption-of-tcf-%C3%AE-catenin-binding-impairs-wnt-signalling-and-induces-apoptosis-in-soft-tissue-sarcoma-cells
#20
Esther Martinez-Font, Irene Felipe-Abrio, Silvia Calabuig-Fariñas, Rafael F Ramos, Josefa Terrasa, Oliver Vögler, Regina Alemany, Javier Martín-Broto, Antònia Obrador-Hevia
Soft tissue sarcomas (STS) are malignant tumours of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumours with more than 50 different subtypes. The Wnt signalling pathway is involved in the development and in the regulation, self-renewal and differentiation of mesenchymal stem cells and plays a role in sarcomagenesis. In this study we have tested pharmacological inhibition of Wnt signalling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects...
March 14, 2017: Molecular Cancer Therapeutics
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