Base de dados : MEDLINE
Pesquisa : D05.500.117.500 [Categoria DeCS]
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[PMID]:29211286
[Au] Autor:Rafighdoost H; Hashemi M; Danesh H; Bizhani F; Bahari G; Taheri M
[Ad] Endereço:Zahedan University of Medical Sciences, Cellular and Molecular Research Center, Zahedan, Iran.
[Ti] Título:Association of single nucleotide polymorphisms in AXIN2, BMP4, and IRF6 with Non-Syndromic Cleft Lip with or without Cleft Palate in a sample of the southeast Iranian population.
[So] Source:J Appl Oral Sci;25(6):650-656, 2017 Nov-Dec.
[Is] ISSN:1678-7765
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:OBJECTIVES: Non-syndromic cleft lip with or without palate (NSCL/P) is a common congenital malformation worldwide, with complex etiology. It has been proposed that interaction of genes and environmental factors play a role in the predisposition to this disease. The aim of this study was to examine the association between AXIN2 (axis inhibition protein 2) rs7224837, BMP4 (bone morphogenetic protein 4) rs17563, and IRF6 (interferon regulatory factor 6) rs861019 and 2235371 polymorphisms and NSCL/P in an Iranian population. MATERIAL AND METHODS: This case-control study was carried out on 132 unrelated NSCL/P patients and 156 healthy subjects. The variants were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The findings suggest that BMP4 rs17563 polymorphism significantly decreased the risk of NSCL/P in codominant (OR=0.36, 95%CI=0.17-0.79, p=0.012, CT vs CC and OR=0.11, 95%CI=0.01-0.88, p = 0.019, TT vs CC), dominant (OR=0.30, 95%CI=0.15-0.62, p = 0.0007, CT+TT vs CC), recessive (OR=0.12, 95%CI=0.02-0.99, p = 0.023, TT vs CC+CT), overdominant (OR=0.39, 95%CI = 0.18-0.84, p=0.021, CT vs CC+TT), and allele (OR=0.28, 95%CI=0.15-0.55, p<0.0001, T vs C) inheritance models. Our findings did not support an association between AXIN2 rs7224837 and IRF6 rs861019 polymorphism and risk/protection of NSCL/P. The IRF6 2235371 variant was not polymorphic in our population. CONCLUSION: The results indicate that the BMP4 rs17563 variant is likely to confer a protective effect against the occurrence of NSCL/P in a sample of the southeast Iranian population.
[Mh] Termos MeSH primário: Proteína Axina/genética
Proteína Morfogenética Óssea 4/genética
Fenda Labial/genética
Fissura Palatina/genética
Fatores Reguladores de Interferon/genética
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Criança
Feminino
Frequência do Gene
Predisposição Genética para Doença
Genótipo
Seres Humanos
Irã (Geográfico)
Masculino
Polimorfismo de Fragmento de Restrição
Polimorfismo de Nucleotídeo Único
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN2 protein, human); 0 (Axin Protein); 0 (Bone Morphogenetic Protein 4); 0 (IRF6 protein, human); 0 (Interferon Regulatory Factors)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:D; IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE


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[PMID]:29307822
[Au] Autor:Hongdan L; Feng L
[Ad] Endereço:Department of Cell Biology, Key Laboratory of Cell Biology, National Health and Family Planning Commission of the PRC, Key Laboratory of Medical Cell Biology, Ministry of Education of the PRC, China Medical University, No. 77, Puhe Road, Shenyang North New Area, Shenyang, Liaoning 110122, China.
[Ti] Título:miR-3120-5p promotes colon cancer stem cell stemness and invasiveness through targeting Axin2.
[So] Source:Biochem Biophys Res Commun;496(2):302-308, 2018 02 05.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:It is well known that colon cancer stemness and invasiveness are the main reasons for tumor recurrence and metastasis. MicroRNAs dysregulation can disrupt the balance of cell signaling and growth processes, resulting in cancer proliferation, invasion and metastasis, chemoresistance and so on. In this study, we used colon cancer cell lines HCT-116 and SW-480 to investigate the effects of miR-3120-5p on stemness and invasiveness of colon cancer. We found that the population of CD133 + and Lgr5+ stem cells in both cell lines expressed miR-3120-5p highly, and introducing miR-3120-5p into both cell lines increased the population of cancer stem cells, as measured by flow cytometry, qRT-PCR and sphere formation assays. Transwell assay, Gelatin zymography assay and Western blot assays further revealed that miR-3120-5p promotes colon cancer cells invasive ability. By the target prediction algorithm TargetScan, we found Axin2 is a potential target for miR-3120-5p, and luciferase reporter assay demonstrated that miR-3120-5p reduces Axin2 expression. Transfection of siRNA against Axin2 into colon cancer cells promoted the stemness and invasion of colon cancer cells. Furthermore, Axin2 overexpression partially reversed the promotion of stemness and invasiveness caused by miR-3120-5p in colon cancer cells. Together, all the results demonstrated miR-3120-5p promotes stemness and invasiveness of colon cancer cells through direct targeting of Axin2. They suggest that antago-miR-3120-5p plays important roles on treatment strategy for colon cancer.
[Mh] Termos MeSH primário: Proteína Axina/genética
Biomarcadores Tumorais/genética
Regulação Neoplásica da Expressão Gênica
MicroRNAs/genética
Células-Tronco Neoplásicas/metabolismo
Esferoides Celulares/metabolismo
[Mh] Termos MeSH secundário: Antígeno AC133/genética
Antígeno AC133/metabolismo
Antagomirs/genética
Antagomirs/metabolismo
Proteína Axina/antagonistas & inibidores
Proteína Axina/metabolismo
Biomarcadores Tumorais/antagonistas & inibidores
Biomarcadores Tumorais/metabolismo
Linhagem Celular Tumoral
Movimento Celular
Proliferação Celular
Genes Reporter
Células HCT116
Seres Humanos
Luciferases/genética
Luciferases/metabolismo
MicroRNAs/antagonistas & inibidores
MicroRNAs/metabolismo
Células-Tronco Neoplásicas/patologia
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
Transdução de Sinais
Esferoides Celulares/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AC133 Antigen); 0 (AXIN2 protein, human); 0 (Antagomirs); 0 (Axin Protein); 0 (Biomarkers, Tumor); 0 (LGR5 protein, human); 0 (MicroRNAs); 0 (PROM1 protein, human); 0 (RNA, Small Interfering); 0 (Receptors, G-Protein-Coupled); EC 1.13.12.- (Luciferases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180214
[Lr] Data última revisão:
180214
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180109
[St] Status:MEDLINE


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[PMID]:29111205
[Au] Autor:Dokanehiifard S; Soltani BM
[Ad] Endereço:Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
[Ti] Título:Hsa-miR-11181 regulates Wnt signaling pathway through targeting of APC2 transcripts in SW480 cell line.
[So] Source:Gene;641:297-302, 2018 Jan 30.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Wnt signaling plays important roles in differentiation, morphogenesis and development. This signaling pathway is highly regulated at all levels and microRNAs are small noncoding RNAs regulating Wnt signaling. Here, we intended to investigate hsa-miR-11181 (a novel miRNA located in TrkC gene) effect on Wnt signaling pathway in SW480 cell line. TOP/FOP flash assay indicated up-regulation of Wnt signaling, following the overexpression of hsa-miR-11181, verified through RT-qPCR. Bioinformatics analysis predicted APC1, APC2 and Axin1 might be targeted by hsa-miR-11181. Then, RT-qPCR analysis indicated that APC2 and Axin1 have been significantly down-regulated following the hsa-miR-11181 overexpression. However dual luciferase assay analysis supported only APC2 3'-UTR is directly targeted by this miRNA. Then, treatment of SW480 cells with Wnt-inhibitory small molecules supported the effect of hsa-miR-11181 at the inhibitory complex level containing APC2 protein. Consistently, viability of SW480 cells overexpressing hsa-miR-11181 was significantly elevated, measured through MTT assay. Overall, these results suggest that hsa-miR-11181 may play a crucial role in Wnt signaling regulation and confirmed that APC2 3'-UTR is targeted by hsa-miR-11181 and propose the presence of its recognition sites in the promoter or coding regions of Axin1 gene.
[Mh] Termos MeSH primário: Proteínas do Citoesqueleto/genética
MicroRNAs/genética
Via de Sinalização Wnt/genética
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas/genética
Subunidade Apc1 do Ciclossomo-Complexo Promotor de Anáfase/genética
Proteína Axina/genética
Linhagem Celular
Regulação para Baixo/genética
Células HEK293
Seres Humanos
Fases de Leitura Aberta/genética
Regiões Promotoras Genéticas/genética
Receptor trkC
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (ANAPC1 protein, human); 0 (APC2 protein, human); 0 (AXIN1 protein, human); 0 (Apc1 Subunit, Anaphase-Promoting Complex-Cyclosome); 0 (Axin Protein); 0 (Cytoskeletal Proteins); 0 (MicroRNAs); EC 2.7.10.1 (Receptor, trkC)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171108
[St] Status:MEDLINE


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[PMID]:28926590
[Au] Autor:Miyamoto K; Ohkawara B; Ito M; Masuda A; Hirakawa A; Sakai T; Hiraiwa H; Hamada T; Ishiguro N; Ohno K
[Ad] Endereço:Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.
[Ti] Título:Fluoxetine ameliorates cartilage degradation in osteoarthritis by inhibiting Wnt/ß-catenin signaling.
[So] Source:PLoS One;12(9):e0184388, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Abnormal activation of the Wnt/ß-catenin signaling is implicated in the osteoarthritis (OA) pathology. We searched for a pre-approved drug that suppresses abnormally activated Wnt/ß-catenin signaling and has a potency to reduce joint pathology in OA. We introduced the TOPFlash reporter plasmid into HCS-2/8 human chondrosarcoma cells to estimate the Wnt/ß-catenin activity in the presence of 10 µM each compound in a panel of pre-approved drugs. We found that fluoxetine, an antidepressant in the class of selective serotonin reuptake inhibitors (SSRI), down-regulated Wnt/ß-catenin signaling in human chondrosarcoma cells. Fluoxetine inhibited both Wnt3A- and LiCl-induced loss of proteoglycans in chondrogenically differentiated ATDC5 cells. Fluoxetine increased expression of Sox9 (the chondrogenic master regulator), and decreased expressions of Axin2 (a marker for Wnt/ß-catenin signaling) and Mmp13 (matrix metalloproteinase 13). Fluoxetine suppressed a LiCl-induced increase of total ß-catenin and a LiCl-induced decrease of phosphorylated ß-catenin in a dose-dependent manner. An in vitro protein-binding assay showed that fluoxetine enhanced binding of ß-catenin with Axin1, which is a scaffold protein forming the degradation complex for ß-catenin. Fluoxetine suppressed LiCl-induced ß-catenin accumulation in human OA chondrocytes. Intraarticular injection of fluoxetine in a rat OA model ameliorated OA progression and suppressed ß-catenin accumulation.
[Mh] Termos MeSH primário: Cartilagem Articular/efeitos dos fármacos
Fluoxetina/farmacologia
Inibidores da Captação de Serotonina/farmacologia
Via de Sinalização Wnt/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Proteína Axina/genética
Proteína Axina/metabolismo
Cartilagem Articular/metabolismo
Cartilagem Articular/patologia
Diferenciação Celular/efeitos dos fármacos
Células Cultivadas
Condrócitos/citologia
Condrócitos/efeitos dos fármacos
Condrócitos/metabolismo
Condrogênese/efeitos dos fármacos
Modelos Animais de Doenças
Regulação para Baixo/efeitos dos fármacos
Fluoxetina/uso terapêutico
Seres Humanos
Cloreto de Lítio/toxicidade
Metaloproteinase 13 da Matriz/genética
Metaloproteinase 13 da Matriz/metabolismo
Osteoartrite/tratamento farmacológico
Osteoartrite/metabolismo
Osteoartrite/patologia
Fosforilação/efeitos dos fármacos
Ratos
Ratos Sprague-Dawley
Fatores de Transcrição SOX9/genética
Fatores de Transcrição SOX9/metabolismo
Inibidores da Captação de Serotonina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN2 protein, human); 0 (Axin Protein); 0 (SOX9 Transcription Factor); 0 (Serotonin Uptake Inhibitors); 01K63SUP8D (Fluoxetine); EC 3.4.24.- (Matrix Metalloproteinase 13); G4962QA067 (Lithium Chloride)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170920
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184388


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[PMID]:28886197
[Au] Autor:Tan SH; Nusse R
[Ad] Endereço:Program in Cancer Biology, School of Medicine, Stanford University, Stanford, California, United States of America.
[Ti] Título:In vivo lineage tracing reveals Axin2-expressing, long-lived cortical thymic epithelial progenitors in the postnatal thymus.
[So] Source:PLoS One;12(9):e0184582, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the thymus, cortical and medullary thymic epithelial cells (TECs) are instrumental for generating a repertoire of functional T cells. Hence, there has been much interest in the ontogeny of TECs. While medullary TEC (mTEC) and bipotent progenitors have been identified, the existence of a cortical TEC (cTEC) progenitor remains ambiguous. In this study, we used lineage tracing based on a target gene of the Wnt pathway, Axin2. We found that Axin2 initially labels cells in both the cortical and medullary compartments. Using Axin2-CreERT2 mice to track the fate of labelled cells, we identified long-lived cortical TEC progenitors that give rise to expanding clones and contribute to homeostasis in postnatal thymus. In contrast, no clonal expansion was found in the medullary or in the K5K8-double positive compartments. The identification of cTEC progenitors and their regulation by Wnt signaling have important implications for our understanding of thymus physiology during homeostasis and TEC-related disorders.
[Mh] Termos MeSH primário: Proteína Axina/metabolismo
Células Epiteliais/citologia
Células Epiteliais/metabolismo
Transdução de Sinais/fisiologia
Células-Tronco/citologia
Células-Tronco/metabolismo
Timo/citologia
Timo/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína Axina/genética
Diferenciação Celular/genética
Diferenciação Celular/fisiologia
Linhagem da Célula
Camundongos
Transdução de Sinais/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Axin Protein); 0 (Axin2 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171016
[Lr] Data última revisão:
171016
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170909
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0184582


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[PMID]:28757184
[Au] Autor:Dietrich L; Rathmer B; Ewan K; Bange T; Heinrichs S; Dale TC; Schade D; Grossmann TN
[Ad] Endereço:Chemical Genomics Centre of the Max Planck Society, 44227 Dortmund, Germany; Department of Chemistry and Chemical Biology, TU Dortmund University, 44227 Dortmund, Germany.
[Ti] Título:Cell Permeable Stapled Peptide Inhibitor of Wnt Signaling that Targets ß-Catenin Protein-Protein Interactions.
[So] Source:Cell Chem Biol;24(8):958-968.e5, 2017 Aug 17.
[Is] ISSN:2451-9456
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Wnt signaling pathway plays a critical role in cell proliferation and differentiation, thus it is often associated with diseases such as cancers. Unfortunately, although attractive, developing anti-cancer strategy targeting Wnt signaling has been challenging given that the most attractive targets are involved in protein-protein interactions (PPIs). Here, we develop a stapled peptide inhibitor that targets the interaction between ß-catenin and T cell factor/lymphoid enhancer-binding factor transcription factors, which are crucially involved in Wnt signaling. Our integrative approach combines peptide stapling to optimize proteolytic stability, with lessons learned from cell-penetrating peptide (CPP) design to maximize cellular uptake resulting in NLS-StAx-h, a selective, cell permeable, stapled peptide inhibitor of oncogenic Wnt signaling that efficiently inhibits ß-catenin-transcription factor interactions. We expect that this type of integrative strategy that endows stapled peptides with CPP features will be generally useful for developing inhibitors of intracellular PPIs.
[Mh] Termos MeSH primário: Peptídeos Penetradores de Células/metabolismo
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteína Axina/genética
Proteína Axina/metabolismo
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo
Linhagem Celular Tumoral
Permeabilidade da Membrana Celular
Movimento Celular
Proliferação Celular/efeitos dos fármacos
Peptídeos Penetradores de Células/química
Peptídeos Penetradores de Células/farmacologia
Expressão Gênica/efeitos dos fármacos
Genes Reporter
Células HeLa
Seres Humanos
Microscopia Confocal
Domínios e Motivos de Interação entre Proteínas
Via de Sinalização Wnt/efeitos dos fármacos
beta Catenina/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (ASCL2 protein, human); 0 (AXIN2 protein, human); 0 (Axin Protein); 0 (Basic Helix-Loop-Helix Transcription Factors); 0 (Cell-Penetrating Peptides); 0 (beta Catenin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171009
[Lr] Data última revisão:
171009
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170801
[St] Status:MEDLINE


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[PMID]:28705114
[Au] Autor:Pecina-Slaus N; Kafka A; Bukovac A; Vladusic T; Tomas D; Hrascan R
[Ad] Endereço:1 Laboratory of Neurooncology, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.
[Ti] Título:Genetic changes of MLH1 and MSH2 genes could explain constant findings on microsatellite instability in intracranial meningioma.
[So] Source:Tumour Biol;39(7):1010428317705791, 2017 Jul.
[Is] ISSN:1423-0380
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Postreplicative mismatch repair safeguards the stability of our genome. The defects in its functioning will give rise to microsatellite instability. In this study, 50 meningiomas were investigated for microsatellite instability. Two major mismatch repair genes, MLH1 and MSH2, were analyzed using microsatellite markers D1S1611 and BAT26 amplified by polymerase chain reaction and visualized by gel electrophoresis on high-resolution gels. Furthermore, genes DVL3 (D3S1262), AXIN1 (D16S3399), and CDH1 (D16S752) were also investigated for microsatellite instability. Our study revealed constant presence of microsatellite instability in meningioma patients when compared to their autologous blood DNA. Altogether 38% of meningiomas showed microsatellite instability at one microsatellite locus, 16% on two, and 13.3% on three loci. The percent of detected microsatellite instability for MSH2 gene was 14%, and for MLH1, it was 26%, for DVL3 22.9%, for AXIN1 17.8%, and for CDH1 8.3%. Since markers also allowed for the detection of loss of heterozygosity, gross deletions of MLH1 gene were found in 24% of meningiomas. Genetic changes between MLH1 and MSH2 were significantly positively correlated (p = 0.032). We also noted a positive correlation between genetic changes of MSH2 and DVL3 genes (p = 0.034). No significant associations were observed when MLH1 or MSH2 was tested against specific histopathological meningioma subtype or World Health Organization grade. However, genetic changes in DVL3 were strongly associated with anaplastic histology of meningioma (χ = 9.14; p = 0.01). Our study contributes to better understanding of the genetic profile of human intracranial meningiomas and suggests that meningiomas harbor defective cellular DNA mismatch repair mechanisms.
[Mh] Termos MeSH primário: Proteínas Desgrenhadas/genética
Meningioma/genética
Instabilidade de Microssatélites
Proteína 1 Homóloga a MutL/genética
Proteína 2 Homóloga a MutS/genética
[Mh] Termos MeSH secundário: Adulto
Idoso
Proteína Axina/genética
Caderinas/genética
Reparo de Erro de Pareamento de DNA/genética
Feminino
Mutação em Linhagem Germinativa/genética
Seres Humanos
Perda de Heterozigosidade/genética
Masculino
Meningioma/patologia
Meia-Idade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (AXIN1 protein, human); 0 (Axin Protein); 0 (CDH1 protein, human); 0 (Cadherins); 0 (DVL3 protein, human); 0 (Dishevelled Proteins); 0 (MLH1 protein, human); EC 3.6.1.3 (MSH2 protein, human); EC 3.6.1.3 (MutL Protein Homolog 1); EC 3.6.1.3 (MutS Homolog 2 Protein)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170728
[Lr] Data última revisão:
170728
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170715
[St] Status:MEDLINE
[do] DOI:10.1177/1010428317705791


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[PMID]:28619731
[Au] Autor:Xu D; Liu J; Fu T; Shan B; Qian L; Pan L; Yuan J
[Ad] Endereço:Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Pudong, Shanghai 201210, China.
[Ti] Título:USP25 regulates Wnt signaling by controlling the stability of tankyrases.
[So] Source:Genes Dev;31(10):1024-1035, 2017 May 15.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Aberrant activation of the Wnt signaling pathway plays an important role in human cancer development. Wnt signaling is negatively regulated by Axin, a scaffolding protein that controls a rate-limiting step in the destruction of ß-catenin, the central activator of the Wnt pathway. In Wnt-stimulated cells, Axin is rapidly modified by tankyrase-mediated poly(ADP-ribosyl)ation, which promotes the proteolysis of Axin and consequent stabilization of ß-catenin. Thus, regulation of the levels and activity of tankyrases is mechanistically important in controlling Wnt signaling. Here, we identify ubiquitin-specific protease 25 (USP25) as a positive regulator of Wnt/ß-catenin signaling. We found that USP25 directly interacted with tankyrases to promote their deubiquitination and stabilization. We demonstrated that USP25 deficiency could promote the degradation of tankyrases and consequent stabilization of Axin to antagonize Wnt signaling. We further characterized the interaction between TNKS1 and USP25 by X-ray crystal structure determination. Our results provide important new insights into the molecular mechanism that regulates the turnover of tankyrases and the possibility of targeting the stability of tankyrases by antagonizing their interaction with USP25 to modulate the Wnt/ß-catenin pathway.
[Mh] Termos MeSH primário: Estabilidade Enzimática/genética
Tanquirases/metabolismo
Ubiquitina Tiolesterase/metabolismo
Via de Sinalização Wnt/fisiologia
[Mh] Termos MeSH secundário: Repetição de Anquirina
Proteína Axina/metabolismo
Linhagem Celular
Cristalografia por Raios X
Células HCT116
Células HEK293
Seres Humanos
Mutação
Ligação Proteica
Tanquirases/química
Ubiquitina Tiolesterase/química
Ubiquitina Tiolesterase/genética
Via de Sinalização Wnt/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Axin Protein); EC 2.4.2.30 (Tankyrases); EC 2.4.4.30 (TNKS protein, human); EC 3.1.2.15 (USP25 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171115
[Lr] Data última revisão:
171115
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE
[do] DOI:10.1101/gad.300889.117


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[PMID]:28581440
[Au] Autor:Matsumoto Y; La Rose J; Lim M; Adissu HA; Law N; Mao X; Cong F; Mera P; Karsenty G; Goltzman D; Changoor A; Zhang L; Stajkowski M; Grynpas MD; Bergmann C; Rottapel R
[Ad] Endereço:Princess Margaret Cancer Center, University Health Network, University of Toronto, Toronto, Ontario, Canada.
[Ti] Título:Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism.
[So] Source:J Clin Invest;127(7):2612-2625, 2017 Jun 30.
[Is] ISSN:1558-8238
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cleidocranial dysplasia (CCD) is an autosomal dominant human disorder characterized by abnormal bone development that is mainly due to defective intramembranous bone formation by osteoblasts. Here, we describe a mouse strain lacking the E3 ubiquitin ligase RNF146 that shows phenotypic similarities to CCD. Loss of RNF146 stabilized its substrate AXIN1, leading to impairment of WNT3a-induced ß-catenin activation and reduced Fgf18 expression in osteoblasts. We show that FGF18 induces transcriptional coactivator with PDZ-binding motif (TAZ) expression, which is required for osteoblast proliferation and differentiation through transcriptional enhancer associate domain (TEAD) and runt-related transcription factor 2 (RUNX2) transcription factors, respectively. Finally, we demonstrate that adipogenesis is enhanced in Rnf146-/- mouse embryonic fibroblasts. Moreover, mice with loss of RNF146 within the osteoblast lineage had increased fat stores and were glucose intolerant with severe osteopenia because of defective osteoblastogenesis and subsequent impaired osteocalcin production. These findings indicate that RNF146 is required to coordinate ß-catenin signaling within the osteoblast lineage during embryonic and postnatal bone development.
[Mh] Termos MeSH primário: Desenvolvimento Ósseo
Displasia Cleidocraniana/metabolismo
Metabolismo Energético
Osteoblastos/metabolismo
Transdução de Sinais
Ubiquitina-Proteína Ligases/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína Axina/biossíntese
Proteína Axina/genética
Displasia Cleidocraniana/genética
Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese
Subunidade alfa 1 de Fator de Ligação ao Core/genética
Seres Humanos
Camundongos
Camundongos Knockout
Osteocalcina/biossíntese
Osteocalcina/genética
Ubiquitina-Proteína Ligases/genética
beta Catenina/genética
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Axin Protein); 0 (Axin1 protein, mouse); 0 (Core Binding Factor Alpha 1 Subunit); 0 (Runx2 protein, mouse); 0 (beta Catenin); 104982-03-8 (Osteocalcin); EC 2.3.2.27 (Rnf146 protein, mouse); EC 2.3.2.27 (Ubiquitin-Protein Ligases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170930
[Lr] Data última revisão:
170930
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE


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Texto completo
[PMID]:28546513
[Au] Autor:Ji L; Jiang B; Jiang X; Charlat O; Chen A; Mickanin C; Bauer A; Xu W; Yan X; Cong F
[Ad] Endereço:Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
[Ti] Título:The SIAH E3 ubiquitin ligases promote Wnt/ß-catenin signaling through mediating Wnt-induced Axin degradation.
[So] Source:Genes Dev;31(9):904-915, 2017 May 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Wnt/ß-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 ß-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. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced ß-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/ß-catenin signaling.
[Mh] Termos MeSH primário: Proteína Axina/metabolismo
Proteínas Nucleares/metabolismo
Transdução de Sinais
Ubiquitina-Proteína Ligases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Proteína Axina/química
Proteína Axina/genética
Neoplasias Ósseas/genética
Neoplasias Ósseas/metabolismo
Regulação da Expressão Gênica
Células HEK293
Seres Humanos
Proteínas Nucleares/química
Proteínas Nucleares/genética
Osteossarcoma/genética
Osteossarcoma/metabolismo
Conformação Proteica
Proteólise
Homologia de Sequência
Células Tumorais Cultivadas
Ubiquitina/metabolismo
Ubiquitina-Proteína Ligases/química
Ubiquitina-Proteína Ligases/genética
Ubiquitinação
Proteínas Wnt/genética
Proteínas Wnt/metabolismo
beta Catenina/genética
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Axin Protein); 0 (Nuclear Proteins); 0 (Ubiquitin); 0 (Wnt Proteins); 0 (beta Catenin); EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.3.2.27 (seven in absentia proteins)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171101
[Lr] Data última revisão:
171101
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170527
[St] Status:MEDLINE
[do] DOI:10.1101/gad.300053.117



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