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1.
Biochim Biophys Acta Mol Cell Res ; 1866(9): 1412-1420, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176697

RESUMO

Src is a known proto-oncogene and its aberrant activity is involved in a variety of cancers, including ovarian cancer, whereas the regulatory mechanism of Src has not been fully clarified. In this study, we identified tripartite motif-containing (TRIM) 50 as a novel negative regulator of Src protein. Our data showed that TRIM50 directly interacted with SH3 domain of Src via its B-box domain; and TRIM50 reduced Src stability by inducing RING domain-dependent K48-linked poly-ubiquitous modification. We further demonstrated that TRIM50 acted as a tumor suppressor in ovarian cancer cells by its negative regulation of Src protein. In vivo animal model verified that TRIM50 inhibited the xenograft tumor growth of ovarian cancer by suppressing Src protein. Clinical investigation showed that expression of TRIM50 in clinical specimens was inversely correlated with the clinical stages, pathology grades and lymph node metastatic status of the patients, which indicated the involvement of aberrant TRIM50 expression in disease progression. Further analysis verified the negative correlation between TRIM50 and Src expression in clinical specimens. Altogether, we identified TRIM50 as a novel suppressor of Src protein, and demonstrated that TRIM50 inhibited ovarian cancer progression by targeting Src and reducing its activity, which provided a novel therapeutic strategy for Src over-activated cancers by positive regulation of TRIM50.

2.
Nat Microbiol ; 4(8): 1378-1388, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31110366

RESUMO

Mycobacterium tuberculosis (Mtb)-derived components are usually recognized by pattern recognition receptors to initiate a cascade of innate immune responses. One striking characteristic of Mtb is their utilization of different type VII secretion systems to secrete numerous proteins across their hydrophobic and highly impermeable cell walls, but whether and how these Mtb-secreted proteins are sensed by host immune system remains largely unknown. Here, we report that MPT53 (Rv2878c), a secreted disulfide-bond-forming-like protein of Mtb, directly interacts with TGF-ß-activated kinase 1 (TAK1) and activates TAK1 in a TLR2- or MyD88-independent manner. MPT53 induces disulfide bond formation at C210 on TAK1 to facilitate its interaction with TRAFs and TAB1, thus activating TAK1 to induce the expression of pro-inflammatory cytokines. Furthermore, MPT53 and its disulfide oxidoreductase activity is required for Mtb to induce the host inflammatory responses via TAK1. Our findings provide an alternative pathway for host signalling proteins to sense Mtb infection and may favour the improvement of current vaccination strategies.

3.
Nature ; 563(7729): 131-136, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30356214

RESUMO

Accurate repair of DNA double-stranded breaks by homologous recombination preserves genome integrity and inhibits tumorigenesis. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor that activates innate immunity by initiating the STING-IRF3-type I IFN signalling cascade1,2. Recognition of ruptured micronuclei by cGAS links genome instability to the innate immune response3,4, but the potential involvement of cGAS in DNA repair remains unknown. Here we demonstrate that cGAS inhibits homologous recombination in mouse and human models. DNA damage induces nuclear translocation of cGAS in a manner that is dependent on importin-α, and the phosphorylation of cGAS at tyrosine 215-mediated by B-lymphoid tyrosine kinase-facilitates the cytosolic retention of cGAS. In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1 via poly(ADP-ribose). The cGAS-PARP1 interaction impedes the formation of the PARP1-Timeless complex, and thereby suppresses homologous recombination. We show that knockdown of cGAS suppresses DNA damage and inhibits tumour growth both in vitro and in vivo. We conclude that nuclear cGAS suppresses homologous-recombination-mediated repair and promotes tumour growth, and that cGAS therefore represents a potential target for cancer prevention and therapy.

5.
Clin Lab ; 64(3): 247-256, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29739113

RESUMO

BACKGROUND: The aim was to establish expression profiles of microRNAs (miRNAs) in Peripheral Blood Mononuclear Cells (PBMC) and of plasma cytokines from the patients with hepatitis B virus related acute-on-chronic liver failure (HBV-ACLF) and high-risk of acute-on-chronic liver failure (ACLF) patients as well as healthy people and to examine the relationships between these profiles and clinical features. METHODS: Herein, we collected PBMCs and plasma from peripheral blood of HBV-ACLF and ACLF patients as well as healthy people. Microarray, real-time qPCR, and ELISA assays were used. RESULTS: In this study, we found 39 miRNAs including miR-146a, miR-150, and miR-29a downregulated and 5 miRNAs elevated in PBMCs from HBV-ACLF patients compared to healthy controls. However, elevated plasma levels of cytokines such as TNF-α, IFN-α, and TGF-ß were found in PBMCs from HBV-ACLF patients compared with the controls, but no significant difference was found between the high-risk and control groups. MiR-146a, miR-150, miR-29a, PTA, and anti-HBc were positively correlated with the survival of ACLF patients, while TNFα, IFN-α, INR, and TBiL were negatively correlated with the survival of these patients. CONCLUSIONS: Combined examination of miRNAs in PBMCs and cytokines in plasma together is a better method for monitoring and evaluating HBV-ACLF patients.

6.
Cell Death Dis ; 9(6): 608, 2018 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-29789583

RESUMO

Tripartite motif-containing 50 (TRIM50) belongs to the tripartite motif (TRIM) protein family, which has been implicated in the pathogenesis of multiple cancers. However, the role of TRIM50 in hepatocellular carcinoma (HCC) remains to be clarified. Here we showed that TRIM50 expression was significantly decreased in liver cancer tissues compared with corresponding non-cancerous liver tissues, and its decreased expression was significantly correlated with advanced disease progression. Gain-of-function assay by exogenous overexpression of TRIM50 in HCC cells showed that proliferation, colony formation, migration and invasion of HCC cells were significantly inhibited, whereas loss-of-function assay by TRIM50 knockdown showed that these malignant behaviors of HCC cells were significantly increased. Further investigation showed that TRIM50 could directly bind with SNAIL and induced K-48 linked poly-ubiquitous degradation of SNAIL protein, which further reversed SNAIL-mediated epithelial-to-mesenchymal transition (EMT) process of HCC cells. In vivo assay by xenograft tumor model verified the antitumor effect of TRIM50 on HCC. Taken together, these results showed that TRIM50 acted as a tumor suppressor in HCC cells by directly targeting SNAIL and reversing EMT, which further indicated that positive modulation of TRIM50 might be a novel therapeutic strategy for SNAIL overexpressed HCC cells.

7.
J Infect Dis ; 218(2): 312-323, 2018 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-29228365

RESUMO

Tuberculosis, caused by Mycobacterium tuberculosis infection, remains a global threat to human health, but knowledge of the molecular mechanisms underlying the pathogenesis of tuberculosis is still limited. Although Notch4, a member of the Notch receptor family, is involved in the initiation of mammary tumors, its function in M. tuberculosis infection remains unclear. In this study, we found that Notch4-deficient mice were more resistant to M. tuberculosis infection, with a much lower bacterial burden and fewer pathological changes in the lungs. Notch4 inhibited M. tuberculosis-induced production of proinflammatory cytokines by interaction with TAK1 and inhibition of its activation. Furthermore, we found that Notch intracellular domain 4 prevented TRAF6 autoubiquitination and suppressed TRAF6-mediated TAK1 polyubiquitination. Finally, Notch inhibitors made mice more resistant to M. tuberculosis infection. These results suggest that Notch4 is a negative regulator of M. tuberculosis-induced inflammatory response, and treatment with a Notch inhibitor could serve as a new therapeutic strategy for tuberculosis.

8.
Virol Sin ; 30(3): 174-89, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26122641

RESUMO

Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte (CTL) responses, Toll-like receptor (TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3K, ERK, and mTOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates mTOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, mTOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, mTOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of mTOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which mTOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.


Assuntos
Hepacivirus/imunologia , Vírus da Hepatite B/imunologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Células Th1/imunologia , Receptores Toll-Like/metabolismo , Vacinas Virais/imunologia , Animais , Células Cultivadas , Células Dendríticas/imunologia , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Macrófagos/imunologia , Camundongos
9.
Biomed Chromatogr ; 29(4): 633-40, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25223404

RESUMO

A specific, sensitive and accurate analytical LC-MS/MS assay was developed for the simultaneous determination of two steroidal glycosides, tenacissoside H and tenacissoside I, in rat plasma. An Agilent ZORBAX SB-C18 column was used with an isocratic mobile phase system composed of methanol-water-formic acid (70:30:0.1, v/v/v) at a flow rate of 0.3 mL/min. The analysis was performed on a positive ionization electrospray mass spectrometer via selected reaction monitoring mode scan. One-step protein precipitation with acetonitrile was chosen to extract the analytes from plasma. The lower limits of quantification were 0.9 ng/mL for tenacissoside H and tenacissoside I. The intra- and inter-day precisions were 2.03-11.56 and 3.76-11.62%, respectively, and the accuracies were <110.28% at all quality control levels. The validated method was applied to a pharmacokinetic study in rats after oral gavage of Marsdenia tenacissima extract.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Medicamentos de Ervas Chinesas/farmacocinética , Glicosídeos/sangue , Espectrometria de Massas em Tandem/métodos , Administração Oral , Animais , Medicamentos de Ervas Chinesas/administração & dosagem , Glicosídeos/administração & dosagem , Glicosídeos/farmacocinética , Masculino , Marsdenia , Ratos , Ratos Sprague-Dawley
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