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1.
Nat Commun ; 12(1): 4917, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389714

RESUMO

APOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.


Assuntos
Citidina Desaminase/genética , Dano ao DNA , Regulação da Expressão Gênica , Imunidade/genética , Proteínas/genética , Transdução de Sinais/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Citidina Desaminase/metabolismo , Interações Hospedeiro-Patógeno , Humanos , Proteínas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células THP-1 , Fator de Transcrição RelA/metabolismo , Regulação para Cima , Vírus/crescimento & desenvolvimento
2.
Nat Genet ; 52(9): 884-890, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719516

RESUMO

Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1-5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.


Assuntos
Citidina Desaminase/genética , Exodesoxirribonucleases/genética , Fosfoproteínas/genética , Telômero/genética , Linhagem Celular Tumoral , Cromotripsia , Citosina Desaminase/genética , Instabilidade Genômica/genética , Humanos , Mutação/genética , Neoplasias/genética , Células U937
3.
Front Immunol ; 10: 569, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30972064

RESUMO

The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Linfócitos Intraepiteliais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Ácido Valproico/farmacologia , Acetilação , Linhagem Celular Tumoral , Proteínas Ligadas por GPI/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Histonas/metabolismo , Humanos , Memória Imunológica/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ativação Linfocitária/imunologia , Masculino , Células PC-3 , Neoplasias Pancreáticas/imunologia , Neoplasias da Próstata/imunologia
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