Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
iScience ; 26(3): 106234, 2023 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-36926655

RESUMO

In thymus, the ablation of T cell receptor (TCR)-activated transcription factor NFATc1 or its inducible isoforms during the double-negative (DN) stages of thymocyte development leads to a marked increase in γδ thymocytes whereas the development of αß thymocytes remains mostly unaffected. These γδ thymocytes are characterized by the upregulation of the promyelocytic leukemia zinc-finger factor (PLZF), the "master regulator" of natural killer T (NKT) cell development, and the acquisition of an NKT γδ cell phenotype with higher cell survival rates. The suppressive function of NFATc1 in NKT γδ cell formation critically depends on the remote enhancer E2, which is essential for the inducible expression of NFATc1 directed by its distal promoter P1. Thus, the enhancer deciphers a strong γδ TCR signal into the expression of inducible NFATc1 isoforms resulting in high levels of NFATc1 protein that are essential to control the numbers of NKT γδ cells.

2.
Cell Mol Immunol ; 16(5): 508-520, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-29907883

RESUMO

B cell development in bone marrow is a precisely regulated complex process. Through successive stages of differentiation, which are regulated by a multitude of signaling pathways and an array of lineage-specific transcription factors, the common lymphoid progenitors ultimately give rise to mature B cells. Similar to early thymocyte development in the thymus, early B cell development in bone marrow is critically dependent on IL-7 signaling. During this IL-7-dependent stage of differentiation, several transcription factors, such as E2A, EBF1, and Pax5, among others, play indispensable roles in B lineage specification and maintenance. Although recent studies have implicated several other transcription factors in B cell development, the role of NFATc1 in early B cell developmental stages is not known. Here, using multiple gene-manipulated mouse models and applying various experimental methods, we show that NFATc1 activity is vital for early B cell differentiation. Lack of NFATc1 activity in pro-B cells suppresses EBF1 expression, impairs immunoglobulin gene rearrangement, and thereby preBCR formation, resulting in defective B cell development. Overall, deficiency in NFATc1 activity arrested the pro-B cell transition to the pre-B cell stage, leading to severe B cell lymphopenia. Our findings suggest that, along with other transcription factors, NFATc1 is a critical component of the signaling mechanism that facilitates early B cell differentiation.


Assuntos
Linfócitos B/imunologia , Células da Medula Óssea/imunologia , Fatores de Transcrição NFATC/metabolismo , Células Precursoras de Linfócitos B/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Interleucina-7/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Transdução de Sinais , Transativadores/genética , Transativadores/metabolismo
3.
Oncotarget ; 9(11): 9632-9644, 2018 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-29515759

RESUMO

The role of NFAT family transcription factors in erythropoiesis is so far unknown, although their involvement has been suggested previously. We have shown recently that Il2-/- mice develop severe anemia due to defects in KLF1 activity during BM erythropoiesis. Although, KLF1 activity is indispensable for erythropoiesis, the molecular details of Klf1 expression have not yet been elucidated. Here we show that an enhanced NFATc1 activity induced by increased integrin-cAMP signaling plays a critical role in the dysregulation of Klf1 expression and thereby cause anemia in Il2-/- mice. Interestingly, enhanced NFATc1 activity augmented apoptosis of immature erythrocytes in Il2-/- mice. On the other hand, ablation of NFATc1 activity enhanced differentiation of Ter119+ cells in BM. Restoring IL-2 signaling in Il2-/- mice reversed the increase in cAMP-NFAT signaling and facilitated normal erythropoiesis. Altogether, our study identified an NFAT-mediated negative signaling axis, manipulation of which could facilitate erythropoiesis and prevent anemia development.

4.
Oncotarget ; 8(18): 29625-29642, 2017 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-28415569

RESUMO

The role of IL-2 in HSC maintenance is unknown. Here we show that Il2-/- mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2-/- mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2-/- mice shows that the IL-2-Treg cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of Treg activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring Treg population successfully rescued HSC maintenance in Il2-/- mice, preventing IFN-γ activity could do the same even in the absence of Treg cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis.


Assuntos
Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Interleucina-2/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Biomarcadores , Autorrenovação Celular/genética , Hematopoese/genética , Hematopoese/imunologia , Imunofenotipagem , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-2/genética , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Transdução de Sinais , Linfócitos T Reguladores/imunologia
5.
Oncotarget ; 7(21): 31014-28, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27105536

RESUMO

Small cell lung cancer (SCLC) is the most aggressive type of lung cancer with high mortality. One of the MYC family genes, MYC, MYCL or MYCN, is amplified in ~20% of the SCLCs; therefore, MYC proteins are potential therapeutic targets in SCLC patients. We investigated the therapeutic impact of Omomyc, a MYC dominant negative, in a panel of SCLC cell lines. Strikingly, Omomyc suppressed the growth of all tested cell lines by inducing cell cycle arrest and/or apoptosis. Induction of G1 arrest by Omomyc was found to be dependent on the activation of CDKN1A, in part, through the TP73 pathway. Our results strongly indicate that SCLC cells carrying amplification of MYC, MYCL or MYCN are addicted to MYC function, suggesting that MYC targeting would be an efficient therapeutic option for SCLC patients.


Assuntos
Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Fragmentos de Peptídeos/biossíntese , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/biossíntese , Proteínas de Ligação a Retinoblastoma/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia , Proteína Supressora de Tumor p53/genética , Ubiquitina-Proteína Ligases/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Pontos de Checagem do Ciclo Celular/genética , Morte Celular/genética , Processos de Crescimento Celular/genética , Amplificação de Genes , Inativação Gênica , Genes p53 , Terapia Genética/métodos , Células HEK293 , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Fragmentos de Peptídeos/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas de Ligação a Retinoblastoma/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Transfecção , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...