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[PMID]:29330478
[Au] Autor:Williams JJL; Alotaiq N; Mullen W; Burchmore R; Liu L; Baillie GS; Schaper F; Pilch PF; Palmer TM
[Ad] Endereço:School of Pharmacy and Medical Sciences, University of Bradford, Bradford, BD7 1DP, UK. j.j.l.williams@bradford.ac.uk.
[Ti] Título:Interaction of suppressor of cytokine signalling 3 with cavin-1 links SOCS3 function and cavin-1 stability.
[So] Source:Nat Commun;9(1):168, 2018 01 12.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Effective suppression of JAK-STAT signalling by the inducible inhibitor "suppressor of cytokine signalling 3" (SOCS3) is essential for limiting signalling from cytokine receptors. Here we show that cavin-1, a component of caveolae, is a functionally significant SOCS3-interacting protein. Biochemical and confocal imaging demonstrate that SOCS3 localisation to the plasma membrane requires cavin-1. SOCS3 is also critical for cavin-1 stabilisation, such that deletion of SOCS3 reduces the expression of cavin-1 and caveolin-1 proteins, thereby reducing caveola abundance in endothelial cells. Moreover, the interaction of cavin-1 and SOCS3 is essential for SOCS3 function, as loss of cavin-1 enhances cytokine-stimulated STAT3 phosphorylation and abolishes SOCS3-dependent inhibition of IL-6 signalling by cyclic AMP. Together, these findings reveal a new functionally important mechanism linking SOCS3-mediated inhibition of cytokine signalling to localisation at the plasma membrane via interaction with and stabilisation of cavin-1.
[Mh] Termos MeSH primário: Proteínas de Membrana/metabolismo
Proteínas de Ligação a RNA/metabolismo
Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
[Mh] Termos MeSH secundário: Animais
Cavéolas/fisiologia
Deleção de Genes
Regulação da Expressão Gênica
Células HEK293
Seres Humanos
Janus Quinases/genética
Janus Quinases/metabolismo
Proteínas de Membrana/genética
Camundongos
Ligação Proteica
Proteínas de Ligação a RNA/genética
Fatores de Transcrição STAT/genética
Fatores de Transcrição STAT/metabolismo
Proteína 3 Supressora da Sinalização de Citocinas/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Membrane Proteins); 0 (PTRF protein, human); 0 (Ptrf protein, mouse); 0 (RNA-Binding Proteins); 0 (SOCS3 protein, human); 0 (STAT Transcription Factors); 0 (Socs3 protein, mouse); 0 (Suppressor of Cytokine Signaling 3 Protein); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180114
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02585-y


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[PMID]:29353701
[Au] Autor:Jere SW; Houreld NN; Abrahamse H
[Ad] Endereço:Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa.
[Ti] Título:Photobiomodulation at 660nm stimulates proliferation and migration of diabetic wounded cells via the expression of epidermal growth factor and the JAK/STAT pathway.
[So] Source:J Photochem Photobiol B;179:74-83, 2018 Feb.
[Is] ISSN:1873-2682
[Cp] País de publicação:Switzerland
[La] Idioma:eng
[Ab] Resumo:Photobiomodulation (PBM) modulates cellular processes to enhance diabetic wound healing. The photon energy activates wounded cells to proliferate and migrate. However, the signalling pathways responsible for these observations remain unknown. This study aimed to determine if PBM stimulates cellular proliferation and migration via the expression of epidermal growth factor (EGF) and activation of the Janus kinase/Signal transducer and activators of transcription (JAK/STAT) signalling pathway. Normal, wounded, diabetic and diabetic wounded cell models were exposed to PBM at a wavelength of 660nm and fluence of 5J/cm and incubated for 48h. Non-irradiated cells (0J/cm ) and cells exposed to exogenous EGF (rh EGF) served as controls. Cellular migration was determined microscopically at 0, 24 and 48h. Flow cytometry (BrdU) was used to determine cell proliferation, while the Trypan blue exclusion assay and adenosine triphosphate (ATP) luminescence was used to determine cell viability. The enzyme linked immunosorbent assay (ELISA) was used to analyse EGF expressed in the culture media, and phosphorylated (p-) EGF receptor (p-EGFR), p-JAK2, p-STAT1 and p-STAT5 in cells. Irradiated diabetic wounded cells showed a significant increase in EGF, and activation of its receptor (p-EGFR) and JAK/STAT (p-JAK2, p-STAT1 and p-STAT5). PBM at 660nm and 5J/cm is able to modulate cellular autocrine signalling, particularly the EGF/EGFR loop leading to activation of the JAK/STAT pathway which in turn stimulates cell proliferation and migration.
[Mh] Termos MeSH primário: Proliferação Celular/efeitos da radiação
Diabetes Mellitus/patologia
Fator de Crescimento Epidérmico/metabolismo
Janus Quinase 2/metabolismo
Luz
Fatores de Transcrição STAT/metabolismo
[Mh] Termos MeSH secundário: Movimento Celular/efeitos da radiação
Células Cultivadas
Ensaio de Imunoadsorção Enzimática
Fator de Crescimento Epidérmico/análise
Fator de Crescimento Epidérmico/genética
Fibroblastos/citologia
Fibroblastos/metabolismo
Fibroblastos/efeitos da radiação
Expressão Gênica/efeitos da radiação
Seres Humanos
Fosforilação/efeitos da radiação
Receptor do Fator de Crescimento Epidérmico/metabolismo
Transdução de Sinais/efeitos da radiação
Pele/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (STAT Transcription Factors); 62229-50-9 (Epidermal Growth Factor); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.10.2 (JAK2 protein, human); EC 2.7.10.2 (Janus Kinase 2)
[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:180123
[St] Status:MEDLINE


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[PMID]:29198037
[Au] Autor:Hu X; Chen S; Jia C; Xue S; Dou C; Dai Z; Xu H; Sun Z; Geng T; Cui H
[Ad] Endereço:Institute of Epigenetics and Epigenomics, College of Animal Science and Technology, Yangzhou University, 48 East Wenhui Road, Yangzhou, 225009, Jiangsu, China.
[Ti] Título:Gene expression profile and long non-coding RNA analysis, using RNA-Seq, in chicken embryonic fibroblast cells infected by avian leukosis virus J.
[So] Source:Arch Virol;163(3):639-647, 2018 Mar.
[Is] ISSN:1432-8798
[Cp] País de publicação:Austria
[La] Idioma:eng
[Ab] Resumo:Avian leukosis virus J (ALVJ) infection induces hematopoietic malignancy in myeloid leukemia and hemangioma in chickens. However, little is known about the mechanisms underpinning the unique pathogenesis of ALVJ. In this study, we investigated the gene expression profiles of ALVJ-infected chicken cells and performed a comprehensive analysis of the long non-coding RNAs (lncRNAs) in CEF cells using RNA-Seq. As a result, 36 differentially expressed lncRNAs and 91 genes (FC > 2 and q-values < 0.05) were identified. Bioinformatics analysis revealed that these differentially expressed genes are involved in the innate immune response. Target prediction analysis revealed that these lncRNAs may act in cis or trans and affect the expression of genes which are involved in the anti-viral innate immune responses. Toll-like receptor, RIG-I receptor, NOD-like receptor and JAK-STAT signaling pathways were enriched. Notably, the induced expression of innate immunity genes, including B2M, DHX58, IFI27L2, IFIH1, IRF10, ISG12(2), MX, OAS*A, RSAD2, STAT1, TLR3, IL4I1, and IRF1 (FC > 2 and correlation > 0.95), were highly correlated with the upregulation of several lncRNAs, including MG066618, MG066617, MG066601, MG066629, MG066609 and MG066616. These findings identify the expression profile of lncRNAs in chicken CEF cells infected by ALVJ virus and provide new insights into the molecular mechanisms of ALVJ infection.
[Mh] Termos MeSH primário: Vírus da Leucose Aviária/genética
Fibroblastos/virologia
Interações Hospedeiro-Patógeno
RNA Longo não Codificante/genética
Transcriptoma/imunologia
[Mh] Termos MeSH secundário: Animais
Vírus da Leucose Aviária/crescimento & desenvolvimento
Vírus da Leucose Aviária/imunologia
Linhagem Celular
Embrião de Galinha
Biologia Computacional
Proteína DEAD-box 58/genética
Proteína DEAD-box 58/imunologia
Fibroblastos/imunologia
Perfilação da Expressão Gênica
Regulação da Expressão Gênica
Imunidade Inata
Janus Quinase 1/genética
Janus Quinase 1/imunologia
Proteínas NLR/genética
Proteínas NLR/imunologia
RNA Longo não Codificante/imunologia
Fatores de Transcrição STAT/genética
Fatores de Transcrição STAT/imunologia
Análise de Sequência de RNA
Transdução de Sinais
Receptores Toll-Like/genética
Receptores Toll-Like/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (NLR Proteins); 0 (RNA, Long Noncoding); 0 (STAT Transcription Factors); 0 (Toll-Like Receptors); EC 2.7.10.2 (Janus Kinase 1); EC 3.6.4.13 (DEAD Box Protein 58)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180220
[Lr] Data última revisão:
180220
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171204
[St] Status:MEDLINE
[do] DOI:10.1007/s00705-017-3659-8


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[PMID]:28461339
[Au] Autor:McGregor G; Irving AJ; Harvey J
[Ad] Endereço:Division of Neuroscience, School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom.
[Ti] Título:Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses.
[So] Source:FASEB J;31(8):3449-3466, 2017 08.
[Is] ISSN:1530-6860
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway is involved in numerous cellular processes and it is implicated in neurodegenerative disorders, like Alzheimer disease. Recent studies identified a crucial role for this pathway in activity-dependent long-term depression (LTD) at hippocampal Schaffer collateral (SC)-CA1 synapses. However, it is unclear whether JAK-STAT signaling also regulates excitatory synaptic function at the anatomically distinct temporoammonic (TA) input to CA1 neurons. Here we demonstrate that LTD at adult TA-CA1 synapses involves JAK-STAT signaling, but unlike SC-CA1 synapses, requires rapid gene transcription. TA-CA1 LTD requires NMDA receptor activation and is independent of PI3K or ERK signaling. JAK-STAT signaling was critical for TA-CA1 LTD as inhibition of JAK or STAT blocked LTD induction and prevented NMDA-induced AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor internalization in hippocampal neurons. Moreover, an increase in phosphorylated JAK2 and STAT3 accompanied chemical induction of LTD and AMPA receptor internalization. STAT3-driven gene transcription was required for LTD as inhibition of STAT3-DNA binding, nuclear export, and gene transcription all prevented LTD induction. These data indicate an essential role for canonical JAK-STAT signaling in activity-dependent LTD at TA-CA1 synapses and provide valuable insight into the role of the TA input in hippocampal synaptic plasticity.-McGregor, G., Irving, A. J., Harvey, J. Canonical JAK-STAT signaling is pivotal for long-term depression at adult hippocampal temporoammonic-CA1 synapses.
[Mh] Termos MeSH primário: Região CA1 Hipocampal/fisiologia
Hipocampo/fisiologia
Janus Quinases/metabolismo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais/fisiologia
[Mh] Termos MeSH secundário: Animais
Potenciais Pós-Sinápticos Excitadores/fisiologia
Regulação da Expressão Gênica/fisiologia
Janus Quinases/genética
Masculino
Plasticidade Neuronal/fisiologia
Neurônios/metabolismo
Transporte Proteico
Ratos
Ratos Sprague-Dawley
Receptores de AMPA/genética
Receptores de AMPA/metabolismo
Receptores de N-Metil-D-Aspartato/genética
Receptores de N-Metil-D-Aspartato/metabolismo
Fatores de Transcrição STAT/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Receptors, AMPA); 0 (Receptors, N-Methyl-D-Aspartate); 0 (STAT Transcription Factors); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1710
[Cu] Atualização por classe:180206
[Lr] Data última revisão:
180206
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1096/fj.201601293RR


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[PMID]:29212804
[Au] Autor:Nangalia J; Green AR
[Ad] Endereço:Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
[Ti] Título:Myeloproliferative neoplasms: from origins to outcomes.
[So] Source:Blood;130(23):2475-2483, 2017 12 07.
[Is] ISSN:1528-0020
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
[Mh] Termos MeSH primário: Transtornos Mieloproliferativos/etiologia
Transtornos Mieloproliferativos/metabolismo
[Mh] Termos MeSH secundário: Animais
Transformação Celular Neoplásica/genética
Transformação Celular Neoplásica/metabolismo
Evolução Clonal
Progressão da Doença
Epistasia Genética
Estudos de Associação Genética
Predisposição Genética para Doença
Seres Humanos
Janus Quinases/metabolismo
Mutação
Transtornos Mieloproliferativos/diagnóstico
Fenótipo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (STAT Transcription Factors); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:180116
[Lr] Data última revisão:
180116
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171208
[St] Status:MEDLINE
[do] DOI:10.1182/blood-2017-06-782037


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[PMID]:29176764
[Au] Autor:Gregersen I; Sandanger Ø; Askevold ET; Sagen EL; Yang K; Holm S; Pedersen TM; Skjelland M; Krohg-Sørensen K; Hansen TV; Dahl TB; Otterdal K; Espevik T; Aukrust P; Yndestad A; Halvorsen B
[Ad] Endereço:Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet,Oslo, Norway.
[Ti] Título:Interleukin 27 is increased in carotid atherosclerosis and promotes NLRP3 inflammasome activation.
[So] Source:PLoS One;12(11):e0188387, 2017.
[Is] ISSN:1932-6203
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:AIM: Interleukin-27 (IL-27) is involved in different inflammatory diseases; however, its role in atherosclerosis is unclear. In this study we investigated the expression of IL-27 and its receptor in patients with carotid atherosclerosis and if IL-27 could modulate the inflammatory effects of the NLRP3 inflammasome in vitro. METHODS: Plasma IL-27 was measured by enzyme immunoassay in patients with carotid stenosis (n = 140) and in healthy controls (n = 19). Expression of IL-27 and IL-27R was analyzed by quantitative PCR and immunohistochemistry in plaques from patients and in non-atherosclerotic vessels. THP-1 monocytes, primary monocytes and peripheral blood mononuclear cells (PBMCs) were used to study effects of IL-27 in vitro. RESULTS: Our main findings were: (i) Plasma levels of IL-27 were significantly elevated in patients with carotid atherosclerotic disease compared to healthy controls. (ii) Gene expression of IL-27 and IL-27R was significantly elevated in plaques compared to control vessels, and co-localized to macrophages. (iii) In vitro, IL-27 increased NLRP3 inflammasome activation in monocytes with enhanced release of IL-1 ß. CONCLUSIONS: We demonstrate increased levels of IL-27 and IL-27R in patients with carotid atherosclerosis. Our in vitro findings suggest an inflammatory role for IL-27, which can possibly be linked to atherosclerotic disease development.
[Mh] Termos MeSH primário: Doenças das Artérias Carótidas/metabolismo
Inflamassomos/metabolismo
Interleucina-27/metabolismo
Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
[Mh] Termos MeSH secundário: Idoso
Antígenos CD/metabolismo
Apirase/metabolismo
Doenças das Artérias Carótidas/sangue
Doenças das Artérias Carótidas/genética
Doenças das Artérias Carótidas/patologia
Feminino
Regulação da Expressão Gênica
Seres Humanos
Interleucina-1beta/metabolismo
Interleucina-27/sangue
Interleucina-27/genética
Interleucinas/metabolismo
Lipopolissacarídeos
Macrófagos/metabolismo
Masculino
Antígenos de Histocompatibilidade Menor/metabolismo
Monócitos/metabolismo
Placa Aterosclerótica/metabolismo
Placa Aterosclerótica/patologia
Receptores de Citocinas/genética
Receptores de Citocinas/metabolismo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais
Fator de Necrose Tumoral alfa/metabolismo
Regulação para Cima/genética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, CD); 0 (EBI3 protein, human); 0 (Inflammasomes); 0 (Interleukin-1beta); 0 (Interleukin-27); 0 (Interleukins); 0 (Lipopolysaccharides); 0 (Minor Histocompatibility Antigens); 0 (NLR Family, Pyrin Domain-Containing 3 Protein); 0 (Receptors, Cytokine); 0 (STAT Transcription Factors); 0 (Tumor Necrosis Factor-alpha); EC 3.6.1.5 (Apyrase); EC 3.6.1.5 (CD39 antigen)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171219
[Lr] Data última revisão:
171219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1371/journal.pone.0188387


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[PMID]:27777077
[Au] Autor:Chen Y; Jiao B; Yao M; Shi X; Zheng Z; Li S; Chen L
[Ad] Endereço:Institute of Blood Transfusion, Chinese Academy of Medical Sciences and Peking Union Medical College, Provincial Key Laboratory for Transfusion-transmitted Infectious Diseases of Sichuan Province, Chengdu, Sichuan, 610052 China.
[Ti] Título:ISG12a inhibits HCV replication and potentiates the anti-HCV activity of IFN-α through activation of the Jak/STAT signaling pathway independent of autophagy and apoptosis.
[So] Source:Virus Res;227:231-239, 2017 01 02.
[Is] ISSN:1872-7492
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Interferon stimulated (sensitive) genes (ISGs) are the effector molecules downstream of type I/III interferon (IFN) signaling pathways in host innate immunity. ISG12a can be induced by IFN-α. Although ISG12a has been reported to inhibit the replication of HCV, the exact mechanism remains to be determined. In this study, we investigated the possible mechanisms of ISG12a anti- HCV property by exploring the production of type I IFN and the activation of Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway, apoptosis and autophagy in Huh7.5.1 cells transiently transfected with ISG12a over-expression plasmid. Interestingly, we found that ISG12a inhibited HCV replication in both Con1b replicon and the HCV JFH1-based cell culture system and potentiated the anti-HCV activity of IFN-α. ISG12a promoted the production of IFN α/ß and activated the type I IFN signaling pathway as shown by increased p-STAT1 level, higher Interferon sensitive response element (ISRE) activity and up-regulated ISG levels. However, ISG12a over-expression did not affect cell autophagy and apoptosis. Data from our current study collectively indicated that ISG12a inhibited HCV replication and potentiated the anti-HCV activity of IFN-α possibly through induced production of type I IFNs and activation of Jak/STAT signaling pathway independent of autophagy and cell apoptosis.
[Mh] Termos MeSH primário: Hepacivirus/fisiologia
Interferon-alfa/metabolismo
Janus Quinases/metabolismo
Proteínas de Membrana/metabolismo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais
Replicação Viral
[Mh] Termos MeSH secundário: Apoptose/genética
Autofagia/genética
Linhagem Celular
Células Cultivadas
Expressão Gênica
Hepatite C/genética
Hepatite C/metabolismo
Hepatite C/virologia
Seres Humanos
Interferon Tipo I/biossíntese
Interferon beta/metabolismo
Proteínas de Membrana/genética
Transdução de Sinais/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (IFI27 protein, human); 0 (Interferon Type I); 0 (Interferon-alpha); 0 (Membrane Proteins); 0 (STAT Transcription Factors); 77238-31-4 (Interferon-beta); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171218
[Lr] Data última revisão:
171218
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161107
[St] Status:MEDLINE


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[PMID]:28462919
[Au] Autor:Slinger E; Thijssen R; Kater AP; Eldering E
[Ad] Endereço:Cancer Center Amsterdam, Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
[Ti] Título:Targeting antigen-independent proliferation in chronic lymphocytic leukemia through differential kinase inhibition.
[So] Source:Leukemia;31(12):2601-2607, 2017 Dec.
[Is] ISSN:1476-5551
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The clinical success of B-cell receptor (BCR) signaling pathway inhibitors in chronic lymphocytic leukemia (CLL) is attributed to inhibition of adhesion in and migration towards the lymph node. Proliferation of CLL cells is restricted to this protective niche, but the underlying mechanism(s) is/are not known. Treatment with BCR pathway inhibitors results in rapid reductions of total clone size, while CLL cell survival is not affected, which points towards inhibition of proliferation. In vitro, BCR stimulation does not induce proliferation of CLL, but triggering via Toll-like receptor, tumor necrosis factor or cytokine receptors does. Here, we investigated the effects of clinically applied inhibitors that target BCR signaling, in the context of proliferation triggered either via CD40L/IL-21 or after CpG stimulation. CD40L/IL-21-induced proliferation could be inhibited by idelalisib and ibrutinib. We demonstrate this was due to blockade of CD40L-induced ERK-signaling. Targeting JAKs, but not SYK, blocked CD40L/IL-21-induced proliferation. In contrast, PI3K, BTK as well as SYK inhibition prevented CpG-induced proliferation. Knockdown experiments showed that CD40L/IL-21 did not co-opt upstream BCR components such as CD79A, in contrast to CpG-induced proliferation. Our data indicate that currently applied BTK/PI3K inhibitors target antigen-independent proliferation in CLL, and suggest that targeting of JAK and/or SYK might be clinically useful.
[Mh] Termos MeSH primário: Antígenos de Neoplasias/imunologia
Leucemia Linfocítica Crônica de Células B/imunologia
Leucemia Linfocítica Crônica de Células B/metabolismo
Fosfotransferases/antagonistas & inibidores
[Mh] Termos MeSH secundário: Biomarcadores
Antígenos CD40/imunologia
Antígenos CD40/metabolismo
Linhagem Celular Tumoral
Proliferação Celular
Seres Humanos
Interleucinas/metabolismo
Janus Quinases/metabolismo
Leucemia Linfocítica Crônica de Células B/genética
NF-kappa B/metabolismo
Fosfotransferases/metabolismo
Inibidores de Proteínas Quinases/farmacologia
Receptores de Antígenos de Linfócitos B/metabolismo
Fatores de Transcrição STAT/metabolismo
Transdução de Sinais/efeitos dos fármacos
Células Tumorais Cultivadas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antigens, Neoplasm); 0 (Biomarkers); 0 (CD40 Antigens); 0 (Interleukins); 0 (NF-kappa B); 0 (Protein Kinase Inhibitors); 0 (Receptors, Antigen, B-Cell); 0 (STAT Transcription Factors); 0 (interleukin-21); EC 2.7.- (Phosphotransferases); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1712
[Cu] Atualização por classe:171215
[Lr] Data última revisão:
171215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1038/leu.2017.129


  9 / 1747 MEDLINE  
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[PMID]:28742217
[Au] Autor:Pirault J; Polyzos KA; Petri MH; Ketelhuth DFJ; Bäck M; Hansson GK
[Ad] Endereço:Center for Molecular Medicine, Department of Medicine, Karolinska Institute, and Karolinska University Hospital, Stockholm, Sweden.
[Ti] Título:The inflammatory cytokine interferon-gamma inhibits sortilin-1 expression in hepatocytes via the JAK/STAT pathway.
[So] Source:Eur J Immunol;47(11):1918-1924, 2017 11.
[Is] ISSN:1521-4141
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Sortilin-1, a receptor of the VPS10p family, has been associated with cardiovascular disease in genome-wide association studies. It is implicated in lipoprotein metabolism, secretion of proprotein convertase subtilisin/kexin type 9 (PCSK9) and secretion of inflammatory cytokines. However, its own regulation remains unclear. Chronic inflammation is a hallmark of atherosclerosis and the absence of regulatory T (Treg) cells is associated with reduced protein expression of sortilin-1 in the liver. Therefore, we postulated that mediator(s) of inflammation known to be downregulated by Treg cells may modulate sortilin-1 expression. In this study, we identify interferon-gamma (IFN-γ) as the key inflammatory mediator controlling sortilin-1 levels. In vitro cultures of murine hepatocytes cell line and in silico experiments showed that the transcription factor Signal transducer and activator of transcription 1 was activated and bound to the Sort-1 gene upon IFN-γ treatment. This reduced the expression of sortilin-1, while disrupting the IFN-γ signaling pathway prevented the effect. These data unravel an intricate mechanism by which inflammation modulates receptors involved in lipoprotein turnover.
[Mh] Termos MeSH primário: Proteínas Adaptadoras de Transporte Vesicular/biossíntese
Hepatócitos/metabolismo
Interferon gama/metabolismo
Janus Quinases/metabolismo
Fatores de Transcrição STAT/metabolismo
[Mh] Termos MeSH secundário: Proteínas Adaptadoras de Transporte Vesicular/imunologia
Animais
Regulação da Expressão Gênica/imunologia
Hepatócitos/imunologia
Interferon gama/imunologia
Janus Quinases/imunologia
Camundongos
Camundongos Endogâmicos C57BL
Fatores de Transcrição STAT/imunologia
Transdução de Sinais/imunologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adaptor Proteins, Vesicular Transport); 0 (STAT Transcription Factors); 0 (sortilin); 82115-62-6 (Interferon-gamma); EC 2.7.10.2 (Janus Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171203
[Lr] Data última revisão:
171203
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1002/eji.201646768


  10 / 1747 MEDLINE  
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[PMID]:28743877
[Au] Autor:Kucinski I; Dinan M; Kolahgar G; Piddini E
[Ad] Endereço:The Wellcome Trust/Cancer Research UK Gurdon Institute and Zoology Department, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
[Ti] Título:Chronic activation of JNK JAK/STAT and oxidative stress signalling causes the loser cell status.
[So] Source:Nat Commun;8(1):136, 2017 07 26.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Cell competition is a form of cell interaction that causes the elimination of less fit cells, or losers, by wild-type (WT) cells, influencing overall tissue health. Several mutations can cause cells to become losers; however, it is not known how. Here we show that Drosophila wing disc cells carrying functionally unrelated loser mutations (Minute and mahjong) display the common activation of multiple stress signalling pathways before cell competition and find that these pathways collectively account for the loser status. We find that JNK signalling inhibits the growth of losers, while JAK/STAT signalling promotes competition-induced winner cell proliferation. Furthermore, we show that losers display oxidative stress response activation and, strikingly, that activation of this pathway alone, by Nrf2 overexpression, is sufficient to prime cells for their elimination by WT neighbours. Since oxidative stress and Nrf2 are linked to several diseases, cell competition may occur in a number of pathological conditions.Cell competition causes the removal of less fit cells ('losers') but why some gene mutations turn cells into losers is unclear. Here, the authors show that Drosophila wing disc cells carrying some loser mutations activate Nrf2 and JNK signalling, which contribute to the loser status.
[Mh] Termos MeSH primário: Proteínas de Drosophila/metabolismo
Drosophila melanogaster/metabolismo
Estresse Oxidativo
Transdução de Sinais
[Mh] Termos MeSH secundário: Animais
Animais Geneticamente Modificados
Apoptose/genética
Proliferação Celular/genética
Proteínas de Drosophila/genética
Drosophila melanogaster/citologia
Drosophila melanogaster/genética
Ativação Enzimática
Perfilação da Expressão Gênica/métodos
Discos Imaginais/citologia
Proteínas Quinases JNK Ativadas por Mitógeno/genética
Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo
Janus Quinases/genética
Janus Quinases/metabolismo
Microscopia Confocal
Mutação
Fatores de Transcrição STAT/genética
Fatores de Transcrição STAT/metabolismo
Fatores de Transcrição/genética
Fatores de Transcrição/metabolismo
Asas de Animais/citologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Drosophila Proteins); 0 (STAT Transcription Factors); 0 (Transcription Factors); EC 2.7.10.2 (Janus Kinases); EC 2.7.10.2 (hopscotch protein, Drosophila); EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171128
[Lr] Data última revisão:
171128
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170727
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-00145-y



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