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  1 / 2609 MEDLINE  
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[PMID]:28468989
[Au] Autor:D'Avino PP
[Ad] Endereço:Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK ppd21@cam.ac.uk.
[Ti] Título:Citron kinase - renaissance of a neglected mitotic kinase.
[So] Source:J Cell Sci;130(10):1701-1708, 2017 May 15.
[Is] ISSN:1477-9137
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cell division controls the faithful segregation of genomic and cytoplasmic materials between the two nascent daughter cells. Members of the Aurora, Polo and cyclin-dependent (Cdk) kinase families are known to regulate multiple events throughout cell division, whereas another kinase, citron kinase (CIT-K), for a long time has been considered to function solely during cytokinesis, the last phase of cell division. CIT-K was originally proposed to regulate the ingression of the cleavage furrow that forms at the equatorial cortex of the dividing cell after chromosome segregation. However, studies in the last decade have clarified that this kinase is, instead, required for the organization of the midbody in late cytokinesis, and also revealed novel functions of CIT-K earlier in mitosis and in DNA damage control. Moreover, CIT-K mutations have recently been linked to the development of human microcephaly, and CIT-K has been identified as a potential target in cancer therapy. In this Commentary, I describe and re-evaluate the functions and regulation of CIT-K during cell division and its involvement in human disease. Finally, I offer my perspectives on the open questions and future challenges that are necessary to address, in order to fully understand this important and yet unjustly neglected mitotic kinase.
[Mh] Termos MeSH primário: Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Mitose
Proteínas Serina-Treonina Quinases/metabolismo
[Mh] Termos MeSH secundário: Animais
Citocinese
Seres Humanos
Modelos Biológicos
Transdução de Sinais
Proteínas rho de Ligação ao GTP/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Intracellular Signaling Peptides and Proteins); EC 2.7.1.- (citron-kinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.6.5.2 (rho GTP-Binding Proteins)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180223
[Lr] Data última revisão:
180223
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1242/jcs.200253


  2 / 2609 MEDLINE  
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[PMID]:29181464
[Au] Autor:He Z; Guo K
[Ad] Endereço:College of Materials Science and Engineering, Hunan University, Changsha, 410082, China. kunkunguo@hnu.edu.cn.
[Ti] Título:Exploration of cell division times during bacterial cytokinesis.
[So] Source:Phys Chem Chem Phys;19(47):32038-32046, 2017 Dec 06.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Filamenting temperature-sensitive mutant Z (FtsZ), an essential cell division protein in bacteria, has recently emerged as an important and exploitable antibacterial target. The perturbation of FtsZ assembly is found to have an effect on cell cytokinesis and cell survival. Cell division time is an important physical parameter in cell cytokinesis. Here, the theoretical framework that has been developed by combining a phase field model for rod-shaped cells with a kinetic description for FtsZ ring maintenance is extended to explore cell division times during bacterial cytokinesis. The cell division times of around 72 s in the numerical studies have the same magnitude as the division time of several minutes observed physiologically. The dependence of the cell division time on parameters such as the initial state of rod-shaped cells and various kinetic rates of FtsZ assembly dynamics is thoroughly investigated. The theoretical analysis of the relations between the cell division time and these parameters is found to coincide well with the numerical calculated results.
[Mh] Termos MeSH primário: Bactérias/citologia
Citocinese/fisiologia
Modelos Biológicos
[Mh] Termos MeSH secundário: Tempo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180205
[Lr] Data última revisão:
180205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171129
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp05050j


  3 / 2609 MEDLINE  
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[PMID]:29212002
[Au] Autor:Li Y; He L; Gonzalez NAP; Graham J; Wolgemuth C; Wirtz D; Sun SX
[Ad] Endereço:Departments of Mechanical Engineering, Johns Hopkins University, Baltimore, Maryland.
[Ti] Título:Going with the Flow: Water Flux and Cell Shape during Cytokinesis.
[So] Source:Biophys J;113(11):2487-2495, 2017 Dec 05.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell shape changes during cytokinesis in eukaryotic cells have been attributed to contractile forces from the actomyosin ring and the actomyosin cortex. Here we propose an additional mechanism where active pumping of ions and water at the cell poles and the division furrow can also achieve the same type of shape change during cytokinesis without myosin contraction. We develop a general mathematical model to examine shape changes in a permeable object subject to boundary fluxes. We find that hydrodynamic flows in the cytoplasm and the relative drag between the cytoskeleton network phase and the water phase also play a role in determining the cell shape during cytokinesis. Forces from the actomyosin contractile ring and cortex do contribute to the cell shape, and can work together with water permeation to facilitate cytokinesis. To influence water flow, we osmotically shock the cell during cell division, and find that the cell can actively adapt to osmotic changes and complete division. Depolymerizing the actin cytoskeleton during cytokinesis also does not affect the contraction speed. We also explore the role of membrane ion channels and pumps in setting up the spatially varying water flux.
[Mh] Termos MeSH primário: Forma Celular
Citocinese
Modelos Biológicos
Movimento
Água/metabolismo
[Mh] Termos MeSH secundário: Actomiosina/metabolismo
Divisão Celular
Replicação do DNA
Pressão Osmótica
Permeabilidade
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
059QF0KO0R (Water); 9013-26-7 (Actomyosin)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180104
[Lr] Data última revisão:
180104
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171207
[St] Status:MEDLINE


  4 / 2609 MEDLINE  
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[PMID]:29262371
[Au] Autor:Menon VV; Soumya SS; Agarwal A; Naganathan SR; Inamdar MM; Sain A
[Ad] Endereço:Center for Research in Nanotechnology and Science, Indian Institute of Technology Bombay, Mumbai, Maharashtra, India.
[Ti] Título:Asymmetric Flows in the Intercellular Membrane during Cytokinesis.
[So] Source:Biophys J;113(12):2787-2795, 2017 Dec 19.
[Is] ISSN:1542-0086
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Eukaryotic cells undergo shape changes during their division and growth. This involves flow of material both in the cell membrane and in the cytoskeletal layer beneath the membrane. Such flows result in redistribution of phospholipid at the cell surface and actomyosin in the cortex. Here we focus on the growth of the intercellular surface during cell division in a Caenorhabditis elegans embryo. The growth of this surface leads to the formation of a double-layer of separating membranes between the two daughter cells. The division plane typically has a circular periphery and the growth starts from the periphery as a membrane invagination, which grows radially inward like the shutter of a camera. The growth is typically not concentric, in the sense that the closing internal ring is located off-center. Cytoskeletal proteins anillin and septin have been found to be responsible for initiating and maintaining the asymmetry of ring closure but the role of possible asymmetry in the material flow into the growing membrane has not been investigated yet. Motivated by experimental evidence of such flow asymmetry, here we explore the patterns of internal ring closure in the growing membrane in response to asymmetric boundary fluxes. We highlight the importance of the flow asymmetry by showing that many of the asymmetric growth patterns observed experimentally can be reproduced by our model, which incorporates the viscous nature of the membrane and contractility of the associated cortex.
[Mh] Termos MeSH primário: Membrana Celular/metabolismo
Citocinese
Movimento
[Mh] Termos MeSH secundário: Animais
Caenorhabditis elegans/citologia
Caenorhabditis elegans/embriologia
Modelos Biológicos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180102
[Lr] Data última revisão:
180102
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171221
[St] Status:MEDLINE


  5 / 2609 MEDLINE  
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[PMID]:28450458
[Au] Autor:Renicke C; Allmann AK; Lutz AP; Heimerl T; Taxis C
[Ad] Endereço:Department of Biology/Genetics, Philipps-Universität Marburg, 35043, Germany.
[Ti] Título:The Mitotic Exit Network Regulates Spindle Pole Body Selection During Sporulation of .
[So] Source:Genetics;206(2):919-937, 2017 06.
[Is] ISSN:1943-2631
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Age-based inheritance of centrosomes in eukaryotic cells is associated with faithful chromosome distribution in asymmetric cell divisions. During ascospore formation, such an inheritance mechanism targets the yeast centrosome equivalents, the spindle pole bodies (SPBs) at meiosis II onset. Decreased nutrient availability causes initiation of spore formation at only the younger SPBs and their associated genomes. This mechanism ensures encapsulation of nonsister genomes, which preserves genetic diversity and provides a fitness advantage at the population level. Here, by usage of an enhanced system for sporulation-induced protein depletion, we demonstrate that the core mitotic exit network (MEN) is involved in age-based SPB selection. Moreover, efficient genome inheritance requires Dbf2/20-Mob1 during a late step in spore maturation. We provide evidence that the meiotic functions of the MEN are more complex than previously thought. In contrast to mitosis, completion of the meiotic divisions does not strictly rely on the MEN whereas its activity is required at different time points during spore development. This is reminiscent of vegetative MEN functions in spindle polarity establishment, mitotic exit, and cytokinesis. In summary, our investigation contributes to the understanding of age-based SPB inheritance during sporulation of and provides general insights on network plasticity in the context of a specialized developmental program. Moreover, the improved system for a developmental-specific tool to induce protein depletion will be useful in other biological contexts.
[Mh] Termos MeSH primário: Proteínas de Ciclo Celular/genética
Mitose/genética
Proteínas Serina-Treonina Quinases/genética
Proteínas de Saccharomyces cerevisiae/genética
Fuso Acromático/genética
Corpos Polares do Fuso/genética
[Mh] Termos MeSH secundário: Citocinese/genética
Saccharomyces cerevisiae/genética
Esporos Fúngicos/genética
Esporos Fúngicos/crescimento & desenvolvimento
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Cell Cycle Proteins); 0 (Saccharomyces cerevisiae Proteins); EC 2.7.11.1 (DBF2 protein, S cerevisiae); EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171213
[Lr] Data última revisão:
171213
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170429
[St] Status:MEDLINE
[do] DOI:10.1534/genetics.116.194522


  6 / 2609 MEDLINE  
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[PMID]:29173494
[Au] Autor:Bolognesi C; Bruzzone M; Ceppi M; Kirsch-Volders M
[Ad] Endereço:Environmental Carcinogenesis Unit, Ospedale Policlinico San Martino, Genoa, Italy. Electronic address: claudia.bolognesi@hsanmartino.it.
[Ti] Título:The lymphocyte cytokinesis block micronucleus test in human populations occupationally exposed to vinyl chloride: A systematic review and meta-analysis.
[So] Source:Mutat Res;774:1-11, 2017 Oct.
[Is] ISSN:1873-135X
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Vinyl chloride (VC) is widely used in industry in the production of polyvinyl chloride (PVC), which is used to manufacture a large variety of materials. VC was classified as a known (Group 1) human carcinogen by IARC on the basis of increased risk for liver angiosarcoma and hepatocellular cancer, and the carcinogenicity of VC was shown to be mediated by a genotoxic mechanism. Following inhalation, the compound is rapidly absorbed and metabolized in the liver to the electrophilic metabolites chloroethylene-oxide and chloroacetaldehyde, which form DNA adducts that can be processed into point mutations in cancer-related genes detected in humans and rats exposed to VC. A number of genotoxicity biomarkers were applied in workers exposed to VC to detect early biological responses associated with the carcinogenesis process. The present systematic review analyzed the published studies in which the cytokinesis-block micronucleus assay in peripheral lymphocytes (L-CBMN) was applied in VC-exposed subjects. Thirteen out of fifteen retrieved studies performed in China showed increased MN frequencies (FR 1.92-3.98) associated with increased cumulative exposure or employment time. Twofold and more than threefold increases were detected in PVC-exposed workers exposed to a mean of 50ppm of VC in the former Yugoslavia and in South India, respectively. The meta-analysis of MN frequency from six eligible studies confirmed this tendency (pooled MR 2.32 - 95% CI 1.64-3.27). The benchmark dose lower limit for 10% excess risk (BMDL 10) calculated from three studies resulted in an estimated exposure limit of 0.03-0.07mg/m . Overall the results of this review showed the need for further studies, especially because PVC products from China may contain high levels of uncoupled VCM that could represent a source of exposure to workers and consumers. Moreover, the results underline the importance of re-evaluating the recommended exposure limits using new biomonitoring methods in addition to MN.
[Mh] Termos MeSH primário: Biomarcadores/análise
Citocinese/efeitos dos fármacos
Monitoramento Ambiental/métodos
Linfócitos/patologia
Testes para Micronúcleos/métodos
Exposição Ocupacional/efeitos adversos
Cloreto de Vinil/efeitos adversos
[Mh] Termos MeSH secundário: Seres Humanos
Linfócitos/efeitos dos fármacos
Linfócitos/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Biomarkers); WD06X94M2D (Vinyl Chloride)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171205
[Lr] Data última revisão:
171205
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE


  7 / 2609 MEDLINE  
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[PMID]:29028801
[Au] Autor:Del Signore SJ; Biber SA; Lehmann KS; Heimler SR; Rosenfeld BH; Eskin TL; Sweeney ST; Rodal AA
[Ad] Endereço:Rosenstiel Basic Medical Sciences Research Center, Department of Biology, Brandeis University, Waltham, Massachusetts, United States of America.
[Ti] Título:dOCRL maintains immune cell quiescence by regulating endosomal traffic.
[So] Source:PLoS Genet;13(10):e1007052, 2017 Oct.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Lowe Syndrome is a developmental disorder characterized by eye, kidney, and neurological pathologies, and is caused by mutations in the phosphatidylinositol-5-phosphatase OCRL. OCRL plays diverse roles in endocytic and endolysosomal trafficking, cytokinesis, and ciliogenesis, but it is unclear which of these cellular functions underlie specific patient symptoms. Here, we show that mutation of Drosophila OCRL causes cell-autonomous activation of hemocytes, which are macrophage-like cells of the innate immune system. Among many cell biological defects that we identified in docrl mutant hemocytes, we pinpointed the cause of innate immune cell activation to reduced Rab11-dependent recycling traffic and concomitantly increased Rab7-dependent late endosome traffic. Loss of docrl amplifies multiple immune-relevant signals, including Toll, Jun kinase, and STAT, and leads to Rab11-sensitive mis-sorting and excessive secretion of the Toll ligand Spåtzle. Thus, docrl regulation of endosomal traffic maintains hemocytes in a poised, but quiescent state, suggesting mechanisms by which endosomal misregulation of signaling may contribute to symptoms of Lowe syndrome.
[Mh] Termos MeSH primário: Citocinese/genética
Imunidade Inata/genética
Síndrome Oculocerebrorrenal/genética
Monoéster Fosfórico Hidrolases/genética
[Mh] Termos MeSH secundário: Animais
Drosophila
Endossomos/genética
Endossomos/patologia
Hemócitos/metabolismo
Hemócitos/patologia
Seres Humanos
Mutação
Síndrome Oculocerebrorrenal/patologia
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.1.3.2 (Phosphoric Monoester Hydrolases); EC 3.1.3.36 (OCRL protein, human)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171111
[Lr] Data última revisão:
171111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171014
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1007052


  8 / 2609 MEDLINE  
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[PMID]:28942021
[Au] Autor:Ifuji A; Kuga T; Kaibori Y; Saito Y; Nakayama Y
[Ad] Endereço:Department of Biochemistry & Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
[Ti] Título:A novel immunofluorescence method to visualize microtubules in the antiparallel overlaps of microtubule-plus ends in the anaphase and telophase midzone.
[So] Source:Exp Cell Res;360(2):347-357, 2017 Nov 15.
[Is] ISSN:1090-2422
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Cell division, in which duplicated chromosomes are separated into two daughter cells, is the most dynamic event during cell proliferation. Chromosome movement is powered mainly by microtubules, which vary in morphology and are organized into characteristic structures according to mitotic progression. During the later stages of mitosis, antiparallel microtubules form the spindle midzone, and the irregular formation of the midzone often leads to failure of cytokinesis, giving rise to the unequal segregation of chromosomes. However, it is difficult to analyze the morphology of these microtubules because microtubules in the antiparallel overlaps of microtubule-plus ends in the midzone are embedded in highly electron-dense matrices, impeding the access of anti-tubulin antibodies to their epitopes during immunofluorescence staining. Here, we developed a novel method to visualize selectively antiparallel microtubule overlaps in the midzone. When cells are air-dried before fixation, aligned α-tubulin staining is observed and colocalized with PRC1 in the center of the midzone of anaphase and telophase cells, suggesting that antiparallel microtubule overlaps can be visualized by this method. In air-dried cells, mCherry-α-tubulin fluorescence and ß-tubulin staining show almost the same pattern as α-tubulin staining in the midzone, suggesting that the selective visualization of antiparallel microtubule overlaps in air-dried cells is not attributed to an alteration of the antigenicity of α-tubulin. Taxol treatment extends the microtubule filaments of the midzone in air-dried cells, and nocodazole treatment conversely decreases the number of microtubules, suggesting that unstable microtubules are depolymerized during the air-drying method. It is of note that the air-drying method enables the detection of the disruption of the midzone and premature midzone formation upon Aurora B and Plk1 inhibition, respectively. These results suggest that the air-drying method is suitable for visualizing microtubules in the antiparallel overlaps of microtubule-plus ends of the midzone and for detecting their effects on midzone formation.
[Mh] Termos MeSH primário: Anáfase
Imunofluorescência/métodos
Microtúbulos/metabolismo
Fuso Acromático/metabolismo
Telófase
[Mh] Termos MeSH secundário: Animais
Células Cultivadas
Segregação de Cromossomos/fisiologia
Citocinese/fisiologia
Células HeLa
Seres Humanos
Microtúbulos/ultraestrutura
Mitose
Fuso Acromático/ultraestrutura
Suínos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[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:170925
[St] Status:MEDLINE


  9 / 2609 MEDLINE  
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[PMID]:28898877
[Au] Autor:El-Zein RA; Abdel-Rahman S; Santee KJ; Yu R; Shete S
[Ad] Endereço:Department of Radiology, Houston Methodist Research Institute, Houston, TX, USA.
[Ti] Título:Identification of Small and Non-Small Cell Lung Cancer Markers in Peripheral Blood Using Cytokinesis-Blocked Micronucleus and Spectral Karyotyping Assays.
[So] Source:Cytogenet Genome Res;152(3):122-131, 2017.
[Is] ISSN:1424-859X
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer. There is an urgent need to develop tools to identify individuals at high risk of developing SCLC. We have previously reported that the cytokinesis-blocked micronucleus (CBMN) assay is a strong predictor of non-small cell lung cancer (NSCLC). Here, we investigate the sensitivity of the CBMN endpoints as predictors of SCLC risk. We conducted the CBMN assay on SCLC patients (n = 216), NSCLC patients (n = 173), and healthy controls (n = 204). Per sample, 1,000 binucleated cells (BN) were scored, and 3 endpoints, micronuclei (BN-MN), nucleoplasmic bridges (BN-NPB), and nuclear buds(BN-BUD), were recorded. Spectral karyotyping was also conducted on SCLC patients (n = 116) and NSCLC patients (n = 137) to identify genomic regions unique to each disease. Significantly higher levels of CBMN endpoints were observed in both cancer groups compared to controls. BN-NPBs were significantly higher among SCLC patients compared to NSCLC patients (p < 0.001). Chromosomes 5 and 17 were associated with BN-MN, and chromosomes 5, 18, 20, and 22 were associated with BN-NPBs in SCLC patients. Given the high frequency of chromosome aberrations observed in SCLC, events such as reinsertion of the micronucleus and chromothripsis may be potential mechanisms for the genetic instability in these patients.
[Mh] Termos MeSH primário: Biomarcadores Tumorais/genética
Carcinoma Pulmonar de Células não Pequenas/diagnóstico
Detecção Precoce de Câncer/métodos
Neoplasias Pulmonares/diagnóstico
Testes para Micronúcleos/métodos
Carcinoma de Pequenas Células do Pulmão/diagnóstico
Cariotipagem Espectral/métodos
[Mh] Termos MeSH secundário: Idoso
Biomarcadores Tumorais/sangue
Carcinoma Pulmonar de Células não Pequenas/sangue
Carcinoma Pulmonar de Células não Pequenas/genética
Mapeamento Cromossômico
Cromotripsia
Citocinese/genética
Feminino
Seres Humanos
Neoplasias Pulmonares/sangue
Neoplasias Pulmonares/genética
Masculino
Meia-Idade
Fatores de Risco
Sensibilidade e Especificidade
Carcinoma de Pequenas Células do Pulmão/sangue
Carcinoma de Pequenas Células do Pulmão/genética
Fumar/efeitos adversos
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Biomarkers, Tumor)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171020
[Lr] Data última revisão:
171020
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170913
[St] Status:MEDLINE
[do] DOI:10.1159/000479809


  10 / 2609 MEDLINE  
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[PMID]:28892560
[Au] Autor:Moawia A; Shaheen R; Rasool S; Waseem SS; Ewida N; Budde B; Kawalia A; Motameny S; Khan K; Fatima A; Jameel M; Ullah F; Akram T; Ali Z; Abdullah U; Irshad S; Höhne W; Noegel AA; Al-Owain M; Hörtnagel K; Stöbe P; Baig SM; Nürnberg P; Alkuraya FS; Hahn A; Hussain MS
[Ad] Endereço:Cologne Center for Genomics, University of Cologne, Cologne, Germany.
[Ti] Título:Mutations of KIF14 cause primary microcephaly by impairing cytokinesis.
[So] Source:Ann Neurol;82(4):562-577, 2017 Oct.
[Is] ISSN:1531-8249
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: Autosomal recessive primary microcephaly (MCPH) is a rare condition characterized by a reduced cerebral cortex accompanied with intellectual disability. Mutations in 17 genes have been shown to cause this phenotype. Recently, mutations in CIT, encoding CRIK (citron rho-interacting kinase)-a component of the central spindle matrix-were added. We aimed at identifying novel MCPH-associated genes and exploring their functional role in pathogenesis. METHODS: Linkage analysis and whole exome sequencing were performed in consanguineous and nonconsanguineous MCPH families to identify disease-causing variants. Functional consequences were investigated by RNA studies and on the cellular level using immunofluorescence and microscopy. RESULTS: We identified homozygous mutations in KIF14 (NM_014875.2;c.263T>A;pLeu88*, c.2480_2482delTTG; p.Val827del, and c.4071G>A;p.Gln1357=) as the likely cause in 3 MCPH families. Furthermore, in a patient presenting with a severe form of primary microcephaly and short stature, we identified compound heterozygous missense mutations in KIF14 (NM_014875.2;c.2545C>G;p.His849Asp and c.3662G>T;p.Gly1221Val). Three of the 5 identified mutations impaired splicing, and 2 resulted in a truncated protein. Intriguingly, Kif14 knockout mice also showed primary microcephaly. Human kinesin-like protein KIF14, a microtubule motor protein, localizes at the midbody to finalize cytokinesis by interacting with CRIK. We found impaired localization of both KIF14 and CRIK at the midbody in patient-derived fibroblasts. Furthermore, we observed a large number of binucleated and apoptotic cells-signs of failed cytokinesis that we also observed in experimentally KIF14-depleted cells. INTERPRETATION: Our data corroborate the role of an impaired cytokinesis in the etiology of primary and syndromic microcephaly, as has been proposed by recent findings on CIT mutations. Ann Neurol 2017;82:562-577.
[Mh] Termos MeSH primário: Citocinese/genética
Regulação da Expressão Gênica/genética
Cinesina/genética
Microcefalia/genética
Mutação/genética
Proteínas Oncogênicas/genética
[Mh] Termos MeSH secundário: Caspase 7/metabolismo
Movimento Celular/genética
Células Cultivadas
Criança
Pré-Escolar
Saúde da Família
Feminino
Fibroblastos/fisiologia
Estudo de Associação Genômica Ampla
Seres Humanos
Peptídeos e Proteínas de Sinalização Intracelular/genética
Peptídeos e Proteínas de Sinalização Intracelular/metabolismo
Masculino
Microcefalia/diagnóstico por imagem
Microcefalia/patologia
Proteínas Serina-Treonina Quinases/genética
Proteínas Serina-Treonina Quinases/metabolismo
Tubulina (Proteína)/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Intracellular Signaling Peptides and Proteins); 0 (Oncogene Proteins); 0 (Tubulin); EC 2.7.1.- (citron-kinase); EC 2.7.11.1 (Protein-Serine-Threonine Kinases); EC 3.4.22.- (CASP7 protein, human); EC 3.4.22.- (Caspase 7); EC 3.6.1.- (KIF14 protein, human); EC 3.6.4.4 (Kinesin)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171030
[Lr] Data última revisão:
171030
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170912
[St] Status:MEDLINE
[do] DOI:10.1002/ana.25044



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