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https://www.readbyqxmd.com/read/29142306/an-exome-sequencing-based-approach-for-genome-wide-association-studies-in-the-dog
#1
Bart J G Broeckx, Thomas Derrien, Stéphanie Mottier, Valentin Wucher, Edouard Cadieu, Benoît Hédan, Céline Le Béguec, Nadine Botherel, Kerstin Lindblad-Toh, Jimmy H Saunders, Dieter Deforce, Catherine André, Luc Peelman, Christophe Hitte
Genome-wide association studies (GWAS) are widely used to identify loci associated with phenotypic traits in the domestic dog that has emerged as a model for Mendelian and complex traits. However, a disadvantage of GWAS is that it always requires subsequent fine-mapping or sequencing to pinpoint causal mutations. Here, we performed whole exome sequencing (WES) and canine high-density (cHD) SNP genotyping of 28 dogs from 3 breeds to compare the SNP and linkage disequilibrium characteristics together with the power and mapping precision of exome-guided GWAS (EG-GWAS) versus cHD-based GWAS...
November 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29127379/rspo3-antagonism-inhibits-growth-and-tumorigenicity-in-colorectal-tumors-harboring-common-wnt-pathway-mutations
#2
Marcus M Fischer, V Pete Yeung, Fiore Cattaruzza, Rajaa Hussein, Wan-Ching Yen, Christopher Murriel, James W Evans, Gilbert O'Young, Alayne L Brunner, Min Wang, Jennifer Cain, Belinda Cancilla, Ann Kapoun, Timothy Hoey
Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43...
November 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29117559/an-eye-organoid-approach-identifies-six3-suppression-of-r-spondin-2-as-a-critical-step-in-mouse-neuroretina-differentiation
#3
Nozomu Takata, Deepti Abbey, Luciano Fiore, Sandra Acosta, Ruopeng Feng, Hyea Jin Gil, Alfonso Lavado, Xin Geng, Ashley Interiano, Geoffrey Neale, Mototsugu Eiraku, Yoshiki Sasai, Guillermo Oliver
Recent advances in self-organizing, 3-dimensional tissue cultures of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) provided an in vitro model that recapitulates many aspects of the in vivo developmental steps. Using Rax-GFP-expressing ESCs, newly generated Six3(-/-) iPSCs, and conditional null Six3(delta/f);Rax-Cre ESCs, we identified Six3 repression of R-spondin 2 (Rspo2) as a required step during optic vesicle morphogenesis and neuroretina differentiation. We validated these results in vivo by showing that transient ectopic expression of Rspo2 in the anterior neural plate of transgenic mouse embryos was sufficient to inhibit neuroretina differentiation...
November 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/28743298/r-spondin2-a-novel-target-of-nobox-identification-of-variants-in-a-cohort-of-women-with-primary-ovarian-insufficiency
#4
Justine Bouilly, Isabelle Beau, Sara Barraud, Valérie Bernard, Brigitte Delemer, Jacques Young, Nadine Binart
BACKGROUND: R-spondin2 (Rspo2) is a secreted agonist of the canonical Wnt/β-catenin signaling pathway. Rspo2 plays a key role in development of limbs, lungs and hair follicles, and more recently during ovarian follicle development. Rspo2 heterozygous deficient female mice become infertile around 4 months of age mimicking primary ovarian insufficiency (POI). The study aimed to investigate the regulation of RSPO2 and its potential involvement in pathophysiology of POI. METHODS: We cloned the RSPO2 promoter and performed transcriptional assays to determine if RSPO2 can be regulated by NOBOX, an ovarian transcription factor...
July 25, 2017: Journal of Ovarian Research
https://www.readbyqxmd.com/read/28731148/molecular-genetics-and-targeted-therapy-of-wnt-related-human-diseases-review
#5
Masuko Katoh, Masaru Katoh
Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription...
September 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28695896/r-spondin-chromosome-rearrangements-drive-wnt-dependent-tumour-initiation-and-maintenance-in-the-intestine
#6
Teng Han, Emma M Schatoff, Charles Murphy, Maria Paz Zafra, John E Wilkinson, Olivier Elemento, Lukas E Dow
Defining the genetic drivers of cancer progression is a key in understanding disease biology and developing effective targeted therapies. Chromosome rearrangements are a common feature of human malignancies, but whether they represent bona fide cancer drivers and therapeutically actionable targets, requires functional testing. Here, we describe the generation of transgenic, inducible CRISPR-based mouse systems to engineer and study recurrent colon cancer-associated EIF3E-RSPO2 and PTPRK-RSPO3 chromosome rearrangements in vivo...
July 11, 2017: Nature Communications
https://www.readbyqxmd.com/read/28651234/microrna-493-suppresses-hepatocellular-carcinoma-tumorigenesis-through-down-regulation-of-anthrax-toxin-receptor-1-antxr1-and-r-spondin-2-rspo2
#7
Yuqiang Xu, Kuikui Ge, Junhao Lu, Jinjiang Huang, Wei Wei, Qingshan Huang
Hepatocellular carcinoma (HCC) is known as a highly prevalent cancer with a poor prognosis and short survival time, despite intensive research and clinical efforts. Increasing numbers of studies have reported that microRNAs are involved in the malignant behavior of hepatocellular carcinoma cells via directly targeting multiple oncogenes or tumor suppressors. Here, we report that the expression of microRNA-493 (miR-493) is decreased in HCC cell lines and in tumor tissues. Overexpression of miR-493 in HCC cells dramatically inhibited cell proliferation and colony-formation in vitro and inhibited tumor formation of HCC cell xenografts in vivo...
September 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28600110/rspo2-suppresses-colorectal-cancer-metastasis-by-counteracting-the-wnt5a-fzd7-driven-noncanonical-wnt-pathway
#8
Xiaoming Dong, Wanqin Liao, Li Zhang, Xi Tu, Jin Hu, Tianke Chen, Xiaowei Dai, Yan Xiong, Weicheng Liang, Chaodong Ding, Rui Liu, Juji Dai, Ouchen Wang, Liting Lu, Xincheng Lu
R-spondins play critical roles in development, stem cell survival, and tumorigenicity by modulating Wnt/β-catenin signaling; however, the role of R-spondins in noncanonical Wnt signaling regulation remains largely unknown. We demonstrate here that R-spondin 2 (RSPO2) has an inhibitory effect on colorectal cancer (CRC) cell migration, invasion, and metastasis. Reduced RSPO2 expression was associated with tumor metastasis and poor survival in CRC patients. The metastasis-suppressive activity of RSPO2 was independent of the Wnt/β-catenin signaling pathway but dependent on the Fzd7-mediated noncanonical Wnt signaling pathway...
August 28, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28543708/comprehensive-characterization-of-rspo-fusions-in-colorectal-traditional-serrated-adenomas
#9
Shigeki Sekine, Reiko Ogawa, Taiki Hashimoto, Kojima Motohiro, Hiroshi Yoshida, Hirokazu Taniguchi, Yutaka Saito, Ohno Yasuhiro, Atsushi Ochiai, Nobuyoshi Hiraoka
AIMS: Traditional serrated adenoma (TSA) is a rare but distinct type of colorectal polyp. Our previous study showed that PTPRK-RSPO3 fusions are frequent and characteristic genetic alterations in TSAs. This study aimed to characterize comprehensively the prevalence and variability of RSPO fusions in colorectal TSAs. METHODS AND RESULTS: We examined RSPO expression and explored novel RSPO fusions in 129 TSAs, including 66 lesions analysed previously for WNT pathway gene mutations...
May 24, 2017: Histopathology
https://www.readbyqxmd.com/read/28472820/clinical-value-of-r-spondins-in-triple-negative-and-metaplastic-breast-cancers
#10
F Coussy, F Lallemand, S Vacher, A Schnitzler, W Chemlali, M Caly, A Nicolas, S Richon, D Meseure, R El Botty, L De-Plater, L Fuhrmann, T Dubois, S Roman-Roman, V Dangles-Marie, E Marangoni, I Bièche
BACKGROUND: RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). METHODS: Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs...
June 6, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28350845/abnormal-expression-of-mrna-microrna-alteration-and-aberrant-dna-methylation-patterns-in-rectal-adenocarcinoma
#11
Yang Hua, Xiukun Ma, Xianglong Liu, Xiangfei Yuan, Hai Qin, Xipeng Zhang
AIM: Rectal adenocarcinoma (READ) is a malignancy cancer with the high morbidity and motility worldwide. Our study aimed to explore the potential pathogenesis of READ through integrated analysis of gene expression profiling and DNA methylation data. METHODS: The miRNA, mRNA expression profiling and corresponding DNA methylation data were downloaded from The Cancer Genome Atlas (TCGA) database. Differentially expressed mRNAs/ miRNAs/methylated regions (DEmRNA/DEmiRNAs) were identified in READ...
2017: PloS One
https://www.readbyqxmd.com/read/28219935/novel-insights-into-gastric-cancer-methylation-of-r-spondins-and-regulation-of-lgr5-by-sp1
#12
Franziska Wilhelm, Eva Simon, Christine Böger, Hans-Michael Behrens, Sandra Krüger, Christoph Röcken
Recently, it was shown that leucine-rich repeat-containing receptor 5 (LGR5)-expressing stem cells are the cellular origin of intestinal-type gastric cancer. The aim of our study was to uncover regulatory mechanisms of LGR5 expression in gastric mucosa and their implications for cancer development. Reporter assays identified an LGR5 promoter fragment, which is highly relevant for active LGR5 expression. Chromatin immunoprecipitation verified that SP1 is bound within this region, and reporter activity increased in SP1 transfected cells...
June 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/27809465/identification-of-growth-trait-related-genes-in-a-yorkshire-purebred-pig-population-by-genome-wide-association-studies
#13
Qingli Meng, Kejun Wang, Xiaolei Liu, Haishen Zhou, Li Xu, Zhaojun Wang, Meiying Fang
OBJECTIVE: The aim of this study is to identify genomic regions or genes controlling growth traits in pigs. METHODS: Using a panel of 54,148 single nucleotide polymorphisms (SNPs), we performed a genome-wide Association (GWA) study in 562 pure Yorshire pigs with four growth traits: average daily gain from 30 kg to 100 kg or 115 kg, and days to 100 kg or 115 kg. Fixed and random model Circulating Probability Unification method was used to identify the associations between 54,148 SNPs and these four traits...
April 2017: Asian-Australasian Journal of Animal Sciences
https://www.readbyqxmd.com/read/27767183/molecular-characterization-of-thy1-expressing-fear-inhibiting-neurons-within-the-basolateral-amygdala
#14
Kenneth M McCullough, Dennis Choi, Jidong Guo, Kelsey Zimmerman, Jordan Walton, Donald G Rainnie, Kerry J Ressler
Molecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or 'Fear-Off' neurons during behaviour...
October 21, 2016: Nature Communications
https://www.readbyqxmd.com/read/27571704/rspo2-suppresses-cd36-mediated-apoptosis-in-oxidized-low-density-lipoprotein-induced-macrophages
#15
Hui Yan, Shuai Wang, Zhenwei Li, Zewei Sun, Jie Zan, Wenting Zhao, Yanyun Pan, Zhen Wang, Mingjie Wu, Jianhua Zhu
Oxidized low density lipoprotein (oxLDL)-induced apoptosis of macrophages contributes to the formation of atherosclerotic plaques. R‑spondin 2 (Rspo2), a member of the cysteine‑rich secreted proteins, has been shown to be involved in the oncogenesis of several types of cancer. It has also been found to be abundantly expressed among the four R‑spondin members in macrophages. The present study was performed to determine whether Rspo2 is involved in the ox‑LDL‑induced apoptosis of macrophages. It was identified that Rspo2 inhibited oxLDL‑induced apoptosis in the presence of endoplasmic reticulum (ER) stress activator using flow cytometry...
October 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27511199/rspo3-expands-intestinal-stem-cell-and-niche-compartments-and-drives-tumorigenesis
#16
John Hilkens, Nikki C Timmer, Mandy Boer, Gerjon J Ikink, Matthias Schewe, Andrea Sacchetti, Martijn A J Koppens, Ji-Ying Song, Elvira R M Bakker
OBJECTIVE: The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models...
June 2017: Gut
https://www.readbyqxmd.com/read/27374772/identification-and-functional-characterization-of-rspo2-as-a-susceptibility-gene-for-ossification-of-the-posterior-longitudinal-ligament-of-the-spine
#17
Masahiro Nakajima, Ikuyo Kou, Hirofumi Ohashi, Shiro Ikegawa
Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common spinal disorder that results from ectopic ossification of the posterior longitudinal ligament and causes intractable myelopathy and radiculopathy. In a previous genome-wide association study (GWAS), we found six loci associated with OPLL; however, susceptibility genes in these loci have not been identified yet. Here, we examined one of the GWAS loci and identified RSPO2 (encoding R-spondin 2) as a susceptibility gene for OPLL...
July 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27338477/control-of-wnt-receptor-turnover-by-r-spondin-znrf3-rnf43-signaling-module-and-its-dysregulation-in-cancer
#18
REVIEW
Huai-Xiang Hao, Xiaomo Jiang, Feng Cong
Aberrant activation of the Wnt/β-catenin pathway is frequently found in various cancers, often through mutations of downstream components. Inhibiting β-catenin signaling in tumors with downstream pathway mutations remains challenging, due to a lack of favorable targets. On the other hand, targeting upstream components of the Wnt pathway is rather straightforward. However, it is difficult to identify tumors addicted to autocrine or paracrine Wnt signaling. Discovery of the R-spondin-ZNRF3/RNF43 signaling module and its genetic alterations in cancers represents a breakthrough in this area...
June 8, 2016: Cancers
https://www.readbyqxmd.com/read/27328992/r-spondin-2-promotes-acetylcholine-receptor-clustering-at-the-neuromuscular-junction-via-lgr5
#19
Hiroaki Nakashima, Bisei Ohkawara, Shinsuke Ishigaki, Takayasu Fukudome, Kenyu Ito, Mikito Tsushima, Hiroyuki Konishi, Tatsuya Okuno, Toshiro Yoshimura, Mikako Ito, Akio Masuda, Gen Sobue, Hiroshi Kiyama, Naoki Ishiguro, Kinji Ohno
At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27314333/n-glycosylation-of-human-r-spondin-1-is-required-for-efficient-secretion-and-stability-but-not-for-its-heparin-binding-ability
#20
Chiung-Fang Chang, Li-Sung Hsu, Chieh-Yu Weng, Chih-Kai Chen, Shu-Ying Wang, Yi-Hwa Chou, Yan-Yu Liu, Zi-Xiu Yuan, Wen-Ying Huang, Ho Lin, Yau-Hung Chen, Jen-Ning Tsai
R-spondin 1 (Rspo1) plays an essential role in stem cell biology by potentiating Wnt signaling activity. Despite the fact that Rspo1 holds therapeutic potential for a number of diseases, its biogenesis is not fully elucidated. All Rspo proteins feature two amino-terminal furin-like repeats, which are responsible for Wnt signal potentiation, and a thrombospondin type 1 (TSR1) domain that can provide affinity towards heparan sulfate proteoglycans. Using chemical inhibitors, deglycosylase and site-directed mutagenesis, we found that human Rspo1 and Rspo3 are both N-glycosylated at N137, a site near the C-terminus of the furin repeat 2 domain, and Rspo2 is N-glycosylated at N160, a position near the N-terminus of TSR1 domain...
June 14, 2016: International Journal of Molecular Sciences
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