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Pesquisa : D08.811.913.555.500.800.750 [Categoria DeCS]
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[PMID]:29346429
[Au] Autor:Ferrigno A; Di Pasqua LG; Berardo C; Siciliano V; Rizzo V; Adorini L; Richelmi P; Vairetti M
[Ad] Endereço:Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy.
[Ti] Título:The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury.
[So] Source:PLoS One;13(1):e0191430, 2018.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. MATERIAL AND METHODS: Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. RESULTS: OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. CONCLUSION: The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
[Mh] Termos MeSH primário: Antiporters/metabolismo
Arginina/análogos & derivados
Sistema Biliar/efeitos dos fármacos
Ácido Quenodesoxicólico/análogos & derivados
Hepatopatias/metabolismo
Proteínas de Transporte de Cátions Orgânicos/metabolismo
Receptores Citoplasmáticos e Nucleares/antagonistas & inibidores
Traumatismo por Reperfusão/metabolismo
Regulação para Cima/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Arginina/sangue
Arginina/metabolismo
Arginina/secreção
Sistema Biliar/metabolismo
Sistema Biliar/secreção
Western Blotting
Proteínas de Transporte/genética
Proteínas de Transporte/metabolismo
Ácido Quenodesoxicólico/farmacologia
Masculino
Óxido Nítrico Sintase/metabolismo
Proteína-Arginina N-Metiltransferases/genética
RNA Mensageiro/genética
Ratos
Ratos Wistar
Reação em Cadeia da Polimerase em Tempo Real
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antiporters); 0 (Carrier Proteins); 0 (MATE1 protein, rat); 0 (Organic Cation Transport Proteins); 0 (RNA, Messenger); 0 (Receptors, Cytoplasmic and Nuclear); 0 (farnesoid X-activated receptor); 0462Z4S4OZ (obeticholic acid); 0GEI24LG0J (Chenodeoxycholic Acid); 63CV1GEK3Y (N,N-dimethylarginine); 94ZLA3W45F (Arginine); EC 1.14.13.39 (Nitric Oxide Synthase); EC 2.1.1.319 (PRMT1 protein, rat); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0191430


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[PMID]:28740119
[Au] Autor:Yap TA; Aerts JG; Popat S; Fennell DA
[Ad] Endereço:The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
[Ti] Título:Novel insights into mesothelioma biology and implications for therapy.
[So] Source:Nat Rev Cancer;17(8):475-488, 2017 07 25.
[Is] ISSN:1474-1768
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Malignant mesothelioma is a universally lethal cancer that is increasing in incidence worldwide. There is a dearth of effective therapies, with only one treatment (pemetrexed and cisplatin combination chemotherapy) approved in the past 13 years. However, the past 5 years have witnessed an exponential growth in our understanding of mesothelioma pathobiology, which is set to revolutionize therapeutic strategies. From a genomic standpoint, mesothelioma is characterized by a preponderance of tumour suppressor alterations, for which novel therapies are currently in development. Other promising antitumour agents include inhibitors against angiogenesis, mesothelin and immune checkpoints, which are at various phases of clinical trial testing.
[Mh] Termos MeSH primário: Antineoplásicos/uso terapêutico
Genes Supressores de Tumor
Imunoterapia
Mesotelioma/genética
Mesotelioma/terapia
Neovascularização Patológica/prevenção & controle
[Mh] Termos MeSH secundário: Animais
Anticorpos Monoclonais/farmacologia
Antineoplásicos/farmacologia
Proteínas Ligadas por GPI/antagonistas & inibidores
Genes da Neurofibromatose 2
Genes p16
Seres Humanos
Mesotelioma/metabolismo
Fosfatidilinositol 3-Quinases/antagonistas & inibidores
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores
Proteínas Proto-Oncogênicas c-akt
Serina-Treonina Quinases TOR/antagonistas & inibidores
Microambiente Tumoral
Proteínas Supressoras de Tumor/genética
Ubiquitina Tiolesterase/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antibodies, Monoclonal); 0 (Antineoplastic Agents); 0 (GPI-Linked Proteins); 0 (Tumor Suppressor Proteins); 0 (mesothelin); EC 2.1.1.319 (PRMT5 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.1 (TOR Serine-Threonine Kinases); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.2.15 (BAP1 protein, human); EC 3.4.19.12 (Ubiquitin Thiolesterase)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1038/nrc.2017.42


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[PMID]:29065155
[Au] Autor:Lubyova B; Hodek J; Zabransky A; Prouzova H; Hubalek M; Hirsch I; Weber J
[Ad] Endereço:Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, IOCB & Gilead Research Center, Prague, Czech Republic.
[Ti] Título:PRMT5: A novel regulator of Hepatitis B virus replication and an arginine methylase of HBV core.
[So] Source:PLoS One;12(10):e0186982, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In mammals, protein arginine methyltransferase 5, PRMT5, is the main type II enzyme responsible for the majority of symmetric dimethylarginine formation in polypeptides. Recent study reported that PRMT5 restricts Hepatitis B virus (HBV) replication through epigenetic repression of HBV DNA transcription and interference with encapsidation of pregenomic RNA. Here we demonstrate that PRMT5 interacts with the HBV core (HBc) protein and dimethylates arginine residues within the arginine-rich domain (ARD) of the carboxyl-terminus. ARD consists of four arginine rich subdomains, ARDI, ARDII, ARDIII and ARDIV. Mutation analysis of ARDs revealed that arginine methylation of HBc required the wild-type status of both ARDI and ARDII. Mass spectrometry analysis of HBc identified multiple potential ubiquitination, methylation and phosphorylation sites, out of which lysine K7 and arginines R150 (within ARDI) and R156 (outside ARDs) were shown to be modified by ubiquitination and methylation, respectively. The HBc symmetric dimethylation appeared to be linked to serine phosphorylation and nuclear import of HBc protein. Conversely, the monomethylated HBc retained in the cytoplasm. Thus, overexpression of PRMT5 led to increased nuclear accumulation of HBc, and vice versa, down-regulation of PRMT5 resulted in reduced levels of HBc in nuclei of transfected cells. In summary, we identified PRMT5 as a potent controller of HBc cell trafficking and function and described two novel types of HBc post-translational modifications (PTMs), arginine methylation and ubiquitination.
[Mh] Termos MeSH primário: Vírus da Hepatite B/fisiologia
Proteína-Arginina N-Metiltransferases/metabolismo
Replicação Viral/fisiologia
[Mh] Termos MeSH secundário: Vírus da Hepatite B/enzimologia
Seres Humanos
Espectrometria de Massas
Metilação
Fosforilação
Proteína-Arginina N-Metiltransferases/fisiologia
Frações Subcelulares/metabolismo
Ubiquitinação
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.1.1.319 (PRMT5 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171025
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0186982


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[PMID]:28978671
[Au] Autor:Siriboonpiputtana T; Zeisig BB; Zarowiecki M; Fung TK; Mallardo M; Tsai CT; Lau PNI; Hoang QC; Veiga P; Barnes J; Lynn C; Wilson A; Lenhard B; So CWE
[Ad] Endereço:Department of Haematological Medicine, Division of Cancer Studies, Leukemia and Stem Cell Biology Team, King's College London, London, UK.
[Ti] Título:Transcriptional memory of cells of origin overrides ß-catenin requirement of MLL cancer stem cells.
[So] Source:EMBO J;36(21):3139-3155, 2017 Nov 02.
[Is] ISSN:1460-2075
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:While ß-catenin has been demonstrated as an essential molecule and therapeutic target for various cancer stem cells (CSCs) including those driven by MLL fusions, here we show that transcriptional memory from cells of origin predicts AML patient survival and allows ß-catenin-independent transformation in MLL-CSCs derived from hematopoietic stem cell (HSC)-enriched LSK population but not myeloid-granulocyte progenitors. Mechanistically, ß-catenin regulates expression of downstream targets of a key transcriptional memory gene, that is highly enriched in LSK-derived MLL-CSCs and helps sustain leukemic self-renewal. Suppression of sensitizes LSK-derived MLL-CSCs to ß-catenin inhibition resulting in abolishment of CSC transcriptional program and transformation ability. In addition, further molecular and functional analyses identified Prmt1 as a key common downstream mediator for ß-catenin/ functions in LSK-derived MLL-CSCs. Together, these findings not only uncover an unexpectedly important role of cells of origin transcriptional memory in regulating CSC self-renewal, but also reveal a novel molecular network mediated by ß-catenin/Hoxa9/Prmt1 in governing leukemic self-renewal.
[Mh] Termos MeSH primário: Regulação Leucêmica da Expressão Gênica
Proteínas de Homeodomínio/genética
Leucemia Mieloide Aguda/genética
Células-Tronco Neoplásicas/metabolismo
Transcrição Genética
beta Catenina/genética
[Mh] Termos MeSH secundário: Animais
Antígenos Ly/genética
Antígenos Ly/metabolismo
Proliferação Celular
Sobrevivência Celular
Modelos Animais de Doenças
Perfilação da Expressão Gênica
Células-Tronco Hematopoéticas/metabolismo
Células-Tronco Hematopoéticas/patologia
Proteínas de Homeodomínio/antagonistas & inibidores
Proteínas de Homeodomínio/metabolismo
Seres Humanos
Leucemia Mieloide Aguda/metabolismo
Leucemia Mieloide Aguda/mortalidade
Leucemia Mieloide Aguda/patologia
Proteínas de Membrana/genética
Proteínas de Membrana/metabolismo
Camundongos
Camundongos Endogâmicos C57BL
Camundongos Knockout
Células-Tronco Neoplásicas/patologia
Proteína-Arginina N-Metiltransferases/genética
Proteína-Arginina N-Metiltransferases/metabolismo
Proteínas Proto-Oncogênicas c-kit/genética
Proteínas Proto-Oncogênicas c-kit/metabolismo
RNA Interferente Pequeno/genética
RNA Interferente Pequeno/metabolismo
Proteínas Repressoras/genética
Proteínas Repressoras/metabolismo
Transdução de Sinais
Análise de Sobrevida
beta Catenina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Ly); 0 (CTNNB1 protein, human); 0 (Homeodomain Proteins); 0 (Ly6a protein, mouse); 0 (Membrane Proteins); 0 (RNA, Small Interfering); 0 (Repressor Proteins); 0 (beta Catenin); 0 (homeobox protein HOXA9); EC 2.1.1.319 (PRMT1 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases); EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171006
[St] Status:MEDLINE
[do] DOI:10.15252/embj.201797994


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[PMID]:28977508
[Au] Autor:Bailey JK; Shen W; Liang XH; Crooke ST
[Ad] Endereço:Department of Core Antisense Research, Ionis Pharmaceuticals, Inc. 2855 Gazelle Court, Carlsbad, CA 92010, USA.
[Ti] Título:Nucleic acid binding proteins affect the subcellular distribution of phosphorothioate antisense oligonucleotides.
[So] Source:Nucleic Acids Res;45(18):10649-10671, 2017 Oct 13.
[Is] ISSN:1362-4962
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Antisense oligonucleotides (ASOs) are versatile tools that can regulate multiple steps of RNA biogenesis in cells and living organisms. Significant improvements in delivery, potency, and stability have been achieved through modifications within the oligonucleotide backbone, sugar and heterocycles. However, these modifications can profoundly affect interactions between ASOs and intracellular proteins in ways that are only beginning to be understood. Here, we report that ASOs with specific backbone and sugar modifications can become localized to cytoplasmic ribonucleoprotein granules such as stress granules and those seeded by the aggregation of specific ASO-binding proteins such as FUS/TLS (FUS) and PSF/SFPQ (PSF). Further investigation into the basis for ASO-FUS binding illustrated the importance of ASO backbone and hydrophobic 2' sugar modifications and revealed that the C-terminal region of FUS is sufficient to retain ASOs in cellular foci. Taken together, the results of this study demonstrate that affinities of various nucleic acid binding domains for ASO depend on chemical modifications and further demonstrate how ASO-protein interactions influence the localization of ASOs.
[Mh] Termos MeSH primário: Oligonucleotídeos Antissenso/análise
Fator de Processamento Associado a PTB/metabolismo
Oligonucleotídeos Fosforotioatos/análise
Proteína FUS de Ligação a RNA/metabolismo
[Mh] Termos MeSH secundário: Linhagem Celular
Núcleo Celular/química
Grânulos Citoplasmáticos/química
Seres Humanos
Mutação
Oligonucleotídeos Antissenso/química
Oligonucleotídeos Antissenso/metabolismo
Fator de Processamento Associado a PTB/genética
Oligonucleotídeos Fosforotioatos/química
Oligonucleotídeos Fosforotioatos/metabolismo
Agregados Proteicos
Ligação Proteica
Proteína-Arginina N-Metiltransferases/metabolismo
Proteína FUS de Ligação a RNA/análise
Proteína FUS de Ligação a RNA/química
Proteína FUS de Ligação a RNA/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Oligonucleotides, Antisense); 0 (PTB-Associated Splicing Factor); 0 (Phosphorothioate Oligonucleotides); 0 (Protein Aggregates); 0 (RNA-Binding Protein FUS); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171005
[St] Status:MEDLINE
[do] DOI:10.1093/nar/gkx709


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[PMID]:28966034
[Au] Autor:Braun CJ; Stanciu M; Boutz PL; Patterson JC; Calligaris D; Higuchi F; Neupane R; Fenoglio S; Cahill DP; Wakimoto H; Agar NYR; Yaffe MB; Sharp PA; Hemann MT; Lees JA
[Ad] Endereço:The David H. Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
[Ti] Título:Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma.
[So] Source:Cancer Cell;32(4):411-426.e11, 2017 Oct 09.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an exploitable cancer vulnerability.
[Mh] Termos MeSH primário: Neoplasias Encefálicas/patologia
Glioma/patologia
Íntrons
Proteína-Arginina N-Metiltransferases/fisiologia
[Mh] Termos MeSH secundário: Animais
Ciclo Celular/efeitos dos fármacos
Diferenciação Celular
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Glioma/tratamento farmacológico
Glioma/genética
Ensaios de Triagem em Larga Escala
Seres Humanos
Isoquinolinas/farmacologia
Camundongos
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores
Pirimidinas/farmacologia
Processamento de RNA
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (GSK3235025); 0 (Isoquinolines); 0 (Pyrimidines); EC 2.1.1.319 (PRMT5 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[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:171003
[St] Status:MEDLINE


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[PMID]:28943242
[Au] Autor:Bao X; Siprashvili Z; Zarnegar BJ; Shenoy RM; Rios EJ; Nady N; Qu K; Mah A; Webster DE; Rubin AJ; Wozniak GG; Tao S; Wysocka J; Khavari PA
[Ad] Endereço:Program in Epithelial Biology, Stanford University, 269 Campus Drive, Room 2145, Stanford, CA 94305, USA; Departments of Molecular Biosciences and Dermatology, Northwestern University, 2205 Tech Drive, Hogan 2-100, Evanston, IL 60208, USA. Electronic address: xiaomin.bao@northwestern.edu.
[Ti] Título:CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue.
[So] Source:Dev Cell;43(2):227-239.e5, 2017 Oct 23.
[Is] ISSN:1878-1551
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Somatic progenitors sustain tissue self-renewal while suppressing premature differentiation. Protein arginine methyltransferases (PRMTs) affect many processes; however, their role in progenitor function is incompletely understood. PRMT1 was found to be the most highly expressed PRMT in epidermal progenitors and the most downregulated PRMT during differentiation. In targeted mouse knockouts and in long-term regenerated human mosaic epidermis in vivo, epidermal PRMT1 loss abolished progenitor self-renewal and led to premature differentiation. Mass spectrometry of the PRMT1 protein interactome identified the CSNK1a1 kinase, which also proved essential for progenitor maintenance. CSNK1a1 directly bound and phosphorylated PRMT1 to control its genomic targeting to PRMT1-sustained proliferation genes as well as PRMT1-suppressed differentiation genes. Among the latter were GRHL3, whose derepression was required for the premature differentiation seen with PRMT1 and CSNK1a1 loss. Maintenance of the progenitors thus requires cooperation by PRMT1 and CSNK1a1 to sustain proliferation gene expression and suppress premature differentiation driven by GRHL3.
[Mh] Termos MeSH primário: Caseína Quinase Ialfa/metabolismo
Autorrenovação Celular/fisiologia
Epiderme/citologia
Queratinócitos/citologia
Proteína-Arginina N-Metiltransferases/fisiologia
Células-Tronco/citologia
[Mh] Termos MeSH secundário: Animais
Diferenciação Celular
Células Cultivadas
Epiderme/metabolismo
Seres Humanos
Recém-Nascido
Queratinócitos/metabolismo
Camundongos
Camundongos Knockout
Fosforilação
Células-Tronco/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.1.1.319 (Prmt1 protein, mouse); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases); EC 2.7.11.1 (Casein Kinase Ialpha)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171107
[Lr] Data última revisão:
171107
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170926
[St] Status:MEDLINE


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[PMID]:28934323
[Au] Autor:Wang YC; Wang CW; Lin WC; Tsai YJ; Chang CP; Lee YJ; Lin MJ; Li C
[Ad] Endereço:Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan.
[Ti] Título:Identification, chromosomal arrangements and expression analyses of the evolutionarily conserved prmt1 gene in chicken in comparison with its vertebrate paralogue prmt8.
[So] Source:PLoS One;12(9):e0185042, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Nine protein arginine methyltransferases (PRMTs) are conserved in mammals and fish. Among these, PRMT1 is the major type I PRMT for asymmetric dimethylarginine (ADMA) formation and is the most conserved and widely distributed one. Two chicken prmt1 splicing variants were assembled and confirmed by RT-PCR experiments. However, only two scaffolds containing single separate prmt1 exon with high GC contents are present in the current chicken genome assembly. Besides, prmt1 exons are scattered in separate small scaffolds in most avian species. Complete prmt1 gene has only been predicted from two falcon species with few neighboring genes. Crocodilians are considered close to the common ancestor shared by crocodilians and birds. The gene arrangements around prmt1 in American alligator are different from that in birds but are largely conserved in human. Orthologues of genes in a large segment of human chromosomal 19 around PRMT1 are missing or not assigned to the current chicken chromosomes. In comparison, prmt8, the prmt1 paralogue, is on chicken chromosome 1 with the gene arrangements downstream of prmt8 highly conserved in birds, crocodilians, and human. However, the ones upstream vary greatly in birds. Biochemically, we found that though prmt1 transcripts were detected, limited or none PRMT1 protein was present in chicken tissues. Moreover, a much higher level of PRMT8 protein was detected in chicken brain than in mouse brain. While PRMT8 is brain specific in other vertebrate species studied, low level of PRMT8 was present in chicken but not mouse liver and muscle. We also showed that the ADMA level in chicken was similar to that in mouse. This study provides the critical information of chicken PRMT1 and PRMT8 for future analyses of the function of protein arginine methyltransferases in birds.
[Mh] Termos MeSH primário: Evolução Biológica
Encéfalo/enzimologia
Aberrações Cromossômicas
Ordem dos Genes
Proteína-Arginina N-Metiltransferases/metabolismo
Vertebrados/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Animais
Galinhas
Seres Humanos
Camundongos
Proteína-Arginina N-Metiltransferases/classificação
Proteína-Arginina N-Metiltransferases/genética
Alinhamento de Sequência
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171017
[Lr] Data última revisão:
171017
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170922
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0185042


  9 / 1244 MEDLINE  
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[PMID]:28927791
[Au] Autor:Yang H; Ouyang Y; Ma H; Cong H; Zhuang C; Lok WT; Wang Z; Zhu X; Sun Y; Hong W; Wang H
[Ad] Endereço:School of Pharmacy, Ningxia Medical University, Yinchuan 750004, PR China.
[Ti] Título:Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling.
[So] Source:Bioorg Med Chem Lett;27(20):4635-4642, 2017 10 15.
[Is] ISSN:1464-3405
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies.
[Mh] Termos MeSH primário: Desenho de Drogas
Inibidores Enzimáticos/síntese química
Proteína-Arginina N-Metiltransferases/antagonistas & inibidores
Proteínas Repressoras/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antineoplásicos/síntese química
Antineoplásicos/química
Antineoplásicos/farmacologia
Sítios de Ligação
Domínio Catalítico
Linhagem Celular Tumoral
Sobrevivência Celular/efeitos dos fármacos
Inibidores Enzimáticos/química
Inibidores Enzimáticos/farmacologia
Células Hep G2
Seres Humanos
Simulação de Dinâmica Molecular
Proteína-Arginina N-Metiltransferases/metabolismo
Proteínas Repressoras/metabolismo
S-Adenosilmetionina/metabolismo
Relação Estrutura-Atividade
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Enzyme Inhibitors); 0 (Repressor Proteins); 7LP2MPO46S (S-Adenosylmethionine); EC 2.1.1.319 (PRMT1 protein, human); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171125
[Lr] Data última revisão:
171125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170921
[St] Status:MEDLINE


  10 / 1244 MEDLINE  
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[PMID]:28878098
[Au] Autor:Penney J; Seo J; Kritskiy O; Elmsaouri S; Gao F; Pao PC; Su SC; Tsai LH
[Ad] Endereço:Picower Institute for Learning and Memory and.
[Ti] Título:Loss of Protein Arginine Methyltransferase 8 Alters Synapse Composition and Function, Resulting in Behavioral Defects.
[So] Source:J Neurosci;37(36):8655-8666, 2017 Sep 06.
[Is] ISSN:1529-2401
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Diverse molecular mechanisms regulate synaptic composition and function in the mammalian nervous system. The multifunctional protein arginine methyltransferase 8 (PRMT8) possesses both methyltransferase and phospholipase activities. Here we examine the role of this neuron-specific protein in hippocampal plasticity and cognitive function. PRMT8 protein localizes to synaptic sites, and conditional whole-brain deletion results in altered levels of multiple synaptic proteins in the hippocampus, using both male and female mice. Interestingly, these altered protein levels are due to post-transcriptional mechanisms as the corresponding mRNA levels are unaffected. Strikingly, electrophysiological recordings from hippocampal slices of mice lacking PRMT8 reveal multiple defects in excitatory synaptic function and plasticity. Furthermore, behavioral analyses show that PRMT8 conditional knock-out mice exhibit impaired hippocampal-dependent fear learning. Together, these findings establish PRMT8 as an important component of the molecular machinery required for hippocampal neuronal function. Numerous molecular processes are critically required for normal brain function. Here we use mice lacking protein arginine methyltransferase 8 (PRMT8) in the brain to examine how loss of this protein affects the structure and function of neurons in the hippocampus. We find that PRMT8 localizes to the sites of communication between neurons. Hippocampal neurons from mice lacking PRMT8 have no detectable structural differences compared with controls; however, multiple aspects of their function are altered. Consistently, we find that mice lacking PRMT8 also exhibit reduced hippocampus-dependent memory. Together, our findings establish important roles for PRMT8 in regulating neuron function and cognition in the mammalian brain.
[Mh] Termos MeSH primário: Hipocampo/fisiopatologia
Transtornos da Memória/fisiopatologia
Transtornos Mentais/fisiopatologia
Proteína-Arginina N-Metiltransferases/metabolismo
Sinapses/metabolismo
Transmissão Sináptica
[Mh] Termos MeSH secundário: Animais
Feminino
Hipocampo/patologia
Masculino
Transtornos da Memória/complicações
Transtornos da Memória/patologia
Transtornos Mentais/complicações
Transtornos Mentais/patologia
Camundongos
Camundongos Knockout
Plasticidade Neuronal
Proteína-Arginina N-Metiltransferases/genética
Sinapses/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 2.1.1.319 (PRMT8 protein, mouse); EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170925
[Lr] Data última revisão:
170925
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170908
[St] Status:MEDLINE
[do] DOI:10.1523/JNEUROSCI.0591-17.2017



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