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[PMID]:28855257
[Au] Autor:Mobbs JI; Illing PT; Dudek NL; Brooks AG; Baker DG; Purcell AW; Rossjohn J; Vivian JP
[Ad] Endereço:From the Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton 3800, Victoria, Australia.
[Ti] Título:The molecular basis for peptide repertoire selection in the human leucocyte antigen (HLA) C*06:02 molecule.
[So] Source:J Biol Chem;292(42):17203-17215, 2017 Oct 20.
[Is] ISSN:1083-351X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Human leukocyte antigen (HLA)-C*06:02 is identified as the allele associated with the highest risk for the development of the autoimmune skin disease psoriasis. However, the diversity and mode of peptide presentation by the HLA-C*06:02 molecule remains unclear. Here, we describe the endogenous peptide repertoire of ∼3,000 sequences for HLA-C*06:02 that defines the peptide-binding motif for this HLA allomorph. We found that HLA-C*06:02 predominantly presents nonamer peptides with dominant arginine anchors at the P2 and P7 positions and a preference for small hydrophobic residues at the C terminus (PΩ). To determine the structural basis of this selectivity, we determined crystal structures of HLA-C*06:02 in complex with two self-peptides (ARTELYRSL and ARFNDLRFV) and an analogue of a melanocyte autoantigen (ADAMTSL5, VRSRR-abu-LRL) implicated in psoriasis. These structures revealed that HLA-C*06:02 possesses a deep peptide-binding groove comprising two electronegative B- and E-pockets that coincide with the preference for P2 and P7 arginine anchors. The ADAMTSL5 autoantigen possessed a P7-Leu instead of the P7-Arg residue, but nevertheless was accommodated within the HLA-C*06:02 antigen-binding cleft. Collectively, our results provide the structural basis for understanding peptide repertoire selection in HLA-C*06:02.
[Mh] Termos MeSH primário: Proteínas ADAMTS
Apresentação do Antígeno
Antígenos HLA-C
Peptídeos
[Mh] Termos MeSH secundário: Proteínas ADAMTS/química
Proteínas ADAMTS/genética
Proteínas ADAMTS/imunologia
Proteínas ADAMTS/metabolismo
Motivos de Aminoácidos
Linhagem Celular
Antígenos HLA-C/química
Antígenos HLA-C/genética
Antígenos HLA-C/imunologia
Antígenos HLA-C/metabolismo
Seres Humanos
Peptídeos/química
Peptídeos/genética
Peptídeos/imunologia
Peptídeos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (HLA-C Antigens); 0 (HLA-C*06:02 antigen); 0 (Peptides); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTSL5 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170901
[St] Status:MEDLINE
[do] DOI:10.1074/jbc.M117.806976


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[PMID]:28854272
[Au] Autor:van der Wekken AJ; Kuiper JL; Saber A; Terpstra MM; Wei J; Hiltermann TJN; Thunnissen E; Heideman DAM; Timens W; Schuuring E; Kok K; Smit EF; van den Berg A; Groen HJM
[Ad] Endereço:Department of Pulmonary Diseases, University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.
[Ti] Título:Overall survival in EGFR mutated non-small-cell lung cancer patients treated with afatinib after EGFR TKI and resistant mechanisms upon disease progression.
[So] Source:PLoS One;12(8):e0182885, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:PURPOSE: To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors. METHODS: Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre- and post-afatinib tumor biopsies and normal tissue. RESULTS: A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3-3.3) and 2.7 months (95% CI 0.9-4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2-13.4) and 3.6 months (95% CI 2.3-5.0), p = 0.14) were observed in T790M+ patients compared to T790M- mutations. Somatic mutations in TP53, ADAMTS2, CNN2 and multiple genes in the Wnt and PI3K-AKT pathway were observed in post-afatinib tumors of six afatinib-responding and in one non-responding patient. No new EGFR mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes (HLA-DRB1, AQP7, FAM198A, SEC31A, CNTLN, and ESX1) in three afatinib responding patients. No known EGFR-TKI resistant-associated copy number gains were acquired in the post-afatinib samples. CONCLUSION: No differences in survival were observed in patients with EGFR-T790M treated with afatinib compared to those without T790M. Tumors from patients who had progressive disease during afatinib treatment were enriched for mutations in genes involved in Wnt and PI3K-AKT pathways.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Carcinoma Pulmonar de Células não Pequenas/mortalidade
Resistência a Medicamentos Antineoplásicos/genética
Regulação Neoplásica da Expressão Gênica
Neoplasias Pulmonares/mortalidade
Quinazolinas/uso terapêutico
Receptor do Fator de Crescimento Epidérmico/genética
[Mh] Termos MeSH secundário: Proteínas ADAMTS/genética
Proteínas ADAMTS/metabolismo
Adulto
Idoso
Idoso de 80 Anos ou mais
Proteínas de Ligação ao Cálcio/genética
Proteínas de Ligação ao Cálcio/metabolismo
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico
Carcinoma Pulmonar de Células não Pequenas/genética
Carcinoma Pulmonar de Células não Pequenas/patologia
Progressão da Doença
Cloridrato de Erlotinib/uso terapêutico
Exoma
Feminino
Estudo de Associação Genômica Ampla
Seres Humanos
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/genética
Neoplasias Pulmonares/patologia
Masculino
Proteínas dos Microfilamentos/genética
Proteínas dos Microfilamentos/metabolismo
Meia-Idade
Mutação
Fosfatidilinositol 3-Quinases/genética
Fosfatidilinositol 3-Quinases/metabolismo
Inibidores de Proteínas Quinases/uso terapêutico
Receptor do Fator de Crescimento Epidérmico/antagonistas & inibidores
Receptor do Fator de Crescimento Epidérmico/metabolismo
Transdução de Sinais
Proteína Supressora de Tumor p53/genética
Proteína Supressora de Tumor p53/metabolismo
Proteínas Wnt/genética
Proteínas Wnt/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; MULTICENTER STUDY
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Calcium-Binding Proteins); 0 (Microfilament Proteins); 0 (Protein Kinase Inhibitors); 0 (Quinazolines); 0 (TP53 protein, human); 0 (Tumor Suppressor Protein p53); 0 (Wnt Proteins); 0 (calponin); 41UD74L59M (afatinib); DA87705X9K (Erlotinib Hydrochloride); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (EGFR protein, human); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.14 (ADAMTS2 protein, human); S65743JHBS (gefitinib)
[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:170831
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0182885


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[PMID]:28843853
[Au] Autor:Zhu R; Cheng M; Ye S; Liu M; Sun L; Lu T; Yang N; Hong T; Dang S; Zhang W
[Ad] Endereço:Key Laboratory of Brain Functional Genomics (Ministry of Education and Shanghai), School of Life Science, East China Normal University, China.
[Ti] Título:The development of monoclonal anti-ADAMTS18 antibodies with precise validation of ADAMTS18 post-translational modification status in living organisms.
[So] Source:Biochem Biophys Res Commun;492(3):404-411, 2017 Oct 21.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ADAMTS18 is a member of a secreted Zn-metalloproteinase ADAMTS family, and has been implicated in development, hemostasis, and various malignancies. It has thus far proven difficult to resolve its post-translational modification status, cleaved forms, and splice variants in living organisms due to the lack of specific antibodies available to characterize this enzyme. In this study, we develop six murine monoclonal antibodies (mAbs) against different functional regions of ADAMTS18 using hybridoma technology. These mAbs exhibit cross-recognition between ADAMTS18 and the homology domain of its family members. Using the tissues from Adamts18 knockout (KO) mice, we find that two of these mAbs (N-3 and C-5) precisely identify five significantly attenuated bands located at 180, 135, 95, 72, and 45 kDa. These bands represent the forms of ADAMTS18 that potentially exist in the tissues. These mAbs will provide a useful tool to investigate the ADAMTS18's biologic significance in the tissues.
[Mh] Termos MeSH primário: Proteínas ADAMTS/imunologia
Proteínas ADAMTS/metabolismo
Anticorpos Monoclonais/imunologia
Processamento de Proteína Pós-Traducional
[Mh] Termos MeSH secundário: Proteínas ADAMTS/química
Proteínas ADAMTS/deficiência
Animais
Feminino
Camundongos
Camundongos Endogâmicos BALB C
Camundongos Endogâmicos C57BL
Camundongos Knockout
Modelos Moleculares
Reprodutibilidade dos Testes
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS18 protein, mouse)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170828
[St] Status:MEDLINE


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[PMID]:28373586
[Au] Autor:Wang X; Chen W; Zhang J; Khan A; Li L; Huang F; Qiu Z; Wang L; Chen X
[Ad] Endereço:From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
[Ti] Título:Critical Role of ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) in Cardiac Hypertrophy Induced by Pressure Overload.
[So] Source:Hypertension;69(6):1060-1069, 2017 Jun.
[Is] ISSN:1524-4563
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) is recognized as a metalloproteinase that promotes the cleavage of amino propeptides of types I, II, III, and V procollagens. However, the role of ADAMTS2 in the heart has not yet been defined. Herein, we observed the upregulated expression of ADAMTS2 in failing human hearts and hypertrophic murine hearts. Mice lacking ADAMTS2 display exacerbated cardiac hypertrophy on pressure overload-induced hypertrophic response, whereas mice with cardiac-specific overexpression of ADAMTS2 display alleviation of this detrimental phenotype. Consistent with these results, in vitro loss or gain of function experiments in neonatal rat cardiomyocytes confirmed that ADAMTS2 negatively regulates cardiomyocyte hypertrophy in response to Ang II. Mechanistically, blockage of the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)-dependent signaling pathway with specific inhibitors both in vivo and in vitro could rescue the aggravated hypertrophic response to the loss of ADAMTS2. Collectively, we propose that ADAMTS2 regulates the hypertrophic response through inhibiting the activation of the PI3K/AKT-dependent signaling pathway. Because ADAMTS2 is an extracellular protein, it could be effectively manipulated using pharmacological means to modulate cardiac hypertrophy.
[Mh] Termos MeSH primário: Proteínas ADAMTS/genética
Cardiomegalia/genética
Transdução de Sinais/genética
Trombospondinas/genética
Regulação para Cima
[Mh] Termos MeSH secundário: Angiotensina II/farmacologia
Animais
Biópsia por Agulha
Cardiomegalia/patologia
Modelos Animais de Doenças
Desintegrinas/metabolismo
Regulação da Expressão Gênica
Seres Humanos
Metaloproteases/metabolismo
Camundongos
Camundongos Transgênicos
Miócitos Cardíacos/metabolismo
Miócitos Cardíacos/patologia
Fosfatidilinositol 3-Quinases/metabolismo
Fosforilação/genética
Proteínas Proto-Oncogênicas c-akt/metabolismo
Distribuição Aleatória
Técnicas de Cultura de Tecidos
Disfunção Ventricular Esquerda/genética
Disfunção Ventricular Esquerda/patologia
Remodelação Ventricular/genética
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Disintegrins); 0 (Thrombospondins); 0 (thrombospondin 2); 11128-99-7 (Angiotensin II); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.- (Metalloproteases); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.14 (ADAMTS2 protein, human); EC 3.4.24.14 (Adamts2 protein, mouse)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170816
[Lr] Data última revisão:
170816
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170405
[St] Status:MEDLINE
[do] DOI:10.1161/HYPERTENSIONAHA.116.08581


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[PMID]:28323982
[Au] Autor:Gueye NA; Mead TJ; Koch CD; Biscotti CV; Falcone T; Apte SS
[Ad] Endereço:Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195.
[Ti] Título:Versican Proteolysis by ADAMTS Proteases and Its Influence on Sex Steroid Receptor Expression in Uterine Leiomyoma.
[So] Source:J Clin Endocrinol Metab;102(5):1631-1641, 2017 May 01.
[Is] ISSN:1945-7197
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Context: Leiomyomas have abundant extracellular matrix (ECM), with upregulation of versican, a large proteoglycan. Objective: We investigated ADAMTS (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs) protease-mediated versican cleavage in myometrium and leiomyoma and the effect of versican knockdown in leiomyoma cells. Design: We used quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blotting, immunohistochemistry, and RNA in situ hybridization for analysis of myometrium, leiomyoma and immortalized myometrium and leiomyoma cells. Short interfering RNA (siRNA) was used to knockdown versican in leiomyoma cells. Setting: This study was performed in an academic laboratory. Patients: Study subjects were women with symptomatic or asymptomatic leiomyoma. Main Outcome Measures: We quantified messenger RNAs (mRNAs) for versican splice variants. We identified ADAMTS-cleaved versican in myometrium and leiomyoma and ADAMTS messenger RNAs and examined the effect of VCAN siRNA on smooth muscle differentiation and expression of estrogen and progesterone receptors. Results: The women in the symptomatic group (n = 7) had larger leiomyoma (P = 0.01), heavy menstrual bleeding (P < 0.01), and lower hemoglobin levels (P = 0.02) compared with the asymptomatic group (n = 7), but were similar in age and menopausal status. Versican V0 and V1 isoforms were upregulated in the leiomyomas of symptomatic versus asymptomatic women (P = 0.03 and P = 0.04, respectively). Abundant cleaved versican was detected in leiomyoma and myometrium, as well as in myometrial and leiomyoma cell lines. ADAMTS4 (P = 0.03) and ADAMTS15 (P = 0.04) were upregulated in symptomatic leiomyomas. VCAN siRNA did not effect cell proliferation, apoptosis, or smooth muscle markers, but reduced ESR1 and PR-A expression (P = 0.001 and P = 0.002, respectively). Conclusions: Versican in myometrium, leiomyomas and in the corresponding immortalized cells is cleaved by ADAMTS proteases. VCAN siRNA suppresses production of estrogen receptor 1 and progesterone receptor-A. These findings have implications for leiomyoma growth.
[Mh] Termos MeSH primário: Proteínas ADAMTS/genética
Proteína ADAMTS4/genética
Receptor alfa de Estrogênio/genética
Leiomioma/metabolismo
RNA Mensageiro/metabolismo
Receptores de Progesterona/genética
Neoplasias Uterinas/metabolismo
Versicanas/metabolismo
[Mh] Termos MeSH secundário: Proteínas ADAMTS/metabolismo
Proteína ADAMTS4/metabolismo
Adulto
Apoptose/genética
Doenças Assintomáticas
Western Blotting
Linhagem Celular Tumoral
Proliferação Celular/genética
Receptor alfa de Estrogênio/metabolismo
Matriz Extracelular/metabolismo
Feminino
Técnicas de Silenciamento de Genes
Hemoglobinas/metabolismo
Seres Humanos
Imuno-Histoquímica
Hibridização In Situ
Leiomioma/patologia
Menorragia/etiologia
Meia-Idade
Miométrio/metabolismo
Isoformas de Proteínas/genética
Proteólise
RNA Interferente Pequeno
Receptores de Progesterona/metabolismo
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Carga Tumoral
Regulação para Cima
Neoplasias Uterinas/patologia
Versicanas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Estrogen Receptor alpha); 0 (Hemoglobins); 0 (Protein Isoforms); 0 (RNA, Messenger); 0 (RNA, Small Interfering); 0 (Receptors, Progesterone); 0 (VCAN protein, human); 0 (estrogen receptor alpha, human); 0 (progesterone receptor A); 126968-45-4 (Versicans); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS15 protein, human); EC 3.4.24.82 (ADAMTS4 Protein); EC 3.4.24.82 (ADAMTS4 protein, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170911
[Lr] Data última revisão:
170911
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170322
[St] Status:MEDLINE
[do] DOI:10.1210/jc.2016-3527


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[PMID]:28292214
[Au] Autor:Abdullah M; Choo CW; Alias H; Abdul Rahman EJ; Mohd Ibrahim H; Jamal R; Hussin NH
[Ad] Endereço:a Immunology Unit, Department of Pathology , UPM, Serdang , Selangor , Malaysia.
[Ti] Título:ADAMTSL5 and CDH11: putative epigenetic markers for therapeutic resistance in acute lymphoblastic leukemia.
[So] Source:Hematology;22(7):386-391, 2017 Aug.
[Is] ISSN:1607-8454
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND OBJECTIVES: DNA hypermethylation has been linked to poor treatment outcome in childhood acute lymphoblastic leukemia (ALL). Genes differentially methylated in the chemoresponsive pre-B-ALL compared to chemoresistant pre-B-ALL cases provide potential prognostic markers. METHODS: DNA methylation profiles of five B-ALL childhood patients who achieved morphological complete remission (chemoresponsive) and five B-ALL patients who did not (chemoresistant) after induction treatments as well as four normal controls were compared on 27 000 CpG sites microarray chips. Subsequently, methylation-specific polymerase chain reaction (MSP) on selected hypermethylated genes was conducted on an additional 37 chemoresponsive and 9 chemoresistant B-ALL samples and 2 normal controls. RESULTS: Both methods were found to be highly correlated. Unsupervised principal component analysis showed that the chemotherapy-responsive and -resistant B-ALL patients could be segregated from one another. Selection of segregated genes at high stringency identified two potential genes (CDH11 and ADAMTSL5). MSP analysis on the larger cohort of samples (42 chemoresponsive, 14 chemoresistant B-ALL samples and 6 normal controls) revealed significantly higher rates of hypermethylation in chemoresistant samples for ADAMTSL5 (93 vs. 38%; p = 0.0001) and CDH11 (79% vs. 40%, p < 0.01). All control cases remained unmethylated. CONCLUSION: Chemoresistant B-ALL patients are associated with increased methylation in ADAMTSL5 and CDH11. These findings need to be validated in a larger group of patients, and the functional biological and prognostic significance of differential methylation needs to be studied further.
[Mh] Termos MeSH primário: Proteínas ADAMTS/genética
Caderinas/genética
Resistência a Medicamentos Antineoplásicos/genética
Epigênese Genética
Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
[Mh] Termos MeSH secundário: Adolescente
Análise de Variância
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
Biomarcadores Tumorais
Estudos de Casos e Controles
Linhagem Celular Tumoral
Criança
Pré-Escolar
Análise por Conglomerados
Biologia Computacional
Ilhas de CpG
Metilação de DNA
Feminino
Perfilação da Expressão Gênica
Seres Humanos
Lactente
Masculino
Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
Prognóstico
Regiões Promotoras Genéticas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Biomarkers, Tumor); 0 (Cadherins); 156621-71-5 (osteoblast cadherin); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTSL5 protein, human)
[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:170316
[St] Status:MEDLINE
[do] DOI:10.1080/10245332.2017.1299417


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[PMID]:28231306
[Au] Autor:Sheu MJ; Hsieh MJ; Chou YE; Wang PH; Yeh CB; Yang SF; Lee HL; Liu YF
[Ad] Endereço:Department of Gastroenterology and Hepatology, Chi Mei Medical Center, Tainan, Taiwan.
[Ti] Título:Effects of ADAMTS14 genetic polymorphism and cigarette smoking on the clinicopathologic development of hepatocellular carcinoma.
[So] Source:PLoS One;12(2):e0172506, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: ADAMTS14 is a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), which are proteolytic enzymes with a variety of further ancillary domain in the C-terminal region for substrate specificity and enzyme localization via extracellular matrix association. However, whether ADAMTS14 genetic variants play a role in hepatocellular carcinoma (HCC) susceptibility remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: Four non-synonymous single-nucleotide polymorphisms (nsSNPs) of the ADAMTS14 gene were examined from 680 controls and 340 patients with HCC. Among 141 HCC patients with smoking behaviour, we found significant associations of the rs12774070 (CC+AA vs CC) and rs61573157 (CT+TT vs CC) variants with a clinical stage of HCC (OR: 2.500 and 2.767; 95% CI: 1.148-5.446 and 1.096-6.483; P = 0.019 and 0.026, respectively) and tumour size (OR: 2.387 and 2.659; 95% CI: 1.098-5.188 and 1.055-6.704; P = 0.026 and 0.034, respectively), but not with lymph node metastasis or other clinical statuses. Moreover, an additional integrated in silico analysis proposed that rs12774070 and rs61573157 affected essential post-translation O-glycosylation site within the 3rd thrombospondin type 1 repeat and a novel proline-rich region embedded within the C-terminal extension, respectively. CONCLUSIONS: Taken together, our results suggest an involvement of ADAMTS14 SNP rs12774070 and rs61573157 in the liver tumorigenesis and implicate the ADAMTS14 gene polymorphism as a predict factor during the progression of HCC.
[Mh] Termos MeSH primário: Proteínas ADAMTS/genética
Carcinoma Hepatocelular/genética
Carcinoma Hepatocelular/patologia
Neoplasias Hepáticas/genética
Neoplasias Hepáticas/patologia
Fígado/patologia
Polimorfismo de Nucleotídeo Único
[Mh] Termos MeSH secundário: Proteínas ADAMTS/química
Idoso
Feminino
Predisposição Genética para Doença
Seres Humanos
Fígado/metabolismo
Masculino
Meia-Idade
Modelos Moleculares
Fumar/genética
Fumar/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS14 protein, human)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170224
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172506


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[PMID]:28213441
[Au] Autor:Ogino H; Hisanaga A; Kohno T; Kondo Y; Okumura K; Kamei T; Sato T; Asahara H; Tsuiji H; Fukata M; Hattori M
[Ad] Endereço:Department of Biomedical Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya, Aichi 467-8603, Japan.
[Ti] Título:Secreted Metalloproteinase ADAMTS-3 Inactivates Reelin.
[So] Source:J Neurosci;37(12):3181-3191, 2017 Mar 22.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The secreted glycoprotein Reelin regulates embryonic brain development and adult brain functions. It has been suggested that reduced Reelin activity contributes to the pathogenesis of several neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease; however, noninvasive methods that can upregulate Reelin activity have yet to be developed. We previously found that the proteolytic cleavage of Reelin within Reelin repeat 3 (N-t site) abolishes Reelin activity , but it remains controversial as to whether this effect occurs Here we partially purified the enzyme that mediates the N-t cleavage of Reelin from the culture supernatant of cerebral cortical neurons. This enzyme was identified as a disintegrin and metalloproteinase with thrombospondin motifs-3 (ADAMTS-3). Recombinant ADAMTS-3 cleaved Reelin at the N-t site. ADAMTS-3 was expressed in excitatory neurons in the cerebral cortex and hippocampus. N-t cleavage of Reelin was markedly decreased in the embryonic cerebral cortex of ADAMTS-3 knock-out (KO) mice. Importantly, the amount of Dab1 and the phosphorylation level of Tau, which inversely correlate with Reelin activity, were significantly decreased in the cerebral cortex of ADAMTS-3 KO mice. Conditional KO mice, in which ADAMTS-3 was deficient only in the excitatory neurons of the forebrain, showed increased dendritic branching and elongation in the postnatal cerebral cortex. Our study shows that ADAMTS-3 is the major enzyme that cleaves and inactivates Reelin in the cerebral cortex and hippocampus. Therefore, inhibition of ADAMTS-3 may be an effective treatment for neuropsychiatric and neurodegenerative disorders. ADAMTS-3 was identified as the protease that cleaves and inactivates Reelin in the cerebral cortex and hippocampus. ADAMTS-3 was expressed in the excitatory neurons of the embryonic and postnatal cerebral cortex and hippocampus. Cleavage by ADAMTS-3 is the major contributor of Reelin inactivation Tau phosphorylation was decreased and dendritic branching and elongation was increased in ADAMTS-3-deficient mice. Therefore, inhibition of ADAMTS-3 upregulates Reelin activity and may be a potential therapeutic strategy for the prevention or treatment of neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease.
[Mh] Termos MeSH primário: Proteínas ADAMTS/secreção
Moléculas de Adesão Celular Neuronais/metabolismo
Córtex Cerebral/metabolismo
Proteínas da Matriz Extracelular/metabolismo
Hipocampo/metabolismo
Proteínas do Tecido Nervoso/metabolismo
Neurônios/metabolismo
Pró-Colágeno N-Endopeptidase/secreção
Serina Endopeptidases/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Ativação Enzimática
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Endogâmicos ICR
Camundongos Knockout
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cell Adhesion Molecules, Neuronal); 0 (Extracellular Matrix Proteins); 0 (Nerve Tissue Proteins); EC 3.4.21.- (Serine Endopeptidases); EC 3.4.21.- (reelin protein); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS3 protein, human); EC 3.4.24.14 (Procollagen N-Endopeptidase)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170219
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.3632-16.2017


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[PMID]:28146470
[Au] Autor:Marouli E; Graff M; Medina-Gomez C; Lo KS; Wood AR; Kjaer TR; Fine RS; Lu Y; Schurmann C; Highland HM; Rüeger S; Thorleifsson G; Justice AE; Lamparter D; Stirrups KE; Turcot V; Young KL; Winkler TW; Esko T; Karaderi T; Locke AE; Masca NG; Ng MC; Mudgal P; Rivas MA; Vedantam S; Mahajan A; Guo X; Abecasis G; Aben KK; Adair LS; Alam DS; Albrecht E; Allin KH; Allison M; Amouyel P; Appel EV; Arveiler D; Asselbergs FW; Auer PL; Balkau B; Banas B; Bang LE; Benn M; Bergmann S; Bielak LF; Blüher M; Boeing H; Boerwinkle E; Böger CA; EPIC-InterAct Consortium; CHD Exome; Consortium; ExomeBP Consortium; T2D-Genes Consortium; GoT2D Genes Consortium; Global Lipids Genetics Consortium; ReproGen Consortium; MAGIC Investigators
[Ad] Endereço:William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
[Ti] Título:Rare and low-frequency coding variants alter human adult height.
[So] Source:Nature;542(7640):186-190, 2017 02 09.
[Is] ISSN:1476-4687
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.
[Mh] Termos MeSH primário: Estatura/genética
Frequência do Gene/genética
Variação Genética/genética
[Mh] Termos MeSH secundário: Proteínas ADAMTS/genética
Adulto
Alelos
Moléculas de Adesão Celular/genética
Feminino
Genoma Humano/genética
Glicoproteínas/genética
Glicoproteínas/metabolismo
Glicosaminoglicanos/biossíntese
Proteínas Hedgehog/genética
Seres Humanos
Peptídeos e Proteínas de Sinalização Intercelular/genética
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo
Fatores Reguladores de Interferon/genética
Subunidade alfa de Receptor de Interleucina-11/genética
Masculino
Herança Multifatorial/genética
NADPH Oxidase 4
NADPH Oxidases/genética
Fenótipo
Proteína Plasmática A Associada à Gravidez/metabolismo
Pró-Colágeno N-Endopeptidase/genética
Proteoglicanas/biossíntese
Proteólise
Receptores Androgênicos/genética
Somatomedinas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (AR protein, human); 0 (CRISPLD2 protein, human); 0 (Cell Adhesion Molecules); 0 (Glycoproteins); 0 (Glycosaminoglycans); 0 (Hedgehog Proteins); 0 (IHH protein, human); 0 (IL11RA protein, human); 0 (Intercellular Signaling Peptides and Proteins); 0 (Interferon Regulatory Factors); 0 (Interleukin-11 Receptor alpha Subunit); 0 (Proteoglycans); 0 (Receptors, Androgen); 0 (STC2 protein, human); 0 (Somatomedins); EC 1.6.3.- (NADPH Oxidase 4); EC 1.6.3.- (NADPH Oxidases); EC 1.6.3.- (NOX4 protein, human); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS3 protein, human); EC 3.4.24.- (Pregnancy-Associated Plasma Protein-A); EC 3.4.24.14 (Procollagen N-Endopeptidase)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171116
[Lr] Data última revisão:
171116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE
[do] DOI:10.1038/nature21039


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[PMID]:28145888
[Au] Autor:Lu T; Dang S; Zhu R; Wang Y; Nie Z; Hong T; Zhang W
[Ad] Endereço:Key Laboratory of Brain Functional Genomics, Ministry of Education, Shanghai Key Laboratory of Brain Functional Genomics, School of Life Science, East China Normal University, Shanghai, China.
[Ti] Título:Adamts18 deficiency promotes colon carcinogenesis by enhancing ß-catenin and p38MAPK/ERK1/2 signaling in the mouse model of AOM/DSS-induced colitis-associated colorectal cancer.
[So] Source:Oncotarget;8(12):18979-18990, 2017 Mar 21.
[Is] ISSN:1949-2553
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:ADAMTS18 is a novel tumor suppressor and is critical to the pathology of human colorectal cancer. However, the underlying mechanism is not clear. Here we generated an Adamts18-deficient mouse strain as an in vivo model to investigate the role of ADAMTS18 in the pathogenesis of colorectal cancer. In AOM/DSS-induced colitis-associated colorectal cancer, the deficiency of Adamts18 in mice resulted in enhanced tumorigenesis and colon inflammation that could be attributed in part to enhanced nuclear translocation of ß-catenin and elevated expression of its downstream target genes, cyclin D1 and c-myc. Moreover, increased p38MAPK and ERK1/2 activities were detected in colon cancer cells from Adamts18-deficient mice. Further studies revealed that ADAMTS18 deficiency reduced intestinal E-cadherin levels in mice, which ultimately led to intestinal barrier dysfunction. These data indicate that Adamts18 deficiency enhances tumorigenesis and intestinal inflammation through elevated Wnt/ß-catenin and p38MAPK/ERK1/2 signaling and promotes colon cancer in this mouse model.
[Mh] Termos MeSH primário: Proteínas ADAMTS/metabolismo
Transformação Celular Neoplásica/metabolismo
Neoplasias Colorretais/patologia
Sistema de Sinalização das MAP Quinases/fisiologia
beta Catenina/metabolismo
[Mh] Termos MeSH secundário: Animais
Western Blotting
Carcinógenos/toxicidade
Transformação Celular Neoplásica/patologia
Colite/induzido quimicamente
Colite/metabolismo
Colite/patologia
Neoplasias Colorretais/metabolismo
Modelos Animais de Doenças
Ensaio de Imunoadsorção Enzimática
Imuno-Histoquímica
Marcação In Situ das Extremidades Cortadas
Masculino
Camundongos
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Carcinogens); 0 (beta Catenin); EC 3.4.24.- (ADAMTS Proteins); EC 3.4.24.- (ADAMTS18 protein, mouse)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170202
[St] Status:MEDLINE
[do] DOI:10.18632/oncotarget.14866



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