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Pesquisa : D08.811.277.656.262.500.126.550.200 [Categoria DeCS]
Referências encontradas : 631 [refinar]
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[PMID]:28943433
[Au] Autor:Kalabova D; Smidova A; Petrvalska O; Alblova M; Kosek D; Man P; Obsil T; Obsilova V
[Ad] Endereço:Department of Structural Biology of Signaling Proteins, Division BIOCEV, Institute of Physiology of the Czech Academy of Sciences, Prumyslova 595, 252 50 Vestec, Czech Republic; 2nd Faculty of Medicine, Charles University, V Uvalu 84, 15006 Prague, Czech Republic.
[Ti] Título:Human procaspase-2 phosphorylation at both S139 and S164 is required for 14-3-3 binding.
[So] Source:Biochem Biophys Res Commun;493(2):940-945, 2017 Nov 18.
[Is] ISSN:1090-2104
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Procaspase-2 phosphorylation at several residues prevents its activation and blocks apoptosis. This process involves procaspase-2 phosphorylation at S164 and its binding to the scaffolding protein 14-3-3. However, bioinformatics analysis has suggested that a second phosphoserine-containing motif may also be required for 14-3-3 binding. In this study, we show that human procaspase-2 interaction with 14-3-3 is governed by phosphorylation at both S139 and S164. Using biochemical and biophysical approaches, we show that doubly phosphorylated procaspase-2 and 14-3-3 form an equimolar complex with a dissociation constant in the nanomolar range. Furthermore, our data indicate that other regions of procaspase-2, in addition to phosphorylation motifs, may be involved in the interaction with 14-3-3.
[Mh] Termos MeSH primário: Proteínas 14-3-3/metabolismo
Caspase 2/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Sítios de Ligação
Caspase 2/química
Seres Humanos
Fosforilação
Ligação Proteica
Domínios Proteicos
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (14-3-3 Proteins); 0 (Recombinant Proteins); EC 3.4.22.- (Caspase 2)
[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:170926
[St] Status:MEDLINE


  2 / 631 MEDLINE  
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[PMID]:28581521
[Au] Autor:Forsberg J; Zhivotovsky B; Olsson M
[Ad] Endereço:Division of Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
[Ti] Título:Caspase-2: an orphan enzyme out of the shadows.
[So] Source:Oncogene;36(39):5441-5444, 2017 Sep 28.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Caspase-2 has been embodied as an initiator or executioner protease in diverse apoptotic scenarios. However, accumulating evidence is challenging this view, pertaining to its true role. The enzyme's catalytic activity is currently implicated in various functions required for correct cell proliferation, such as counteracting genomic instability, as well as suppressing tumorigenesis. Here, apart from summarizing the latest observations in caspase-2-related research, we make an attempt to reconcile these findings and discuss their implications for future directions.
[Mh] Termos MeSH primário: Caspase 2/fisiologia
[Mh] Termos MeSH secundário: Animais
Instabilidade Genômica
Seres Humanos
Neoplasias/enzimologia
Neoplasias/patologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
EC 3.4.22.- (Caspase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171024
[Lr] Data última revisão:
171024
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170606
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2017.169


  3 / 631 MEDLINE  
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[PMID]:28500181
[Au] Autor:O'Byrne KJ; Richard DJ
[Ad] Endereço:School of Biomedical Research, Institute of Health and Biomedical Innovation at the Translational Research Institute, Queensland University of Technology, Woolloongabba QLD 4102, Australia.
[Ti] Título:Nucleolar caspase-2: Protecting us from DNA damage.
[So] Source:J Cell Biol;216(6):1521-1523, 2017 Jun 05.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Caspase-2 triggers apoptosis, but how it is activated by different stimuli is unclear. In this issue, Ando et al. (2017. https://doi.org/10.1083/jcb.201608095) delineate two pathways of caspase-2 activation and show that, in response to DNA damage, caspase-2 forms a complex with the PIDDosome and NPM1 within the nucleolus.
[Mh] Termos MeSH primário: Caspase 2
Dano ao DNA
[Mh] Termos MeSH secundário: Apoptose
Nucléolo Celular
Seres Humanos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.22.- (Caspase 2)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:171026
[Lr] Data última revisão:
171026
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170514
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201704114


  4 / 631 MEDLINE  
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[PMID]:28432080
[Au] Autor:Ando K; Parsons MJ; Shah RB; Charendoff CI; Paris SL; Liu PH; Fassio SR; Rohrman BA; Thompson R; Oberst A; Sidi S; Bouchier-Hayes L
[Ad] Endereço:Department of Medicine, Division of Hematology/Oncology, Tisch Cancer Institute at Mount Sinai, New York, NY 10029.
[Ti] Título:NPM1 directs PIDDosome-dependent caspase-2 activation in the nucleolus.
[So] Source:J Cell Biol;216(6):1795-1810, 2017 Jun 05.
[Is] ISSN:1540-8140
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The PIDDosome (PIDD-RAIDD-caspase-2 complex) is considered to be the primary signaling platform for caspase-2 activation in response to genotoxic stress. Yet studies of PIDD-deficient mice show that caspase-2 activation can proceed in the absence of PIDD. Here we show that DNA damage induces the assembly of at least two distinct activation platforms for caspase-2: a cytoplasmic platform that is RAIDD dependent but PIDD independent, and a nucleolar platform that requires both PIDD and RAIDD. Furthermore, the nucleolar phosphoprotein nucleophosmin (NPM1) acts as a scaffold for PIDD and is essential for PIDDosome assembly in the nucleolus after DNA damage. Inhibition of NPM1 impairs caspase-2 processing, apoptosis, and caspase-2-dependent inhibition of cell growth, demonstrating that the NPM1-dependent nucleolar PIDDosome is a key initiator of the caspase-2 activation cascade. Thus we have identified the nucleolus as a novel site for caspase-2 activation and function.
[Mh] Termos MeSH primário: Apoptose
Caspase 2/metabolismo
Nucléolo Celular/enzimologia
Cisteína Endopeptidases/metabolismo
Dano ao DNA
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo
Proteínas Nucleares/metabolismo
[Mh] Termos MeSH secundário: Animais
Proteína Adaptadora de Sinalização CRADD/metabolismo
Caspase 2/genética
Cisteína Endopeptidases/genética
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética
Ativação Enzimática
Genótipo
Células HEK293
Células HeLa
Seres Humanos
Camundongos Knockout
Microscopia Confocal
Microscopia de Fluorescência
Microscopia de Vídeo
Complexos Multiproteicos
Proteínas Nucleares/genética
Fenótipo
Ligação Proteica
Interferência de RNA
Transdução de Sinais
Transfecção
Peixe-Zebra/genética
Peixe-Zebra/metabolismo
Proteínas de Peixe-Zebra/genética
Proteínas de Peixe-Zebra/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; VIDEO-AUDIO MEDIA
[Nm] Nome de substância:
0 (CRADD Signaling Adaptor Protein); 0 (CRADD protein, human); 0 (Death Domain Receptor Signaling Adaptor Proteins); 0 (Lrdd protein, mouse); 0 (Multiprotein Complexes); 0 (Nuclear Proteins); 0 (PIDD protein, human); 0 (Zebrafish Proteins); 117896-08-9 (nucleophosmin); EC 3.4.22.- (CASP2 protein, human); EC 3.4.22.- (Casp2 protein, mouse); EC 3.4.22.- (Caspase 2); EC 3.4.22.- (Cysteine Endopeptidases)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:171027
[Lr] Data última revisão:
171027
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170423
[St] Status:MEDLINE
[do] DOI:10.1083/jcb.201608095


  5 / 631 MEDLINE  
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[PMID]:28219770
[Au] Autor:Badawi A; Hehlgans S; Pfeilschifter J; Rödel F; Eberhardt W
[Ad] Endereço:pharmazentrum frankfurt/ZAFES, University of Frankfurt, Medical School, Frankfurt/Main, Germany.
[Ti] Título:Silencing of the mRNA-binding protein HuR increases the sensitivity of colorectal cancer cells to ionizing radiation through upregulation of caspase-2.
[So] Source:Cancer Lett;393:103-112, 2017 May 01.
[Is] ISSN:1872-7980
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:Increased abundance of the mRNA-binding protein human antigen R (HuR) is a characteristic feature of many cancers and frequently associated with a high grade malignancy and therapy resistance. HuR elicits a broad cell survival program mainly by stabilizing or increasing the translation of mRNAs coding for anti-apoptotic effector proteins. Conversally, we previously identified the pro-apoptotic caspase-2 as a novel HuR target which is mainly regulated at the level of translation. In this study, we investigated whether siRNA-mediated HuR knockdown interferes with cell survival and radiation sensitivity by monitoring apoptosis, DNA repair and three-dimensional (3D) clonogenic survival. We observed a significant elevation in caspase-2 upon HuR depletion and in turn, a sensitization of colorectal DLD-1 and HCT-15 cells to radiation-induced apoptosis as implicated by the dose-dependent elevation of sub-G phase cell entry and increased caspase-2, -3 and poly ADP-ribose polymerase (PARP)-cleavage, respectively. Coincidentally, HuR deficiency significantly elevated the number of radiation-induced γH2AX/53BP1-positive foci indicating an increase in DNA damage. Accordingly, the irradiation-dependent reduction in clonogenic cell survival was further impaired after knockdown of HuR. Importantly, HuR knockdown remained ineffective to radiation-induced cell responses after additional knockdown of caspase-2. Furthermore, by using RNA-pull down assay we demonstrate that irradiation (6 Gy) robustly increased HuR binding to caspase-2 mRNA. Collectively, sensitization of colon carcinoma cells to radiation-induced cell death and DNA-damage by HuR knockdown critically depends on caspase-2 and may represent a valuable approach to intervene with therapy resistance of colorectal cancer (CRC).
[Mh] Termos MeSH primário: Apoptose/efeitos da radiação
Caspase 2/metabolismo
Neoplasias Colorretais/radioterapia
Cisteína Endopeptidases/metabolismo
Proteína Semelhante a ELAV 1/genética
Interferência de RNA
Tolerância a Radiação
[Mh] Termos MeSH secundário: Regiões 5' não Traduzidas
Apoptose/genética
Sítios de Ligação
Caspase 2/genética
Linhagem Celular Tumoral
Neoplasias Colorretais/enzimologia
Neoplasias Colorretais/genética
Neoplasias Colorretais/patologia
Cisteína Endopeptidases/genética
Relação Dose-Resposta à Radiação
Proteína Semelhante a ELAV 1/metabolismo
Regulação Enzimológica da Expressão Gênica
Regulação Neoplásica da Expressão Gênica
Seres Humanos
Tolerância a Radiação/genética
Fatores de Tempo
Transfecção
Regulação para Cima
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5' Untranslated Regions); 0 (ELAV-Like Protein 1); 0 (ELAVL1 protein, human); EC 3.4.22.- (CASP2 protein, human); EC 3.4.22.- (Caspase 2); EC 3.4.22.- (Cysteine Endopeptidases)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170814
[Lr] Data última revisão:
170814
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170222
[St] Status:MEDLINE


  6 / 631 MEDLINE  
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[PMID]:28207763
[Au] Autor:Kamber Kaya HE; Ditzel M; Meier P; Bergmann A
[Ad] Endereço:Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
[Ti] Título:An inhibitory mono-ubiquitylation of the Drosophila initiator caspase Dronc functions in both apoptotic and non-apoptotic pathways.
[So] Source:PLoS Genet;13(2):e1006438, 2017 02.
[Is] ISSN:1553-7404
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Apoptosis is an evolutionary conserved cell death mechanism, which requires activation of initiator and effector caspases. The Drosophila initiator caspase Dronc, the ortholog of mammalian Caspase-2 and Caspase-9, has an N-terminal CARD domain that recruits Dronc into the apoptosome for activation. In addition to its role in apoptosis, Dronc also has non-apoptotic functions such as compensatory proliferation. One mechanism to control the activation of Dronc is ubiquitylation. However, the mechanistic details of ubiquitylation of Dronc are less clear. For example, monomeric inactive Dronc is subject to non-degradative ubiquitylation in living cells, while ubiquitylation of active apoptosome-bound Dronc triggers its proteolytic degradation in apoptotic cells. Here, we examined the role of non-degradative ubiquitylation of Dronc in living cells in vivo, i.e. in the context of a multi-cellular organism. Our in vivo data suggest that in living cells Dronc is mono-ubiquitylated on Lys78 (K78) in its CARD domain. This ubiquitylation prevents activation of Dronc in the apoptosome and protects cells from apoptosis. Furthermore, K78 ubiquitylation plays an inhibitory role for non-apoptotic functions of Dronc. We provide evidence that not all of the non-apoptotic functions of Dronc require its catalytic activity. In conclusion, we demonstrate a mechanism whereby Dronc's apoptotic and non-apoptotic activities can be kept silenced in a non-degradative manner through a single ubiquitylation event in living cells.
[Mh] Termos MeSH primário: Apoptose/genética
Caspases/genética
Proteínas de Drosophila/genética
Ubiquitinação/genética
[Mh] Termos MeSH secundário: Animais
Caspase 2/genética
Caspase 9/genética
Drosophila melanogaster/genética
Ligação Proteica
Domínios Proteicos/genética
Proteólise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Drosophila Proteins); EC 3.4.22.- (Caspase 2); EC 3.4.22.- (Caspase 9); EC 3.4.22.- (Caspases); EC 3.4.22.- (Nc protein, Drosophila)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:171013
[Lr] Data última revisão:
171013
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170217
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pgen.1006438


  7 / 631 MEDLINE  
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[PMID]:28130345
[Au] Autor:Fava LL; Schuler F; Sladky V; Haschka MD; Soratroi C; Eiterer L; Demetz E; Weiss G; Geley S; Nigg EA; Villunger A
[Ad] Endereço:Division of Developmental Immunology, Biocenter, Medical University of Innsbruck, 6020 Innsbruck, Austria.
[Ti] Título:The PIDDosome activates p53 in response to supernumerary centrosomes.
[So] Source:Genes Dev;31(1):34-45, 2017 Jan 01.
[Is] ISSN:1549-5477
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Centrosomes, the main microtubule-organizing centers in animal cells, are replicated exactly once during the cell division cycle to form the poles of the mitotic spindle. Supernumerary centrosomes can lead to aberrant cell division and have been causally linked to chromosomal instability and cancer. Here, we report that an increase in the number of mature centrosomes, generated by disrupting cytokinesis or forcing centrosome overduplication, triggers the activation of the PIDDosome multiprotein complex, leading to Caspase-2-mediated MDM2 cleavage, p53 stabilization, and p21-dependent cell cycle arrest. This pathway also restrains the extent of developmentally scheduled polyploidization by regulating p53 levels in hepatocytes during liver organogenesis. Taken together, the PIDDosome acts as a first barrier, engaging p53 to halt the proliferation of cells carrying more than one mature centrosome to maintain genome integrity.
[Mh] Termos MeSH primário: Centrossomo/fisiologia
Genes p53/genética
Complexos Multiproteicos/metabolismo
Ativação Transcricional/genética
[Mh] Termos MeSH secundário: Células A549
Animais
Proteína Adaptadora de Sinalização CRADD/metabolismo
Caspase 2/metabolismo
Pontos de Checagem do Ciclo Celular/genética
Células Cultivadas
Centrossomo/patologia
Citocinese/genética
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo
Seres Humanos
Fígado/citologia
Fígado/embriologia
Camundongos
Organogênese/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (CRADD Signaling Adaptor Protein); 0 (Cradd protein, mouse); 0 (Death Domain Receptor Signaling Adaptor Proteins); 0 (Lrdd protein, mouse); 0 (Multiprotein Complexes); EC 3.4.22.- (Caspase 2)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171117
[Lr] Data última revisão:
171117
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170129
[St] Status:MEDLINE
[do] DOI:10.1101/gad.289728.116


  8 / 631 MEDLINE  
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[PMID]:28073006
[Au] Autor:López-García C; Sansregret L; Domingo E; McGranahan N; Hobor S; Birkbak NJ; Horswell S; Grönroos E; Favero F; Rowan AJ; Matthews N; Begum S; Phillimore B; Burrell R; Oukrif D; Spencer-Dene B; Kovac M; Stamp G; Stewart A; Danielsen H; Novelli M; Tomlinson I; Swanton C
[Ad] Endereço:Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
[Ti] Título:BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.
[So] Source:Cancer Cell;31(1):79-93, 2017 Jan 09.
[Is] ISSN:1878-3686
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors. BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID. Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
[Mh] Termos MeSH primário: Aneuploidia
Caspase 2/fisiologia
Neoplasias Colorretais/genética
Cisteína Endopeptidases/fisiologia
Proteínas de Ligação a DNA/fisiologia
Fatores de Transcrição/fisiologia
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Animais
Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/fisiologia
Caspase 2/análise
Segregação de Cromossomos
Cisteína Endopeptidases/análise
Proteínas de Ligação a DNA/genética
Células HCT116
Seres Humanos
Camundongos
Meia-Idade
Mutação
Proteínas Proto-Oncogênicas c-mdm2/fisiologia
Fatores de Transcrição/genética
Proteína Supressora de Tumor p53/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (BCL9L protein, human); 0 (BH3 Interacting Domain Death Agonist Protein); 0 (BID protein, human); 0 (DNA-Binding Proteins); 0 (TP53 protein, human); 0 (Transcription Factors); 0 (Tumor Suppressor Protein p53); EC 2.3.2.27 (MDM2 protein, human); EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2); EC 3.4.22.- (CASP2 protein, human); EC 3.4.22.- (Caspase 2); EC 3.4.22.- (Cysteine Endopeptidases)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170922
[Lr] Data última revisão:
170922
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170111
[St] Status:MEDLINE


  9 / 631 MEDLINE  
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[PMID]:27991927
[Au] Autor:Dawar S; Lim Y; Puccini J; White M; Thomas P; Bouchier-Hayes L; Green DR; Dorstyn L; Kumar S
[Ad] Endereço:Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia.
[Ti] Título:Caspase-2-mediated cell death is required for deleting aneuploid cells.
[So] Source:Oncogene;36(19):2704-2714, 2017 May 11.
[Is] ISSN:1476-5594
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Caspase-2, one of the most evolutionarily conserved of the caspase family, has been implicated in maintenance of chromosomal stability and tumour suppression. Caspase-2 deficient (Casp2 ) mice develop normally but show premature ageing-related traits and when challenged by certain stressors, succumb to enhanced tumour development and aneuploidy. To test how caspase-2 protects against chromosomal instability, we utilized an ex vivo system for aneuploidy where primary splenocytes from Casp2 mice were exposed to anti-mitotic drugs and followed up by live cell imaging. Our data show that caspase-2 is required for deleting mitotically aberrant cells. Acute silencing of caspase-2 in cultured human cells recapitulated these results. We further generated Casp2 mutant mice to demonstrate that caspase-2 catalytic activity is essential for its function in limiting aneuploidy. Our results provide direct evidence that the apoptotic activity of caspase-2 is necessary for deleting cells with mitotic aberrations to limit aneuploidy.
[Mh] Termos MeSH primário: Aneuploidia
Apoptose/genética
Caspase 2/genética
Instabilidade Cromossômica/genética
[Mh] Termos MeSH secundário: Animais
Caspase 2/metabolismo
Seres Humanos
Camundongos
Camundongos Knockout
Estresse Oxidativo/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.22.- (Caspase 2)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170907
[Lr] Data última revisão:
170907
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161220
[St] Status:MEDLINE
[do] DOI:10.1038/onc.2016.423


  10 / 631 MEDLINE  
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[PMID]:27906175
[Au] Autor:Dawar S; Shahrin NH; Sladojevic N; D'Andrea RJ; Dorstyn L; Hiwase DK; Kumar S
[Ad] Endereço:Centre for Cancer Biology, University of South Australia, Adelaide, South Australia 5001, Australia.
[Ti] Título:Impaired haematopoietic stem cell differentiation and enhanced skewing towards myeloid progenitors in aged caspase-2-deficient mice.
[So] Source:Cell Death Dis;7(12):e2509, 2016 Dec 01.
[Is] ISSN:2041-4889
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The apoptotic cysteine protease caspase-2 has been shown to suppress tumourigenesis in mice and its reduced expression correlates with poor prognosis in some human malignancies. Caspase-2-deficient mice develop normally but show ageing-related traits and, when challenged by oncogenic stimuli or certain stress, show enhanced tumour development, often accompanied by extensive aneuploidy. As stem cells are susceptible to acquiring age-related functional defects because of their self-renewal and proliferative capacity, we examined whether loss of caspase-2 promotes such defects with age. Using young and aged Casp2 mice, we demonstrate that deficiency of caspase-2 results in enhanced aneuploidy and DNA damage in bone marrow (BM) cells with ageing. Furthermore, we demonstrate for the first time that caspase-2 loss results in significant increase in immunophenotypically defined short-term haematopoietic stem cells (HSCs) and multipotent progenitors fractions in BM with a skewed differentiation towards myeloid progenitors with ageing. Caspase-2 deficiency leads to enhanced granulocyte macrophage and erythroid progenitors in aged mice. Colony-forming assays and long-term culture-initiating assay further recapitulated these results. Our results provide the first evidence of caspase-2 in regulating HSC and progenitor differentiation, as well as aneuploidy, in vivo.
[Mh] Termos MeSH primário: Envelhecimento/metabolismo
Caspase 2/deficiência
Diferenciação Celular
Células-Tronco Hematopoéticas/patologia
Células Progenitoras Mieloides/patologia
[Mh] Termos MeSH secundário: Aneuploidia
Animais
Caspase 2/metabolismo
Células Cultivadas
Dano ao DNA
Camundongos Endogâmicos C57BL
Camundongos Knockout
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
EC 3.4.22.- (Caspase 2)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170828
[Lr] Data última revisão:
170828
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161202
[St] Status:MEDLINE
[do] DOI:10.1038/cddis.2016.406



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