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[PMID]:29338044
[Au] Autor:Andley UP; Tycksen E; McGlasson-Naumann BN; Hamilton PD
[Ad] Endereço:Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
[Ti] Título:Probing the changes in gene expression due to α-crystallin mutations in mouse models of hereditary human cataract.
[So] Source:PLoS One;13(1):e0190817, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The mammalian eye lens expresses a high concentration of crystallins (α, ß and γ-crystallins) to maintain the refractive index essential for lens transparency. Crystallins are long-lived proteins that do not turnover throughout life. The structural destabilization of crystallins by UV exposure, glycation, oxidative stress and mutations in crystallin genes leads to protein aggregation and development of cataracts. Several destabilizing mutations in crystallin genes are linked with human autosomal dominant hereditary cataracts. To investigate the mechanism by which the α-crystallin mutations Cryaa-R49C and Cryab-R120G lead to cataract formation, we determined whether these mutations cause an altered expression of specific transcripts in the lens at an early postnatal age by RNA-seq analysis. Using knock-in mouse models previously generated in our laboratory, in the present work, we identified genes that exhibited altered abundance in the mutant lenses, including decreased transcripts for Clic5, an intracellular water channel in Cryaa-R49C heterozygous mutant lenses, and increased transcripts for Eno1b in Cryab-R120G heterozygous mutant lenses. In addition, RNA-seq analysis revealed increased histones H2B, H2A, and H4 gene expression in Cryaa-R49C mutant lenses, suggesting that the αA-crystallin mutation regulates histone expression via a transcriptional mechanism. Additionally, these studies confirmed the increased expression of histones H2B, H2A, and H4 by proteomic analysis of Cryaa-R49C knock-in and Cryaa;Cryab gene knockout lenses reported previously. Taken together, these findings offer additional insight into the early transcriptional changes caused by Cryaa and Cryab mutations associated with autosomal dominant human cataracts, and indicate that the transcript levels of certain genes are affected by the expression of mutant α-crystallin in vivo.
[Mh] Termos MeSH primário: Catarata/genética
Mutação
Cadeia A de alfa-Cristalina/genética
Cadeia B de alfa-Cristalina/genética
[Mh] Termos MeSH secundário: Animais
Carboxipeptidases/genética
Carboxipeptidases/metabolismo
Catarata/metabolismo
Canais de Cloreto/genética
Canais de Cloreto/metabolismo
Modelos Animais de Doenças
Expressão Gênica
Técnicas de Introdução de Genes
Histonas/genética
Histonas/metabolismo
Seres Humanos
Cristalino/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Mutantes
Camundongos Transgênicos
Proteínas/genética
Proteínas/metabolismo
Proteômica
Proteínas Repressoras/genética
Proteínas Repressoras/metabolismo
Cadeia A de alfa-Cristalina/metabolismo
Cadeia B de alfa-Cristalina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Aebp1 protein, mouse); 0 (CLIC5 protein, mouse); 0 (Chloride Channels); 0 (Cryab protein, mouse); 0 (Histones); 0 (Proteins); 0 (Repressor Proteins); 0 (alpha-Crystallin A Chain); 0 (alpha-Crystallin B Chain); 0 (vig1 protein, mouse); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180213
[Lr] Data última revisão:
180213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0190817


  2 / 6128 MEDLINE  
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[PMID]:29196255
[Au] Autor:Gao C; Xing X; He Z; Chen S; Wang S; Li Q; Guo P; Zhang H; Li H; Chen L; Wang Q; Zhao J; Xiao Y; Chen W; Li D
[Ad] Endereço:Department of Toxicology, Guangzhou Key Laboratory of Environmental Pollution and Health Risk Assessment, School of Public Health, Sun Yat-sen University, Guangzhou, China.
[Ti] Título:Hypermethylation of PGCP gene is associated with human bronchial epithelial cells immortalization.
[So] Source:Gene;642:505-512, 2018 Feb 05.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Cell immortalization is the initial step for cancer development. To identify the differentially expressed genes regulated by DNA methylation over the course of human primary bronchial epithelial cell (HPBECs) immortalization, an immortalized HBE cell line (HBETT) was generated via introduction of an SV40 LT and a catalytic subunit of human telomerase reverse transcriptase (hTERT) into the HPBECs. Microarrays of mRNA and DNA methylation were performed to compare the transcriptomes and DNA methylomes between these two types of cells. The results from the mRNA microarray revealed many genes whose expression changed upon cell immortalization. We identified signatures including global hypomethylation, perturbation of ECM-receptor interaction, focal adhesion, and PI3K-Akt pathways associated with cell immortalization. Moreover, we revealed 155 differentiated methylation regions (DMRs) within the CpG islands (CGIs) of 42 genes and the perturbation of several key pathways that might be involved in HBE cell immortalization. Among these genes, the hypermethylation of the plasma glutamate carboxypeptidase (PGCP) gene appeared specifically in lung cancer tissues. The inhibition of PGCP expression by promoter hypermethylation was observed in both immortal HBETT cells and benzo[a]pyrene (Bap)-transformed HBE cells. In conclusion, these findings provide new insight into the epigenetic modifications that are critical in the transition and maintenance of cell immortalization.
[Mh] Termos MeSH primário: Benzo(a)pireno/toxicidade
Brônquios/patologia
Carboxipeptidases/genética
Transformação Celular Neoplásica/genética
Metilação de DNA
Neoplasias Pulmonares/genética
[Mh] Termos MeSH secundário: Brônquios/citologia
Brônquios/efeitos dos fármacos
Brônquios/metabolismo
Linhagem Celular
Ilhas de CpG
Células Epiteliais/citologia
Células Epiteliais/efeitos dos fármacos
Células Epiteliais/metabolismo
Células Epiteliais/patologia
Perfilação da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Análise de Sequência com Séries de Oligonucleotídeos/métodos
Regiões Promotoras Genéticas
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
3417WMA06D (Benzo(a)pyrene); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171226
[Lr] Data última revisão:
171226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171203
[St] Status:MEDLINE


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[PMID]:28699813
[Au] Autor:Graham TH
[Ad] Endereço:a Merck Research Laboratories , Merck & Co., Inc ., Kenilworth , NJ , USA.
[Ti] Título:Prolylcarboxypeptidase (PrCP) inhibitors and the therapeutic uses thereof: a patent review.
[So] Source:Expert Opin Ther Pat;27(10):1077-1088, 2017 Oct.
[Is] ISSN:1744-7674
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Prolylcarboxypeptidase (PrCP) is a serine protease that produces or degrades signaling proteins in several important pathways including the renin-angiotensin system (RAS), kallikrein-kinin system (KKS) and pro-opiomelanocortin (POMC) system. PrCP has the potential to be a therapeutic target for cardiovascular, inflammatory and metabolic diseases. Numerous classes of PrCP inhibitors have been developed by rational drug design and from high-throughput screening hits. These inhibitors have been tested in mouse models to assess their potential as new therapeutics. Areas Covered: This review covers the relevant studies that support PrCP as a target for drug discovery. All the significant patent applications and primary literature concerning the development of PrCP inhibitors are discussed. Expert Opinion: The pathways where PrCP is known to operate are complex and many aspects remain to be characterized. Many potent inhibitors of PrCP have been tested in vivo. The variable results obtained from in vivo studies with PrCP inhibitors suggest that additional understanding of the biochemistry and the required therapeutic inhibitor levels is necessary. Additional fundamental research into the signaling pathways is likely required before the true therapeutic potential of PrCP inhibition will be realized.
[Mh] Termos MeSH primário: Carboxipeptidases/antagonistas & inibidores
Desenho de Drogas
Inibidores Enzimáticos/farmacologia
[Mh] Termos MeSH secundário: Animais
Carboxipeptidases/metabolismo
Doenças Cardiovasculares/tratamento farmacológico
Doenças Cardiovasculares/fisiopatologia
Descoberta de Drogas/métodos
Ensaios de Triagem em Larga Escala/métodos
Seres Humanos
Inflamação/tratamento farmacológico
Inflamação/fisiopatologia
Doenças Metabólicas/tratamento farmacológico
Doenças Metabólicas/fisiopatologia
Camundongos
Patentes como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Enzyme Inhibitors); EC 3.4.- (Carboxypeptidases); EC 3.4.16.2 (lysosomal Pro-X carboxypeptidase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1080/13543776.2017.1349104


  4 / 6128 MEDLINE  
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[PMID]:28545128
[Au] Autor:McDaniel LD; Conkrite KL; Chang X; Capasso M; Vaksman Z; Oldridge DA; Zachariou A; Horn M; Diamond M; Hou C; Iolascon A; Hakonarson H; Rahman N; Devoto M; Diskin SJ
[Ad] Endereço:Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America.
[Ti] Título:Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma.
[So] Source:PLoS Genet;13(5):e1006787, 2017 May.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis.
[Mh] Termos MeSH primário: Carboxipeptidases/genética
Cromossomos Humanos Par 3/genética
Cromossomos Humanos Par 4/genética
Neuroblastoma/genética
Polimorfismo de Nucleotídeo Único
Proteínas/genética
[Mh] Termos MeSH secundário: Estudos de Casos e Controles
Linhagem Celular Tumoral
Proliferação Celular
Feminino
Inativação Gênica
Homozigoto
Seres Humanos
Masculino
Proteínas Nucleares/genética
Proteínas/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (MLF1 protein, human); 0 (Nuclear Proteins); 0 (Proteins); 0 (RSRC1 protein, human); EC 3.4.- (CPZ protein, human); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170526
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006787


  5 / 6128 MEDLINE  
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[PMID]:28520992
[Au] Autor:Yao P; Wu J; Lindner D; Fox PL
[Ad] Endereço:Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
[Ti] Título:Interplay between miR-574-3p and hnRNP L regulates VEGFA mRNA translation and tumorigenesis.
[So] Source:Nucleic Acids Res;45(13):7950-7964, 2017 Jul 27.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:MicroRNAs (miRNAs) and heterogeneous nuclear ribonucleoproteins (hnRNPs) are families of sequence-specific, posttranscriptional modulators of gene expression. Despite extensive mechanistic and functional studies on both regulatory classes, the interactions and crosstalk between them are largely unexplored. We have reported that competition between miR-297 and hnRNP L to bind a 3΄UTR-localized CA-rich element (CARE) of VEGFA mRNA regulates its translation. Here, we show that translation of VEGFA mRNA in human myeloid cells is dictated by a bi-directional interaction between miR-574-3p, a CA-rich microRNA, and hnRNP L. In normoxia, miR-574-3p, acting as a decoy, binds cytoplasmic hnRNP L and prevents its binding to the CARE and stimulation of VEGFA mRNA translation, simultaneously permitting miR-297-mediated translational silencing. However, in hypoxia, cytoplasmic accumulation of Tyr359-phosphorylated hnRNP L sequesters miR-574-3p, overcoming its decoy activity and seed sequence-dependent gene silencing activity. Ectopically expressed miR-574-3p binds multiple RNA recognition motif (RRM) domains of hnRNP L, synergizes with miR-297, reduces VEGFA mRNA translation, and triggers apoptosis, thereby suppressing tumorigenesis. Our studies establish a novel condition-dependent interplay between a miRNA and an hnRNP that regulates their functions in a bidirectional manner.
[Mh] Termos MeSH primário: Ribonucleoproteínas Nucleares Heterogêneas Grupo L/genética
Ribonucleoproteínas Nucleares Heterogêneas Grupo L/metabolismo
MicroRNAs/genética
MicroRNAs/metabolismo
RNA Mensageiro/genética
RNA Mensageiro/metabolismo
Fator A de Crescimento do Endotélio Vascular/biossíntese
Fator A de Crescimento do Endotélio Vascular/genética
[Mh] Termos MeSH secundário: Regiões 3' não Traduzidas
Carboxipeptidases/antagonistas & inibidores
Carboxipeptidases/metabolismo
Carcinogênese/genética
Carcinogênese/metabolismo
Hipóxia Celular/genética
Hipóxia Celular/fisiologia
Transformação Celular Neoplásica/genética
Seres Humanos
Mutagênese Sítio-Dirigida
Células Mieloides/citologia
Células Mieloides/metabolismo
Biossíntese de Proteínas
Proteínas Recombinantes/genética
Proteínas Recombinantes/metabolismo
Células U937
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (3' Untranslated Regions); 0 (Heterogeneous-Nuclear Ribonucleoprotein L); 0 (MIRN574 microRNA, human); 0 (MicroRNAs); 0 (RNA, Messenger); 0 (Recombinant Proteins); 0 (VEGFA protein, human); 0 (Vascular Endothelial Growth Factor A); EC 3.4.- (Carboxypeptidases); EC 3.4.16.- (SCPEP1 protein, human)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171010
[Lr] Data última revisão:
171010
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170519
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx440


  6 / 6128 MEDLINE  
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[PMID]:28425166
[Au] Autor:Elnegaard RLB; Møllegaard NE; Zhang Q; Kjeldsen F; Jørgensen TJD
[Ad] Endereço:Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230, Odense M, Denmark.
[Ti] Título:Uranyl Photocleavage of Phosphopeptides Yields Truncated C-Terminally Amidated Peptide Products.
[So] Source:Chembiochem;18(12):1117-1122, 2017 Jun 19.
[Is] ISSN:1439-7633
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The uranyl ion (UO ) binds phosphopeptides with high affinity, and when irradiated with UV-light, it can cleave the peptide backbone. In this study, high-accuracy tandem mass spectrometry and enzymatic assays were used to characterise the photocleavage products resulting from the uranyl photocleavage reaction of a tetraphosphorylated ß-casein model peptide. We show that the primary photocleavage products of the uranyl-catalysed reaction are C-terminally amidated. This could be of great interest to the pharmaceutical industry, as efficient peptide amidation reactions are one of the top challenges in green pharmaceutical chemistry.
[Mh] Termos MeSH primário: Amidas/química
Caseínas/química
Fosfopeptídeos/química
Compostos de Urânio/química
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Carboxipeptidases/química
Caseínas/efeitos da radiação
Cátions Bivalentes
Ensaios Enzimáticos
Química Verde
Fosfopeptídeos/efeitos da radiação
Fotólise
Ligação Proteica
Espectrometria de Massas em Tandem
Raios Ultravioleta
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (Caseins); 0 (Cations, Divalent); 0 (Phosphopeptides); 0 (Uranium Compounds); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170725
[Lr] Data última revisão:
170725
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170421
[St] Status:MEDLINE
[do] DOI:10.1002/cbic.201700103


  7 / 6128 MEDLINE  
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[PMID]:28370587
[Au] Autor:Feng X; Ramamoorthy V; Pandit SS; Prieto A; Espeso EA; Calvo AM
[Ad] Endereço:Department of Biological Sciences, Northern Illinois University, Dekalb, IL, 60115, USA.
[Ti] Título:cpsA regulates mycotoxin production, morphogenesis and cell wall biosynthesis in the fungus Aspergillus nidulans.
[So] Source:Mol Microbiol;105(1):1-24, 2017 07.
[Is] ISSN:1365-2958
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The model fungus Aspergillus nidulans synthesizes numerous secondary metabolites, including sterigmatocystin (ST). The production of this toxin is positively controlled by the global regulator veA. In the absence of veA (ΔveA), ST biosynthesis is blocked. Previously, we performed random mutagenesis in a ΔveA strain and identified revertant mutants able to synthesize ST, among them RM1. Complementation of RM1 with a genomic library revealed that the mutation occurred in a gene designated as cpsA. While in the ΔveA genetic background cpsA deletion restores ST production, in a veA wild-type background absence of cpsA reduces and delays ST biosynthesis decreasing the expression of ST genes. Furthermore, cpsA is also necessary for the production of other secondary metabolites, including penicillin, affecting the expression of PN genes. In addition, cpsA is necessary for normal asexual and sexual development. Chemical and microscopy analyses revealed that CpsA is found in cytoplasmic vesicles and it is required for normal cell wall composition and integrity, affecting adhesion capacity and oxidative stress sensitivity. The conservation of cpsA in Ascomycetes suggests that cpsA homologs might have similar roles in other fungal species.
[Mh] Termos MeSH primário: Aspergillus nidulans/metabolismo
Carboxipeptidases/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Ascomicetos/metabolismo
Aspergillus nidulans/genética
Parede Celular/metabolismo
Proteínas Fúngicas/metabolismo
Regulação Fúngica da Expressão Gênica/genética
Morfogênese
Mutagênese
Mutação
Micotoxinas/biossíntese
Micotoxinas/metabolismo
Esporos Fúngicos/crescimento & desenvolvimento
Esterigmatocistina/biossíntese
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Nome de substância:
0 (Fungal Proteins); 0 (Mycotoxins); 10048-13-2 (Sterigmatocystin); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171031
[Lr] Data última revisão:
171031
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170404
[St] Status:MEDLINE
[do] DOI:10.1111/mmi.13682


  8 / 6128 MEDLINE  
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[PMID]:28234994
[Au] Autor:Pan X; Wang Y; Lübke T; Hinek A; Pshezhetsky AV
[Ad] Endereço:Department of Medical Genetics, CHU Sainte-Justine Research Center, University of Montreal, Montreal, Quebec, Canada.
[Ti] Título:Mice, double deficient in lysosomal serine carboxypeptidases Scpep1 and Cathepsin A develop the hyperproliferative vesicular corneal dystrophy and hypertrophic skin thickenings.
[So] Source:PLoS One;12(2):e0172854, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Vasoactive and mitogenic peptide, endothelin-1 (ET-1) plays an important role in physiology of the ocular tissues by regulating the growth of corneal epithelial cells and maintaining the hemodynamics of intraocular fluids. We have previously established that ET-1 can be degraded in vivo by two lysosomal/secreted serine carboxypeptidases, Cathepsin A (CathA) and Serine Carboxypeptidase 1 (Scpep1) and that gene-targeted CathAS190A /Scpep1-/- mice, deficient in CathA and Scpep1 have a prolonged half-life of circulating ET-1 associated with systemic hypertension. In the current work we report that starting from 6 months of age, ~43% of CathAS190A /Scpep1-/- mice developed corneal clouding that eventually caused vision impairment. Histological evaluation of these mice demonstrated a selective fibrotic thickening and vacuolization of the corneas, resembling human hyperproliferative vesicular corneal stromal dystrophy and coexisting with a peculiar thickening of the skin epidermis. Moreover, we found that cultured corneal epithelial cells, skin fibroblasts and vascular smooth muscle cells derived from CathA/Scpep1-deficient mice, demonstrated a significantly higher proliferative response to treatment with exogenous ET-1, as compared with cells from wild type mice. We also detected increased activation level of ERK1/2 and AKT kinases involved in cell proliferation in the ET-1-treated cultured cells from CathA/Scpep1 deficient mice. Together, results from our experimental model suggest that; in normal tissues the tandem of serine carboxypeptidases, Scpep1 and CathA likely constitutes an important part of the physiological mechanism responsible for the balanced elimination of heightened levels of ET-1 that otherwise would accumulate in tissues and consequently contribute to development of the hyper-proliferative corneal dystrophy and abnormal skin thickening.
[Mh] Termos MeSH primário: Carboxipeptidases/genética
Catepsina A/genética
Distrofias Hereditárias da Córnea/genética
Lisossomos/enzimologia
Pele/patologia
[Mh] Termos MeSH secundário: Animais
Humor Aquoso/metabolismo
Carboxipeptidases/metabolismo
Catepsina A/metabolismo
Proliferação Celular
Distrofias Hereditárias da Córnea/metabolismo
Endotelina-1/farmacologia
Epiderme/patologia
Feminino
Fibroblastos/citologia
Fibrose
Hemodinâmica
Masculino
Camundongos
Camundongos Knockout
Miócitos de Músculo Liso/citologia
Miofibroblastos/citologia
Fosforilação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Endothelin-1); EC 3.4.- (Carboxypeptidases); EC 3.4.16.- (Scpep1 protein, mouse); EC 3.4.16.5 (Cathepsin A)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170906
[Lr] Data última revisão:
170906
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170225
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0172854


  9 / 6128 MEDLINE  
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[PMID]:28214827
[Au] Autor:Lou Y; Chen YD; Sun FR; Shi JP; Song Y; Yang J
[Ti] Título:Potential Regulators Driving the Transition in Nonalcoholic Fatty Liver Disease: a Stage-Based View.
[So] Source:Cell Physiol Biochem;41(1):239-251, 2017.
[Is] ISSN:1421-9778
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND AIM: The incidence of nonalcoholic fatty liver disease (NAFLD), ranging from mild steatosis to hepatocellular injury and inflammation, increases with the rise of obesity. However, the implications of transcription factors network in progressive NAFLD remain to be determined. METHODS: A co-regulatory network approach by combining gene expression and transcription influence was utilized to dissect transcriptional regulators in different NAFLD stages. In vivo, mice models of NAFLD were used to investigate whether dysregulated expression be undertaken by transcriptional regulators. RESULTS: Through constructing a large-scale co-regulatory network, sample-specific regulator activity was estimated. The combinations of active regulators that drive the progression of NAFLD were identified. Next, top regulators in each stage of NAFLD were determined, and the results were validated using the different experiments and bariatric surgical samples. In particular, Adipocyte enhancer-binding protein 1 (AEBP1) showed increased transcription activity in nonalcoholic steatohepatitis (NASH). Further characterization of the AEBP1 related transcription program defined its co-regulators, targeted genes, and functional organization. The dynamics of AEBP1 and its potential targets were verified in an animal model of NAFLD. CONCLUSIONS: This study identifies putative functions for several transcription factors in the pathogenesis of NAFLD and may thus point to potential targets for therapeutic interventions.
[Mh] Termos MeSH primário: Hepatopatia Gordurosa não Alcoólica/patologia
[Mh] Termos MeSH secundário: Adulto
Idoso
Animais
Apolipoproteínas E/deficiência
Apolipoproteínas E/genética
Carboxipeptidases/metabolismo
Modelos Animais de Doenças
Progressão da Doença
Redes Reguladoras de Genes
Seres Humanos
Fígado/metabolismo
Fígado/patologia
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Meia-Idade
Hepatopatia Gordurosa não Alcoólica/metabolismo
Proteínas Repressoras/metabolismo
Índice de Gravidade de Doença
Transcriptoma
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Aebp1 protein, mouse); 0 (Apolipoproteins E); 0 (Repressor Proteins); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170606
[Lr] Data última revisão:
170606
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170220
[St] Status:MEDLINE
[do] DOI:10.1159/000456061


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[PMID]:28161633
[Au] Autor:Okai M; Yamamura A; Hayakawa K; Tsutsui S; Miyazono KI; Lee WC; Nagata K; Inoue Y; Tanokura M
[Ad] Endereço:Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan; Tokyo University of Marine Science and Technology, 4-5-7 Konan, Minato-ku, Tokyo 108-8477, Japan.
[Ti] Título:Insight into the transition between the open and closed conformations of Thermus thermophilus carboxypeptidase.
[So] Source:Biochem Biophys Res Commun;484(4):787-793, 2017 Mar 18.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Carboxypeptidase cleaves the C-terminal amino acid residue from proteins and peptides. Here, we report the functional and structural characterizations of carboxypeptidase belonging to the M32 family from the thermophilic bacterium Thermus thermophilus HB8 (TthCP). TthCP exhibits a relatively broad specificity for both hydrophilic (neutral and basic) and hydrophobic (aliphatic and aromatic) residues at the C-terminus and shows optimal activity in the temperature range of 75-80 °C and in the pH range of 6.8-7.2. Enzyme activity was significantly enhanced by cobalt or cadmium and was moderately inhibited by Tris at 25 °C. We also determined the crystal structure of TthCP at 2.6 Å resolution. Two dimer types of TthCP are present in the crystal. One type consists of two subunits in different states, open and closed, with a C RMSD value of 2.2 Å; the other type consists of two subunits in the same open state. This structure enables us to compare the open and closed states of an M32 carboxypeptidase. The TthCP subunit can be divided into two domains, L and S, which are separated by a substrate-binding groove. The L and S domains in the open state are almost identical to those in the closed state, with C RMSD values of 0.84 and 0.53 Å, respectively, suggesting that the transition between the open and closed states proceeds with a large hinge-bending motion. The superimposition between the closed states of TthCP and BsuCP, another M32 family member, revealed that most putative substrate-binding residues in the grooves are oriented in the same direction.
[Mh] Termos MeSH primário: Carboxipeptidases/química
Modelos Químicos
Simulação de Dinâmica Molecular
Thermus thermophilus/enzimologia
[Mh] Termos MeSH secundário: Sítios de Ligação
Ativação Enzimática
Ligação Proteica
Conformação Proteica
Relação Estrutura-Atividade
Especificidade por Substrato
Trometamina
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
023C2WHX2V (Tromethamine); EC 3.4.- (Carboxypeptidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:171120
[Lr] Data última revisão:
171120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170206
[St] Status:MEDLINE



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