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1.
Nat Immunol ; 13(6): 560-8, 2012 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-22561606

RESUMO

Signaling via the T cell antigen receptor (TCR) during the CD4(+)CD8(+) double-positive developmental stage determines thymocyte selection and lineage commitment. Here we describe a previously uncharacterized T cell-expressed protein, Tespa1, with critical functions during the positive selection of thymocytes. Tespa1(-/-) mice had fewer mature thymic CD4(+) and CD8(+) T cells, which reflected impaired thymocyte development. Tespa1 associated with the TCR signaling components PLC-γ1 and Grb2, and Tespa1 deficiency resulted in attenuated TCR signaling, as reflected by defective activation of the Erk-AP-1 and Ca(2+)-NFAT pathways. Our findings demonstrate that Tespa1 is a component of the TCR signalosome and is essential for T cell selection and maturation through the regulation of TCR signaling during T cell development.


Assuntos
Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Timo/imunologia , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Diferenciação Celular/imunologia , Clonagem Molecular , Proteína Adaptadora GRB2/imunologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Fosfolipase C gama/imunologia , RNA Mensageiro/química , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Alinhamento de Sequência , Transdução de Sinais/imunologia , Timo/citologia
2.
Biochim Biophys Acta Mol Basis Dis ; 1869(2): 166600, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36402263

RESUMO

WD repeat domain 5 (WDR5) is a prominent target for pharmacological inhibition in cancer through its scaffolding role with various oncogenic partners such as MLL and MYC. WDR5-related drug discovery efforts center on blocking these binding interfaces or degradation have been devoted to developing small-molecule inhibitors or degraders of WDR5 for cancer treatment. Nevertheless, the precise role of WDR5 in these cancer cells has not been well elucidated genetically. Here, by using an MLL-AF9 murine leukemia model, we found that genetically deletion of Wdr5 impairs cell growth and colony forming ability of MLL-AF9 leukemia cells in vitro or ex vivo and attenuates the leukemogenesis in vivo as well, which acts through direct regulation of ribosomal genes. Pharmacological inhibition of Wdr5 recapitulates genetic study results in the same model. In conclusion, our current study demonstrated the first genetic evidence for the indispensable role of Wdr5 in MLL-r leukemogenesis in vivo, which supports therapeutically targeting WDR5 in MLL-rearranged leukemia by strengthening its disease linkage genetically and deepening insights into its mechanism of action.


Assuntos
Carcinogênese , Leucemia , Animais , Camundongos , Carcinogênese/genética , Descoberta de Drogas , Leucemia/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
3.
J Exp Med ; 214(5): 1453-1469, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28400474

RESUMO

T helper type 17 cells (Th17 cells) are major contributors to many autoimmune diseases. In this study, we demonstrate that the germinal center kinase family member MINK1 (misshapen/NIK-related kinase 1) negatively regulates Th17 cell differentiation. The suppressive effect of MINK1 on induction of Th17 cells is mediated by the inhibition of SMAD2 activation through direct phosphorylation of SMAD2 at the T324 residue. The importance of MINK1 to Th17 cell differentiation was strengthened in the animal model of experimental autoimmune encephalomyelitis (EAE). Moreover, we show that the reactive oxygen species (ROS) scavenger N-acetyl cysteine boosts Th17 cell differentiation in a MINK1-dependent manner and exacerbates the severity of EAE. Thus, we have not only established MINK1 as a critical regulator of Th17 cell differentiation, but also clarified that accumulation of ROS may limit the generation of Th17 cells. The contribution of MINK1 to ROS-regulated Th17 cell differentiation may suggest an important mechanism for the development of autoimmune diseases influenced by antioxidant dietary supplements.


Assuntos
Proteínas Serina-Treonina Quinases/fisiologia , Células Th17/fisiologia , Animais , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Masculino , Camundongos , Camundongos Knockout , Espécies Reativas de Oxigênio/metabolismo , Proteína Smad2/fisiologia
4.
J Exp Med ; 211(13): 2635-49, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25422497

RESUMO

Antigen-mediated cross-linking of IgE on mast cells triggers a signaling cascade that results in their degranulation and proinflammatory cytokine production, which are key effectors in allergic reactions. We show that the activation of mast cells is negatively regulated by the newly identified adaptor protein Tespa1. Loss of Tespa1 in mouse mast cells led to hyper-responsiveness to stimulation via FcεRI. Mice lacking Tespa1 also displayed increased sensitivity to IgE-mediated allergic responses. The dysregulated signaling in KO mast cells was associated with increased activation of Grb2-PLC-γ1-SLP-76 signaling within the LAT1 (linker for activation of T cells family, member 1) signalosome versus the LAT2 signalosome. Collectively, these findings show that Tespa1 orchestrates mast cell activation by tuning the balance of LAT1 and LAT2 signalosome assembly.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Hipersensibilidade/imunologia , Mastócitos/imunologia , Receptores de IgE/metabolismo , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+L de Transporte de Aminoácidos , Anafilaxia/imunologia , Animais , Degranulação Celular , Movimento Celular , Quimiocinas/biossíntese , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Hipersensibilidade/patologia , Mastócitos/patologia , Mastócitos/fisiologia , Mastócitos/ultraestrutura , Camundongos Endogâmicos C57BL , Camundongos Knockout
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