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1.
J Pediatr Ophthalmol Strabismus ; 56: e45-e48, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31282960

RESUMO

Ectopia lentis is displacement of the lens from its original position. It can be inherited or acquired with isolated or systemic findings. The authors describe a 4-year-old girl with isolated ectopia lentis et pupillae caused by pathogenic variants in the ADAMTSL4 gene and discuss the molecular genetic work-up of individuals with ectopia lentis. [J Pediatr Ophthalmol Strabismus. 2019;56:e45-e48.].


Assuntos
Proteínas ADAMTS/genética , Algoritmos , DNA/genética , Ectopia do Cristalino/genética , Cristalino/diagnóstico por imagem , Mutação , Distúrbios Pupilares/genética , Proteínas ADAMTS/metabolismo , Pré-Escolar , Análise Mutacional de DNA , Ectopia do Cristalino/diagnóstico , Ectopia do Cristalino/metabolismo , Feminino , Humanos , Linhagem , Distúrbios Pupilares/diagnóstico , Distúrbios Pupilares/metabolismo , Tomografia de Coerência Óptica
2.
Cell Physiol Biochem ; 52(5): 1003-1016, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30977985

RESUMO

BACKGROUND/AIMS: The composition of the extracellular matrix (ECM) in the central nervous system (CNS) has several features that make it unique. For instance, it is remarkable for the presence of proteoglycans such as versican, brevican, and neurocan, some of which have been identified as substrates of different members of the ADAMTS family of secreted metalloproteases. Previous studies have associated ADAMTSs with the repair of the CNS, including recovery following degradation of glial scar tissue and the stimulation of axonal growth after brain injury. However, the involvement of ADAMTSs in diseases of the CNS is complex and not understood fully, and a current challenge is unraveling the precise roles of these metalloproteases in the brain. METHODS: ADAMTS12 and neurocan gene expression was examined by quantitative PCR. Western blot analysis was employed to detect ADAMTS12 and neurocan protein expression in cell lines, and immunostaining techniques were used to detect neurocan in mouse brain tissues. Neurocan cleavage using recombinant ADAMTS1, ADAMTS4, ADAMTS5, and ADAMTS12 metalloproteases was evaluated by western blotting. Cell adhesion and migration were assessed using uncoated culture dishes or dishes coated with Matrigel or ECM components. RESULTS: We identified neurocan as a novel component of brain ECM that can be cleaved by ADAMTS12. In addition, we showed that neurocan cleavage by ADAMTS12 altered the adhesive properties of the human neuroglioma H4 cell line. Moreover, immunohistochemical analysis of Adamts12-deficient mice revealed the significant accumulation of neurocan in the brain of neonatal mice. CONCLUSION: Overall, our results suggest that ADAMTS12 could be involved in the repair of the CNS through its ability to degrade neurocan. Moreover, it can be inferred that alterations in neurocan degradation processes could be associated with the pathogenesis of neurological disorders.


Assuntos
Proteínas ADAMTS/biossíntese , Proteínas ADAMTS/metabolismo , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Doenças dos Nervos Cranianos/metabolismo , Lectinas Tipo C/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteoglicanas/metabolismo , Proteólise , Proteínas ADAMTS/genética , Animais , Adesão Celular , Linhagem Celular Tumoral , Movimento Celular , Proteoglicanas de Sulfatos de Condroitina/genética , Doenças dos Nervos Cranianos/genética , Doenças dos Nervos Cranianos/patologia , Regulação da Expressão Gênica , Humanos , Lectinas Tipo C/genética , Camundongos , Proteínas do Tecido Nervoso/genética , Proteoglicanas/genética
3.
Biol Pharm Bull ; 42(3): 354-356, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30828067

RESUMO

Reelin is a secreted protein that antagonizes the deposition and toxicity of amyloid ß peptide (Aß). Therefore, augmentation of Reelin activity may ameliorate Alzheimer's disease (AD). We have recently reported that a disintegrin and metalloproteinase with thrombospondin motifs 3 (ADAMTS-3) cleaves and inactivates Reelin in the mouse brain. In the present study, we investigated the effect of reducing ADAMTS-3 on deposition of Aß by crossbreeding drug-inducible ADAMTS-3 conditional knock-out (cKO) mice with "next-generation" AD model mice. We found that reducing ADAMTS-3 inhibited deposition of Aß significantly in AppNL-F mice, which produce human wild-type Aß. On the other hand, reducing ADAMTS-3 had no effect in AppNL-G-F mice, which produce the Arctic mutant Aß (E22G) that forms protofibrils more efficiently than does wild-type Aß. Thus, the findings suggest that the administration of an inhibitor against ADAMTS-3 will prevent the progression of AD pathology caused by deposition of wild-type Aß.


Assuntos
Proteínas ADAMTS/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Proteínas ADAMTS/antagonistas & inibidores , Proteínas ADAMTS/genética , Doença de Alzheimer , Animais , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo
4.
Nat Commun ; 10(1): 953, 2019 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-30814516

RESUMO

Although hundreds of cytosolic or transmembrane molecules form the primary cilium, few secreted molecules are known to contribute to ciliogenesis. Here, homologous secreted metalloproteases ADAMTS9 and ADAMTS20 are identified as ciliogenesis regulators that act intracellularly. Secreted and furin-processed ADAMTS9 bound heparan sulfate and was internalized by LRP1, LRP2 and clathrin-mediated endocytosis to be gathered in Rab11 vesicles with a unique periciliary localization defined by super-resolution microscopy. CRISPR-Cas9 inactivation of ADAMTS9 impaired ciliogenesis in RPE-1 cells, which was restored by catalytically active ADAMTS9 or ADAMTS20 acting in trans, but not by their proteolytically inactive mutants. Their mutagenesis in mice impaired neural and yolk sac ciliogenesis, leading to morphogenetic anomalies resulting from impaired hedgehog signaling, which is transduced by primary cilia. In addition to their cognate extracellular proteolytic activity, ADAMTS9 and ADAMTS20 thus have an additional proteolytic role intracellularly, revealing an unexpected regulatory dimension in ciliogenesis.


Assuntos
Proteínas ADAMTS/metabolismo , Proteína ADAMTS9/metabolismo , Cílios/metabolismo , Cílios/ultraestrutura , Proteínas ADAMTS/deficiência , Proteínas ADAMTS/genética , Proteína ADAMTS9/deficiência , Proteína ADAMTS9/genética , Animais , Linhagem Celular , Endocitose , Técnicas de Inativação de Genes , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Eletrônica de Varredura , Modelos Biológicos , Mutação , Defeitos do Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Proteólise , Transdução de Sinais , Versicanas/genética , Versicanas/metabolismo , Saco Vitelino/embriologia , Saco Vitelino/metabolismo
5.
Nat Commun ; 10(1): 1030, 2019 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833571

RESUMO

Carpal tunnel syndrome (CTS) is a common and disabling condition of the hand caused by entrapment of the median nerve at the level of the wrist. It is the commonest entrapment neuropathy, with estimates of prevalence ranging between 5-10%. Here, we undertake a genome-wide association study (GWAS) of an entrapment neuropathy, using 12,312 CTS cases and 389,344 controls identified in UK Biobank. We discover 16 susceptibility loci for CTS with p < 5 × 10-8. We identify likely causal genes in the pathogenesis of CTS, including ADAMTS17, ADAMTS10 and EFEMP1, and using RNA sequencing demonstrate expression of these genes in surgically resected tenosynovium from CTS patients. We perform Mendelian randomisation and demonstrate a causal relationship between short stature and higher risk of CTS. We suggest that variants within genes implicated in growth and extracellular matrix architecture contribute to the genetic predisposition to CTS by altering the environment through which the median nerve transits.


Assuntos
Síndrome do Túnel Carpal/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Proteínas ADAMTS/genética , Idoso , Mapeamento Cromossômico , Simulação por Computador , Proteínas da Matriz Extracelular/genética , Feminino , Genoma Humano/genética , Genótipo , Humanos , Masculino , Nervo Mediano , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Análise de Sequência de RNA , Punho
6.
Acta Orthop Traumatol Turc ; 53(2): 140-144, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30655094

RESUMO

PURPOSE: The aim of this study is to investigate which ADAMTS genes play a major role in the development of primary hip osteoarthritis, by comparing the tissue and blood samples in patients with hip osteoarthritis and a control group. MATERIAL AND METHODS: Human articular cartilage was obtained from femoral heads of 15 patients with end stage osteoarthritis undergoing total hip replacement. As the control group, the cartilages was obtained from femoral heads of 15 patients, who did not have osteoarthritis or degenerative changes in hip joint, undergoing hip replacement following the fracture of the femoral neck. After the cartilage samples were taken from the resection materials, the DNA polymorphisms in the patients' cartilage samples were tested by Polymerase Chain Reaction (PCR), the serum levels of aggrecanase genes were analyzed with Enzyme-Linked ImmunoSorbent Assay (ELISA). RESULTS: The level of ADAMTS5 and ADAMTS9 genes were found significantly lower as a result of ELISA analysis degenerative arthritis group than the control group (p < 0,05). ADAMTS 1, 4, 8, 15 were similar between the two groups in ELISA analysis (p > 0,05). As a result of quantitative real time RT-PCR analysis, the level of ADAMTS8 mRNA increased 3.5 fold in hip degenerative arthritis group when compared with femoral neck fractures group. ADAMTS1, ADAMTS4 and ADAMTS5 expression levels in hip degenerative arthritis group were decreased 2.5, 2 and 2.5 fold, respectively. ADAMTS9, 15 were found to be similar between two groups. CONCLUSON: As a result of this study on hip osteoarthritis, the ADAMTS8 levels was found to be significantly higher in the end stage of hip osteoarthritis. Unlike similar studies on knee osteoarthritis, ADAMTS1,4,5 levels were found to be lower.


Assuntos
Proteínas ADAMTS/genética , Proteína ADAMTS1/genética , Cartilagem Articular , Endopeptidases , Osteoartrite do Quadril , Proteínas ADAMTS/análise , Idoso , Artroplastia de Quadril/métodos , Cartilagem Articular/enzimologia , Cartilagem Articular/patologia , Correlação de Dados , Endopeptidases/sangue , Endopeptidases/genética , Feminino , Fraturas do Colo Femoral/genética , Fraturas do Colo Femoral/patologia , Fraturas do Colo Femoral/cirurgia , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/sangue , Osteoartrite do Quadril/genética , Osteoartrite do Quadril/patologia , Osteoartrite do Quadril/cirurgia
7.
Neuroscience ; 399: 53-64, 2019 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-30579834

RESUMO

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that modify extracellular matrix components and play crucial roles in development and numerous diseases. ADAMTS18 is a member of the ADAMTS family, and genome-wide association studies made an initial association of ADAMTS18 with white matter integrity in healthy people of 72-74 years old. However, the potential roles of ADAMTS18 in central nervous system remain unclear. In this study, we showed that Adamts18 mRNA is highly abundant in developing brains, especially in the cerebellum granular cell layer and the hippocampus dentate gyrus (DG) granular cell layer. Adamts18 knockout (KO) mice displayed higher dendritic branching complexity and spine density on hippocampal DG granular cells. Behavioral tests showed that Adamts18 KO mice had reduced levels of depression-like behaviors compared to their wild-type (WT) littermates. The increased neurite formation could be attributed in part to reduced phosphorylation levels of the collapsin response mediator protein-2 (CRMP2) due to activation of the laminin/PI3K/AKT/GSK-3ß signaling pathway. Our findings revealed a critical role of ADAMTS18 in neuronal morphogenesis and emotional control in mice.


Assuntos
Proteínas ADAMTS/deficiência , Transtorno Depressivo/enzimologia , Transtorno Depressivo/patologia , Neurônios/enzimologia , Neurônios/patologia , Proteínas ADAMTS/genética , Animais , Encéfalo/enzimologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/fisiologia , RNA Mensageiro/metabolismo
9.
Genome Biol ; 19(1): 87, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30012220

RESUMO

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.


Assuntos
Proteínas ADAMTS/genética , Conexina 43/genética , Exoma , Loci Gênicos , Sistema de Condução Cardíaco/metabolismo , Miocárdio/metabolismo , Grupo com Ancestrais do Continente Africano , Animais , Eletrocardiografia , Grupo com Ancestrais do Continente Europeu , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Miocárdio/patologia , Fases de Leitura Aberta , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
10.
Med Sci Monit ; 24: 3726-3735, 2018 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-29860265

RESUMO

BACKGROUND The aim of this study was to investigate the correlations between ADAMTSs expression and breast invasive ductal carcinoma (IDC), and to offer a theoretical basis for novel treatment methods for IDC patients. MATERIAL AND METHODS Non-proliferative catheter of breast fibroadenoma (FA) and IDC were used as the normal control and experimental group, respectively. Immunohistochemical (IHC) staining and Western blot (WB) analysis was used to assess protein expression levels of ADAMTS8, ADAMTS18, and ADAMTS20 in both FA and IDC tissues. The results of IHC, the relationship between the protein expression and the tumor molecular classification, and clinical pathological parameters were all evaluated. RESULTS IHC and WB results showed that the expression of ADAMTS8/18 in IDC samples was higher than in FA samples, while the expression of ADAMTS20 in IDC samples was lower than that in FA samples. According to the results of WB, the level of ADAMTS8 was higher in the HER2+ group than in the HER2- group and FA group. The expression of ADAMTS18 in the HR+ (including ER+ and PR+) group was significantly higher than in the HR- group and FA group. The expression of ADAMTS18 protein was also higher in the Ki67+ group than in the Ki67- group. ADAMTS20 was higher in HER2+ IDC compared with the basal subtype of IDC. CONCLUSIONS ADAMTS8/18/20 levels were not significantly correlated to the molecular subtype of IDC. ADAMTS18/20 was significantly associated with histological grade of IDC. ADAMTS8 may predict poor prognosis results of IDC patients.


Assuntos
Proteínas ADAMTS/biossíntese , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Proteínas ADAMTS/genética , Adulto , Idoso , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/genética , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Receptores Estrogênicos/metabolismo , Transcriptoma
11.
Nat Commun ; 9(1): 1864, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29760442

RESUMO

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r = -0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r = -0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.


Assuntos
Córnea/metabolismo , Genoma Humano , Glaucoma de Ângulo Aberto/genética , Ceratocone/genética , Polimorfismo de Nucleotídeo Único , Característica Quantitativa Herdável , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Grupo com Ancestrais do Continente Asiático , Córnea/anormalidades , Córnea/patologia , Doenças da Córnea/etnologia , Doenças da Córnea/genética , Doenças da Córnea/metabolismo , Doenças da Córnea/patologia , Distrofias Hereditárias da Córnea/etnologia , Distrofias Hereditárias da Córnea/genética , Distrofias Hereditárias da Córnea/metabolismo , Distrofias Hereditárias da Córnea/patologia , Decorina/genética , Decorina/metabolismo , Síndrome de Ehlers-Danlos/etnologia , Síndrome de Ehlers-Danlos/genética , Síndrome de Ehlers-Danlos/metabolismo , Síndrome de Ehlers-Danlos/patologia , Grupo com Ancestrais do Continente Europeu , Oftalmopatias Hereditárias/etnologia , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Oftalmopatias Hereditárias/patologia , Fibrilina-1/genética , Fibrilina-1/metabolismo , Expressão Gênica , Estudo de Associação Genômica Ampla , Glaucoma de Ângulo Aberto/etnologia , Glaucoma de Ângulo Aberto/metabolismo , Glaucoma de Ângulo Aberto/patologia , Humanos , Ceratocone/etnologia , Ceratocone/metabolismo , Ceratocone/patologia , Síndrome de Loeys-Dietz/etnologia , Síndrome de Loeys-Dietz/genética , Síndrome de Loeys-Dietz/metabolismo , Síndrome de Loeys-Dietz/patologia , Lumicana/genética , Lumicana/metabolismo , Síndrome de Marfan/etnologia , Síndrome de Marfan/genética , Síndrome de Marfan/metabolismo , Síndrome de Marfan/patologia , Análise da Randomização Mendeliana , Miopia/etnologia , Miopia/genética , Miopia/metabolismo , Miopia/patologia
12.
Beijing Da Xue Xue Bao Yi Xue Ban ; 50(2): 279-283, 2018 Apr 18.
Artigo em Chinês | MEDLINE | ID: mdl-29643527

RESUMO

OBJECTIVE: To investigate the association between single nucleotide polymorphisms (SNP) of ADAMTS14 gene rs4747096 and osteoarthritis of the temporomandibular joint in Chinese Han females. METHODS: As a case-control study, a total of 213 Chinese Han females were involved in the present study, which contained 103 temporomandibular joint osteoarthritis patients and 110 healthy people who had no symptoms or signs of temporomandibular joint osteoarthritis as control. Peripheral blood samples were collected from each participant. Genomic DNAs of temporomandibular joint osteoarthritis patients and healthy control were extracted from peripheral venous blood, which were stored in -80 °C refrigerator by using DNA extraction kits. The designed primers were used for polymerase chain reaction (PCR) amplification of specific DNA fragments. Genotype was determined by sequencing the PCR products. The software Chromas 2.22 was used to analyze the genotype. The genotype distributions, allele frequencies and genetic models between the patients and controls were compared. The age distribution was checked by t-test. Genotype and allele frequency were detected by Chi-square test. RESULTS: In the present study, there were no significant differences between the osteoarthritis patients and healthy controls in terms of age. The genotype distribution was in accordance with Hardy-Weinberg equilibrium in the two groups. The genotype frequency of the ADAMTS14 (rs4747096) in the experimental group was 38.8% (AA), 55.4% (AG), and 5.8% (GG), respectively. The genotype frequency in the control group was 40.9% (AA), 43.6% (AG), and 15.5% (GG), respectively. The difference of genotype frequency of the ADAMTS14 (rs4747096) was significant between the experimental group and the control group (P=0.047). There was no significant difference in allele frequency between the two groups (P=0.415). AA and AG genotypes significantly increased the risk of the disease compared with GG in dominant model (OR=1.114, 95% CI: 1.015-1.223, P=0.028). CONCLUSION: A significant correlationship was found between the ADAMTS14 (rs4747096) SNP and the temporomandibular joint osteoarthritis in Chinese Han females. The distribution of rs4747096 may be different between temporomandibular joint osteoarthritis and healthy population.


Assuntos
Proteínas ADAMTS/genética , Predisposição Genética para Doença , Osteoartrite/genética , Polimorfismo de Nucleotídeo Único , Articulação Temporomandibular/patologia , Grupo com Ancestrais do Continente Asiático , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Osteoartrite/etnologia , Reação em Cadeia da Polimerase
13.
Gene ; 659: 1-10, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29518549

RESUMO

ADAMTS3 is a member of procollagen N-proteinase subfamily of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family. It has an important function in the procollagen maturation process. The removal of N-peptidases is required for the accurate processing of fibrillar collagens. Otherwise, several disorders can occur that is related with the collagenous tissues. ADAMTS3 mainly maturates type II collagen molecule which is the main component of the bone and cartilage. There are several expression studies about ADAMTS3 gene however its transcriptional regulation has not been lightened up, yet. Here we first time cloned and functionally analyzed the promoter region of ADAMTS3 gene, approximately 1380 bp upstream of the transcription start site. Transient transfection experiments showed that all truncated promoter constructs are active and 171 bp fragment is sufficient to activate gene expression in both Saos-2 and MG63 cells. In silico analysis showed that ADAMTS3 has a TATA-less promoter and contains several SP1/GC box binding motifs and a CpG island. Therefore we mainly investigated the SP1 dependent regulation of ADAMTS3 promoter. SP1 downregulated ADAMTS3 transcriptional activity. As consistent with the transcriptional activity, mRNA, and protein expression levels were also decreased by SP1. On the other hand, functional binding of the SP1 on multiple regions of ADAMTS3 promoter was confirmed by EMSA studies. As ADAMTS3 is responsible for the collagen maturation and biosynthesis, further we investigated the effect of SP1 on type I-II and III collagen gene expressions. We point out that SP1 increased type II and III collagen expression and in contrast decreased type I collagen expression levels in Saos-2 cells. mRNA expression level was decreased for all collagen types in MG63 model. Decrease in the type II collagen expression was also demonstrated at the protein level by SP1. Collectively these results provide first findings for the SP1-related transcriptional regulation of ADAMTS3 and collagen genes in osteosarcoma cell lines.


Assuntos
Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Neoplasias Ósseas/genética , Osteossarcoma/genética , Pró-Colágeno N-Endopeptidase/genética , Pró-Colágeno N-Endopeptidase/metabolismo , Fator de Transcrição Sp1/metabolismo , Proteínas ADAMTS/química , Sítios de Ligação , Neoplasias Ósseas/metabolismo , Linhagem Celular Tumoral , Clonagem Molecular , Colágeno/genética , Simulação por Computador , Ilhas de CpG , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Biológicos , Osteossarcoma/metabolismo , Pró-Colágeno N-Endopeptidase/química , Regiões Promotoras Genéticas
14.
Biochem Biophys Res Commun ; 496(4): 1362-1368, 2018 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-29421655

RESUMO

ADAMTS18 is a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) that are known for their crucial role in development, angiogenesis, inflammation and coagulation. It was previously reported that ADAMTS18 cleaved by thrombin induced platelet fragmentation, through which thrombus were dissolved. However, it remains unclear whether this represents a dominant physiologic mechanism controlling thrombus growth in vivo. Here, we used an established Adamts18 knockout (KO) mouse model to determine its function in thrombus formation. ADAMTS18 deficiency accelerated FeCl3-induced carotid artery thrombosis and aggravated postischemic cerebral infarction in mice. However, this accelerated thrombus phenotype in Adamts18 KO mice was not due to the lack of ADAMTS18-mediated-platelet fragmentation. Moreover, Adamts18 deficiency exerted little effects on mouse platelet functions. The underlying molecular mechanisms could be attributed in part to the abnormal vascular remodeling, including deficiency of carotid body (glomus) and aberrant carotid basal lamina. These results indicate a novel function of ADAMTS18 in vascular remodeling and associated thrombus formation.


Assuntos
Proteínas ADAMTS/metabolismo , Trombose das Artérias Carótidas/metabolismo , Infarto Cerebral/metabolismo , Trombose/metabolismo , Trombose/patologia , Proteínas ADAMTS/genética , Animais , Trombose das Artérias Carótidas/patologia , Infarto Cerebral/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
15.
Int J Mol Sci ; 19(2)2018 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-29393911

RESUMO

Approximately sixty per cent of ovarian cancer patients die within the first five years of diagnosis due to recurrence associated with chemoresistance. The metzincin family of metalloproteinases is enzymes involved in matrix remodeling in response to normal physiological changes and diseased states. Recently, there has been a mounting awareness of these proteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), as superb modulators of cellular communication and signaling regulating key biological processes in cancer progression. This review investigates the role of metzincins and their inhibitors in ovarian cancer. We propose that understanding the metzincins and TIMP biology in ovarian cancer may provide valuable insights in combating ovarian cancer progression and chemoresistance-mediated recurrence in patients.


Assuntos
Proteínas ADAMTS/genética , Regulação Neoplásica da Expressão Gênica , Metaloproteinases da Matriz/genética , Recidiva Local de Neoplasia/genética , Neoplasias Ovarianas/genética , Inibidores Teciduais de Metaloproteinases/genética , Proteínas ADAMTS/metabolismo , Antineoplásicos/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Metaloproteinases da Matriz/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Ovário/efeitos dos fármacos , Ovário/metabolismo , Ovário/patologia , Transdução de Sinais , Análise de Sobrevida , Inibidores Teciduais de Metaloproteinases/metabolismo
16.
Diabetes Res Clin Pract ; 135: 143-149, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29162515

RESUMO

AIMS: The aim of this study was to clarify the genetic background of a family with multiple cases of diabetes accompanied by absolute insulin deficiency using whole-exome sequencing (WES). METHODS: In a Japanese family, WES was performed in four affected members with absolute insulin deficiency and two unaffected members. We focused on variants that were predicted to be disease-causing by bioinformatics and were shared by all of the four affected members but were not present in the two unaffected members. We assumed that the familial clustering of diabetes was caused by rare variants excluding those with allele frequency of more than 0.01 in the 1000 Genomes Project, the Human Genetic Variation Database, or a cohort of 105 normoglycemic controls in Japan. The rare variants were then genotyped in 2102 Japanese without diabetes and 119 Japanese with diabetes. RESULTS: Among the variants detected by WES and predicted to be disease-causing, 16 variants shared by all of the four of the affected members and not present in the two unaffected members were confirmed to be rare. Genotyping of the 16 rare variants revealed that only A137T in ADAMTSL3 (rs181914721) was observed more frequently in the 119 subjects with diabetes than in the 105 normoglycemic controls, and the allele frequency of the variant was significantly higher in the 119 subjects with diabetes than in another cohort of 2102 Japanese without diabetes. CONCLUSIONS: We propose that A137T in ADAMTSL3 is a candidate mutation for susceptibility to diabetes in this family and in the Japanese population.


Assuntos
Proteínas ADAMTS/genética , Diabetes Mellitus/genética , Exoma/genética , Proteínas da Matriz Extracelular/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem
17.
Nucl Med Commun ; 39(2): 110-117, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29194287

RESUMO

OBJECTIVE: The aim of this study was to investigate the presence of ADAMTS2 and ADAMTS5 in the salivary gland (SG) of rats after high-dose radioiodine therapy. METHODS: A total of 36 male Wistar albino rats were used for this study. Thirty-six male rats were divided randomly into six groups: control and five radioactive iodine (RAI) treatment groups of six rats each. All animals were killed. The evaluation of biodistribution and histopathological studies were carried out on the SGs removed. Real-time PCR and immunohistochemical analysis were carried out to determine mRNA and protein expression levels of ADAMTS genes. Differences between the groups were evaluated statistically. RESULTS: In RAI-treated groups, ADAMTS2 and ADAMTS5 gene expression was observed to increase, whereas there was no mRNA or protein expression in the control group. There were statistically significant increases in the mRNA expression of ADAMTS2 (all RAI-administered groups in parathyroid gland and at 4, 24, and 48 h in submandibular gland) and ADAMTS5 (all RAI-administered groups, except on the 30th day in the parathyroid gland and all RAI groups in submandibular gland). Through immunohistochemical analysis, the staining pattern in the extracellular source was also observed in the overexpressed ADAMTS2 and ADAMTS5 groups. Nuclear coarsening and partial focal subnuclei vacuolization were determined in all RAI-administered groups with histopathological examinations. CONCLUSION: An increase in the mRNA expression levels of ADAMTS2 and ADAMTS5 genes was detected in the RAI-administered groups. These results suggested that ADAMTS2 and ADAMTS5 genes might play a role in radiation exposure and radioiodine-induced SG changes.


Assuntos
Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Proteína ADAMTS5/genética , Proteína ADAMTS5/metabolismo , Regulação da Expressão Gênica/efeitos da radiação , Radioisótopos do Iodo/uso terapêutico , Glândulas Salivares/metabolismo , Glândulas Salivares/efeitos da radiação , Animais , Radioisótopos do Iodo/farmacocinética , Masculino , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Dosagem Radioterapêutica , Ratos , Distribuição Tecidual
18.
Am J Vet Res ; 79(1): 98-106, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29287154

RESUMO

OBJECTIVE To evaluate the coding regions of ADAMTS17 for potential mutations in Chinese Shar-Pei with a diagnosis of primary open-angle glaucoma (POAG), primary lens luxation (PLL), or both. ANIMALS 63 Shar-Pei and 96 dogs of other breeds. PROCEDURES ADAMTS17 exon resequencing was performed on buccal mucosal DNA from 10 Shar-Pei with a diagnosis of POAG, PLL, or both (affected dogs). A candidate causal variant sequence was identified, and additional dogs (53 Shar-Pei [11 affected and 42 unaffected] and 95 dogs of other breeds) were genotyped for the variant sequence by amplified fragment length polymorphism analysis. Total RNA was extracted from ocular tissues of 1 affected Shar-Pei and 1 ophthalmologically normal Golden Retriever; ADAMTS17 cDNA was reverse transcribed and sequenced, and ADAMTS17 expression was evaluated by quantitative reverse-transcription PCR assay. RESULTS All affected Shar-Pei were homozygous for a 6-bp deletion in exon 22 of ADAMTS17 predicted to affect the resultant protein. All unaffected Shar-Pei were heterozygous or homozygous for the wild-type allele. The variant sequence was significantly associated with affected status (diagnosis of POAG, PLL, or both). All dogs of other breeds were homozygous for the wild-type allele. The cDNA sequencing confirmed presence of the expected variant mRNA sequence in ocular tissue from the affected dog only. Gene expression analysis revealed a 4.24-fold decrease in the expression of ADAMTS17 in ocular tissue from the affected dog. CONCLUSIONS AND CLINICAL RELEVANCE Results supported that the phenotype (diagnosis of POAG, PLL, or both) is an autosomal recessive trait in Shar-Pei significantly associated with the identified mutation in ADAMTS17.


Assuntos
Proteínas ADAMTS/genética , Doenças do Cão/genética , Glaucoma de Ângulo Aberto/veterinária , Subluxação do Cristalino/veterinária , Análise do Polimorfismo de Comprimento de Fragmentos Amplificados/veterinária , Animais , Cruzamento , Cães , Feminino , Genótipo , Glaucoma de Ângulo Aberto/genética , Subluxação do Cristalino/genética , Masculino , Mutação , Fenótipo
19.
Mol Carcinog ; 57(1): 22-31, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28796414

RESUMO

Metzincins are key molecules in the degradation of the extracellular matrix and play an important role in cellular processes such as cell migration, adhesion, and cell fusion of malignant tumors, including cutaneous melanoma (CM). We hypothesized that genetic variants of the metzincin metallopeptidase family genes would be associated with CM-specific survival (CMSS). To test this hypothesis, we first performed Cox proportional hazards regression analysis to evaluate the associations between genetic variants of 75 metzincin metallopeptidase family genes and CMSS using the dataset from the genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC) which included 858 non-Hispanic white patients with CM, and then validated using the dataset from the Harvard GWAS study which had 409 non-Hispanic white patients with invasive CM. Four independent SNPs (MMP16 rs10090371 C>A, ADAMTS3 rs788935 T>C, TLL2 rs10882807 T>C and MMP9 rs3918251 A>G) were identified as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) of 1.73 (1.32-2.29, 9.68E-05), 1.46 (1.15-1.85, 0.002), 1.68 (1.31-2.14, 3.32E-05) and 0.67 (0.51-0.87, 0.003), respectively, in the meta-analysis of these two GWAS studies. Combined analysis of risk genotypes of these four SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased (Ptrend < 0.001). An improvement was observed in the prediction model (area under the curve [AUC] = 81.4% vs. 78.6%), when these risk genotypes were added to the model containing non-genotyping variables. Our findings suggest that these genetic variants may be promising prognostic biomarkers for CMSS.


Assuntos
Proteínas ADAMTS/genética , Metaloproteinase 16 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Melanoma/genética , Polimorfismo de Nucleotídeo Único , Pró-Colágeno N-Endopeptidase/genética , Neoplasias Cutâneas/genética , Metaloproteases Semelhantes a Toloide/genética , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla/métodos , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genótipo , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias Cutâneas/patologia
20.
Gene ; 638: 26-35, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28943345

RESUMO

The present study was conducted to clarify the involvement of the basement membrane (BM) in insect metamorphosis through analysis of the expression profile of two types of metalloproteinase (MMP and ADAMTS) genes in several organs, their ecdysone involvement, and the histological change of BM. BM was observed around wing sac and in the wing cavity and around fat bodies at the W0 stage but disappeared after the W3 stage, and wing discs evaginated and fat body cells scattered after the W3 stage. The disappearance of the BM of midgut and silk glands was not observed after the W3 stage, but degenerated epithelium cells in the midgut and shrunken cells in the silk gland were observed after the W3 stage. BmMMP1 showed a peak at P0 in the wing discs, fat bodies, midgut, and silk gland. BmMMP2 showed a broad peak around pupation in the wing discs, fat bodies, midgut, and silk gland. BmADAMTS-1 showed enhanced expression at W2 in the wing discs, fat bodies, midgut, and hemocyte, while BmADAMTS-L showed enhanced expression at W3 in the fat bodies, midgut, silk gland, and hemocyte. After pupation, they showed a different expression in different organs. All of four genes were induced by 20-hydroxyecdysone in wing discs in vitro. The present results suggested the involvement of MMPs and ADAMTS in the BM digestion and the morphogenesis of organs during Bombyx metamorphosis.


Assuntos
Bombyx/crescimento & desenvolvimento , Bombyx/genética , Metaloproteinases da Matriz/genética , Proteínas ADAMTS/genética , Proteínas ADAMTS/metabolismo , Animais , Membrana Basal/metabolismo , Bombyx/enzimologia , Bombyx/metabolismo , Ecdisona/metabolismo , Larva/crescimento & desenvolvimento , Larva/metabolismo , Metamorfose Biológica , Asas de Animais/crescimento & desenvolvimento , Asas de Animais/metabolismo
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