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1.
BMB Rep ; 54(9): 482-487, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34488926

RESUMO

Interferon regulatory factors (IRFs) play roles in various biological processes including cytokine signaling, cell growth regulation and hematopoietic development. Although it has been reported that several IRFs are involved in bone metabolism, the role of IRF2 in bone cells has not been elucidated. Here, we investigated the involvement of IRF2 in RANKL-induced osteoclast differentiation. IRF2 overexpression in osteoclast precursor cells enhanced osteoclast differentiation by regulating the expression of NFATc1, a master regulator of osteoclastogenesis. Conversely, IRF2 knockdown inhibited osteoclast differentiation and decreased the NFATc1 expression. Moreover, IRF2 increased the translocation of NF-κB subunit p65 to the nucleus in response to RANKL and subsequently induced the expression of NFATc1. IRF2 plays an important role in RANKL-induced osteoclast differentiation by regulating NF-κB/NFATc1 signaling pathway. Taken together, we demonstrated the molecular mechanism of IRF2 in osteoclast differentiation, and provide a molecular basis for potential therapeutic targets for the treatment of bone diseases characterized by excessive bone resorption. [BMB Reports 2021; 54(9): 482-487].


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fator Regulador 2 de Interferon/metabolismo , Osteogênese/efeitos dos fármacos , Ligante RANK/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Núcleo Celular/metabolismo , Fator Regulador 2 de Interferon/antagonistas & inibidores , Fator Regulador 2 de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fatores de Transcrição NFATC/metabolismo , Osteoclastos/citologia , Osteoclastos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Fator de Transcrição RelA/metabolismo
2.
Biosci Rep ; 38(3)2018 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-29599126

RESUMO

Interferon regulatory factors (IRFs) are a group of closely related proteins collectively referred to as the IRF family. Members of this family were originally recognized for their roles in inflammatory responses; however, recent research has suggested that they are also involved in tumor biology. This review focusses on current knowledge of the roles of IRF-1 and IRF-2 in human cancer, with particular attention paid to the impact of IRF-1 inactivation. The different mechanisms underlying IRF-1 inactivation and their implications for human cancers and the potential importance of IRF-1 in immunotherapy are also summarized.


Assuntos
Inflamação/genética , Fator Regulador 1 de Interferon/genética , Fator Regulador 2 de Interferon/genética , Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/terapia , Fator Regulador 1 de Interferon/antagonistas & inibidores , Fator Regulador 1 de Interferon/imunologia , Fator Regulador 2 de Interferon/antagonistas & inibidores , Fator Regulador 2 de Interferon/imunologia , Neoplasias/imunologia , Neoplasias/terapia
3.
Int J Biochem Cell Biol ; 95: 113-120, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29275213

RESUMO

MicroRNAs are small endogenous non-coding RNAs, which can frequently emerge as regulators in many cancer types. MiR-1290 was found to be abnormally elevated in non small cell lung cancer (NSCLC). However, the underlying molecular mechanism still needs to be investigated. Here, we demonstrated that miR-1290 expression levels were remarkably upregulated in NSCLC tissues compared to adjacent normal tissues. Higher miR-1290 expression levels positively associated with lymph node metastasis and advanced tumor stage. Functional assays showed that upregulated miR-1290 expression in NSCLC cells enhanced cell proliferation, cell colony formation and invasion capacities in vitro. Furthermore, we found that miR-1290 promoted cell proliferation related protein CDK2 and CDK4 expression and enhanced Epithelial-Mesenchymal Transition (EMT) process by downregulating E-cadherin expression and upregulating N-cadherin expression. Bioinformatics analysis and luciferase reporter gene assays revealed that Interferon regulatory factor 2 (IRF2) was a direct target of miR-1290. Overexpression of miR-1290 can degrade IRF2 mRNA and downregulated IRF2 protein expression in NSCLC cells. Upregulated IRF2 could partly rescue the promoting effects induced by miR-1290 overexpression on cell proliferation and invasion of NSCLC. Additionally, we confirmed that reduced miR-1290 expression could suppress tumor growth using a tumor xenograft model in vivo. Thus, we concluded that miR-1290 may serve as a potential target of NSCLC treatment.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator Regulador 2 de Interferon/antagonistas & inibidores , Neoplasias Pulmonares/metabolismo , Pulmão/metabolismo , MicroRNAs/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Idoso , Animais , Antagomirs/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Feminino , Humanos , Fator Regulador 2 de Interferon/genética , Fator Regulador 2 de Interferon/metabolismo , Pulmão/patologia , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Masculino , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Invasividade Neoplásica/prevenção & controle , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , RNA/antagonistas & inibidores , RNA/metabolismo , RNA Neoplásico/metabolismo , Terapêutica com RNAi , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Cell Death Dis ; 8(5): e2764, 2017 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-28471447

RESUMO

Lung cancer is the major form of cancer resulting in cancer-related mortality around the world. MicroRNAs are endogenous small non-coding single-stranded RNAs, which can engage in the regulation of gene expression. In this study, miR-18a-5p significantly upregulated in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines, suggesting an oncogenic function in lung cancer. Additionally, miR-18a-5p can promote carcinogenesis by directly targeting interferon regulatory factor 2 (IRF2). Further experiments indicated that IRF2 can increase cell apoptosis, inhibit cell proliferation and migration ability. Our study demonstrates that miR-18a-5p promotes autophagy in NSCLC. Collectively, these results indicate that miR-18a-5p can not only promote NSCLC by suppressing IRF2, but also will be a promising target in the near future.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Fator Regulador 2 de Interferon/metabolismo , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , Células A549 , Animais , Antagomirs/metabolismo , Autofagia , Sequência de Bases , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Fator Regulador 2 de Interferon/antagonistas & inibidores , Fator Regulador 2 de Interferon/genética , Antígeno Ki-67/metabolismo , Neoplasias Pulmonares/genética , Camundongos , Camundongos Nus , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Alinhamento de Sequência , Regulação para Cima
5.
Vet Microbiol ; 178(1-2): 41-9, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-25975521

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that contribute to the repertoire of host-pathogen interactions during viral infections. In the current study, miRNA analysis showed that a panel of microRNAs, including gga-miR-9*, were markedly upregulated in specific-pathogen-free (SPF) chickens upon infection with infectious bursal disease virus (IBDV); however, the biological function of gga-miR-9* during viral infection remains unknown. Using a TCID50 assay, it was found that ectopic expression of gga-miR-9* significantly promoted IBDV replication. In turn, gga-miR-9* negatively regulated IBDV-triggered type I IFN production, thus promoting IBDV replication in DF-1 cells. Bioinformatics analysis indicates that the 3' untranslated region (UTR) of interferon regulatory factor 2 (IRF2) has two putative binding sites for gga-miR-9*. Targeting of IRF2 3'UTR by gga-miR-9* was determined by luciferase assay. Functional overexpression of gga-miR-9*, using gga-miR-9* mimics, inhibited IRF2 mRNA and protein expression. Transfection of the gga-miR-9* inhibitor abolished the suppression of IRF2 protein expression. Furthermore, IRF2 knockdown mediated the enhancing effect of gga-miR-9* on the type I IFN-mediated antiviral response. These findings indicate that inducible gga-miR-9* feedback negatively regulates the host antiviral innate immune response by suppressing type I IFN production via targeting IRF2.


Assuntos
Infecções por Birnaviridae/veterinária , Galinhas , Imunidade Inata/imunologia , Vírus da Doença Infecciosa da Bursa/imunologia , Interferon Tipo I/antagonistas & inibidores , MicroRNAs/farmacologia , Doenças das Aves Domésticas/imunologia , Doenças das Aves Domésticas/virologia , Animais , Antivirais/imunologia , Infecções por Birnaviridae/imunologia , Técnicas de Silenciamento de Genes/veterinária , Interações Hospedeiro-Patógeno/imunologia , Vírus da Doença Infecciosa da Bursa/genética , Fator Regulador 2 de Interferon/antagonistas & inibidores , Fator Regulador 2 de Interferon/genética , Luciferases , MicroRNAs/genética , Replicação Viral/fisiologia
6.
Int J Oncol ; 33(1): 175-83, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18575764

RESUMO

Interferon regulatory factor (IRF) 1 and its functional antagonist IRF2 were originally discovered as transcription factors that regulate the interferon-beta gene. Control of cell growth has led to the definition of IRF1 as a tumour suppressor gene and IRF2 as an oncogene. Clinically, approximately 70% of cases of acute myeloid leukaemia demonstrate dysregulated expression of IRF1 and/or IRF2. Our previous studies have shown that human leukaemic TF-1 cells exhibit abnormally high expression of both IRF1 and IRF2, the latter acting to abrogate IRF1 tumour suppression, making these cells ideal for analysis of down-regulation of IRF2 expression. A novel G418 screening protocol was developed and used for identifying effective siRNA that targets IRF2 (siIRF2). Using optimized siIRF2 in leukaemic TF-1 cells, IRF2 was down-regulated by approximately 70% at both mRNA and protein levels. Phenotypically, this resulted in growth inhibition associated with G2/M arrest as well as induction of polyploidy, differentiation and apoptosis. In contrast to these results, siIRF2 targeting did not affect normal haematopoietic stem/progenitor cell growth. These results indicate the potential utility of IRF2 inhibition as a therapeutic approach to cancer.


Assuntos
Fator Regulador 2 de Interferon/antagonistas & inibidores , Leucemia/terapia , RNA Interferente Pequeno/genética , Antígenos CD34/análise , Ciclo Celular , Linhagem Celular Tumoral , Hematopoese , Humanos , Fator Regulador 2 de Interferon/genética , Leucemia/patologia , Receptores de Lipopolissacarídeos/análise
7.
Biochem Biophys Res Commun ; 370(3): 519-24, 2008 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-18395009

RESUMO

Nuclear Factor-kappa B (NF-kappaB) is a transcription factor essential to the control of cell proliferation, survival, differentiation, immune response, and inflammation. Constitutive NF-kappaB activation has been observed in a broad variety of solid tumors and hematological malignancies, which suggests that NF-kappaB signaling may perform a critical role in the development of human cancers. Interferon regulatory factor-2 (IRF-2), an antagonistic transcriptional repressor of IRF-1, evidences oncogenic potential, but little is currently known regarding the mechanism underlying the oncogenic activities of IRF-2. In this study, we report that IRF-2 recruits RelA/p65 transcription factors into the nucleus via physical interaction. While the nuclear recruitment of RelA by IRF-2 augments TNFalpha-induced NF-kappaB dependent transcription, the N-terminal truncated mutant form of IRF-2 inhibits the nuclear localization of RelA, and thus interferes with NF-kappaB activation. Furthermore, the knockdown of IRF-2 by IRF-2 siRNA attenuates TNFalpha-induced NF-kappaB dependent transcription by inhibiting the nuclear localization of RelA. Thus, these results show that IRF-2 regulates NF-kappaB activity via the modulation of NF-kappaB subcellular localization.


Assuntos
Núcleo Celular/metabolismo , Fator Regulador 2 de Interferon/metabolismo , Fator de Transcrição RelA/metabolismo , Transcrição Gênica , Linhagem Celular , Núcleo Celular/química , Humanos , Fator Regulador 2 de Interferon/antagonistas & inibidores , Fator Regulador 2 de Interferon/genética , RNA Interferente Pequeno/genética , Deleção de Sequência , Fator de Transcrição RelA/análise , Transcrição Gênica/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
8.
Int J Cancer ; 120(1): 39-47, 2007 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17036321

RESUMO

We previously identified a 1.2 Kb DNA element (P-1161/+16), 5' to caspase-8 exon-1, that acts as promoter in caspase-8-positive, but not in caspase-8-negative neuroblastoma (NB) cells. The P-1161/+16 DNA element regulates both constitutive and interferon IFN-gamma-inducible caspase-8 expression. Two GAS (IFN-activated sequence, STAT-1 binding site) and two ISRE (interferon sensitive response element, IRF binding site) were present in P-1161/+16. Deletion studies indicated that elements essential for promoter activity in NB cells were present in a 167 bp region 5' flanking exon-1 (P-151/+16), which contains an ISRE at position -32. The transcription initiation site was mapped by 5' rapid amplification of cDNA end (RACE) at position -20 from caspase-8 cDNA reference sequence. Disruption of the ISRE-32 indicated that it is required for both constitutive and IFN-gamma-inducible caspase-8 expression. IRF-1 and IRF-2 transcription factors bind to the (-151/+16) DNA fragment in vitro. Chromatin immunoprecipitation (ChIP) assays showed that IRF-1 and IRF-2 bind to the DNA region at the 5' of caspase-8 gene in NB cells, which show constitutive expression but not in caspase-8 negative cells. In these last cells, up-regulation of caspase-8 by IFN-gamma was associated to induction of IRF-1 and IRF-2 binding to caspase-8 promoter and increased histone acetylation. Moreover, RNA interference experiments also supported the involvement of IRF-1 and IRF-2 in constitutive caspase-8 expression in NB cells.


Assuntos
Antivirais/farmacologia , Caspase 8/genética , Regulação Neoplásica da Expressão Gênica , Interferon gama/farmacologia , Neuroblastoma/genética , Elementos de Resposta/genética , Sequência de Bases , Sítios de Ligação , Caspase 8/metabolismo , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Deleção de Genes , Humanos , Fator Regulador 1 de Interferon/antagonistas & inibidores , Fator Regulador 1 de Interferon/genética , Fator Regulador 1 de Interferon/metabolismo , Fator Regulador 2 de Interferon/antagonistas & inibidores , Fator Regulador 2 de Interferon/genética , Fator Regulador 2 de Interferon/metabolismo , Dados de Sequência Molecular , Neuroblastoma/enzimologia , Neuroblastoma/patologia , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Homologia de Sequência do Ácido Nucleico , Transcrição Gênica , Ativação Transcricional , Regulação para Cima
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