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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(5): 1496-1503, 2020 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-33067944

RESUMO

OBJECTIVE: To explore the correlation of SOCS1 gene methylation with the activity of JAK2/STAT signaling pathway, genesis and progress of acute myeloid leukemia. METHODS: Several techniques, such as cell culture, qPCR, MS-PCR, Western bolt, CCK-8 assay, flow cytometry and gene transfection were used to analyze the relation of expression and methylation statues of SOCS1 gene with the genesis and progression of AML in 120 AML patients and leukemia cell lines U937 and THP-1, at the same time to analyze the changes of downstream protein expression in JAK2/STAT signaling pathway and their effect on the growth and apoptosis of leukemia cell lines. RESULTS: The positive rate of WT1/ABL in SOCS1 methylated group was significantly higher than that in SOCS1 non-methylated group, and the complete remission rate of one course treatment in SOCS1-methylated group was significantly lower than that in SOCS1 non-methylated group. The expression level of SOCS1 gene in low methylation rate group was higher, and the expression of down-stream proteins p-JAK2, p-STAT3 and p-STAT5 in JAK2/STAT signaling pathway decreased, while the expression of t-JAK2,t-STAT3 and t-STAT5 was not changed statistically significantly. The growth rate of leukemia cells graduated decreased, and the apoptosis rate of leukemia cells graduated increased along with the enhancement of methylation drug concentration. CONCLUSION: The methylation of SOCS1 gene results in the gene silencing, thereby declines its inhibition on the down-stream proteins in JAK2/STAT signaling pathway, and finally promotes the growth and proliferation of AML cells.


Assuntos
Leucemia Mieloide Aguda , Apoptose , Humanos , Janus Quinase 2 , Leucemia Mieloide Aguda/genética , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo
2.
Nat Commun ; 11(1): 2866, 2020 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-32513959

RESUMO

The Cullin 5 (CUL5) Ring E3 ligase uses adaptors Elongins B and C (ELOB/C) to bind different SOCS-box-containing substrate receptors, determining the substrate specificity of the ligase. The 18-member ankyrin and SOCS box (ASB) family is the largest substrate receptor family. Here we report cryo-EM data for the substrate, creatine kinase (CKB) bound to ASB9-ELOB/C, and for full-length CUL5 bound to the RING protein, RBX2, which binds various E2s. To date, no full structures are available either for a substrate-bound ASB nor for CUL5. Hydrogen-deuterium exchange (HDX-MS) mapped onto a full structural model of the ligase revealed long-range allostery extending from the substrate through CUL5. We propose a revised allosteric mechanism for how CUL-E3 ligases function. ASB9 and CUL5 behave as rigid rods, connected through a hinge provided by ELOB/C transmitting long-range allosteric crosstalk from the substrate through CUL5 to the RBX2 flexible linker.


Assuntos
Creatina Quinase/metabolismo , Microscopia Crioeletrônica , Elonguina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/química , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Regulação Alostérica , Creatina Quinase/ultraestrutura , Proteínas Culina/química , Proteínas Culina/metabolismo , Elonguina/ultraestrutura , Humanos , Modelos Moleculares , Ligação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Relação Estrutura-Atividade , Especificidade por Substrato , Proteínas Supressoras da Sinalização de Citocina/ultraestrutura , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo
3.
Mol Immunol ; 121: 195-203, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32298923

RESUMO

Cells recognize virus nucleic acid by pattern recognition receptors (PRRs), virus involve in the activation of signaling cascade of variable adaptor proteins, TANK-binding kinase1(TBK1)/ inhibitor of nuclear factor kappa-B kinase subunit epsilon(IKKi) complex, IκB kinase(IKKs) to trigger activation of transcription factor, interferon regulatory factor 3/7(IRF3/7), ultimately, leading to the production of type I interferon and exert anti-viral effects. In this study, E3 ubiquitin ligase ankyrin repeat and SOCS box-containing 8(ASB8) interacted with TBK1/IKKi and phosphorylation modification of ASB8 at site of Ser17 to further strengthen its ubiquitination activity were verified. Conversely, phosphorylated ASB8 accelerate K48-linked ubiquitination and degradation of TBK1/IKKi, which further reduces phosphorylation level of IRF3 and inhibits production of IFN-ß. At the same time, a new bridge molecule Leucine-rich repeat containing protein 10B(LRRC10B) upregulated after viral infection are involved in the formation and interaction with ASB8-TBK1/IKKi complex was reported. Our study reveals a new mechanism of ubiquitin ligase ASB8 modulating antiviral innate immunity by altering stability of TBK1/IKKi kinase complex.


Assuntos
Quinase I-kappa B/metabolismo , Interferon beta/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Células HEK293 , Células HeLa , Humanos , Quinase I-kappa B/imunologia , Imunidade Inata , Fator Regulador 3 de Interferon/metabolismo , Fator Regulador 7 de Interferon/metabolismo , Interferon beta/imunologia , Fosforilação/imunologia , Proteínas Serina-Treonina Quinases/imunologia , RNA Interferente Pequeno/metabolismo , Serina/metabolismo , Transdução de Sinais/imunologia , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/imunologia , Ubiquitina-Proteína Ligases/imunologia , Ubiquitinação/imunologia
4.
Biomed Res Int ; 2020: 2430640, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149091

RESUMO

Enterovirus 71 (EV71) is the causative pathogen of hand, foot, and mouth disease (HFMD). However, no effective antiviral therapy is currently available. Some viruses could escape the host's innate immunity by upregulating suppressor of cytokine signaling (SOCS) proteins. Until now, whether EV71 evades the host immune system by regulating the expression of SOCS proteins remains unknown. In this study, we found that EV71 infection promoted SOCS expression at both mRNA and protein levels in vitro and in vivo. Consistently, the infectivity of EV71 was decreased significantly in the SOCS3 or SOCS1 knockdown cells, suggesting that SOCS1 and especially SOCS3 are crucial for EV71 infection. Further investigation showed that SOCS3 promoted virus infection by inhibiting interferon-induced STAT3 phosphorylation. SOCS1 and SOCS3 mRNA expressions were independent on virus-induced type I interferon expression but were blocked by the inhibitor of NF-κB. Therefore, EV71 infection stimulates the expression of SOCS proteins in an interferon-independent way and negatively regulates the JAK/STAT signaling pathway, thus escaping host immunity. All these results may add new information to the mechanism of EV71 in fighting against type I interferon responses.


Assuntos
Infecções por Enterovirus/metabolismo , Enterovirus/efeitos dos fármacos , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Proteínas Supressoras da Sinalização de Citocina/farmacologia , Replicação Viral/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Infecções por Enterovirus/imunologia , Imunidade Inata/imunologia , Interferon Tipo I/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , RNA Mensageiro , Receptor de Interferon alfa e beta/genética , Proteína 1 Supressora da Sinalização de Citocina , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Regulação para Cima
5.
Comp Biochem Physiol B Biochem Mol Biol ; 243-244: 110424, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088257

RESUMO

In all eukaryotic organisms, the control of growth, metabolism, reproduction, and lifespan is realized by interactions of genetic and environmental signals. An important player in the regulatory network is the target of rapamycin (TOR) signaling pathway, which is triggered by nutritional cues. Given the pivotal role of TOR in regulating multiple processes in organisms, we inhibited TOR by inducible expression of specific RNAi in Drosophila intestinal stem and progenitor cells or progenitor cells alone. We found that TOR inhibition in stem and progenitor cells shortened the lifespan on both regular diet and under malnutrition. Moreover, flies became more short-lived under starvation or oxidative stress conditions if TOR was inhibited. TOR-RNAi expression resulted in a decrease in body glycogen and TAG levels. All these physiological and metabolic changes might be partially explained by significant changes in mRNA levels for genes encoding the Drosophila insulin-like peptides (dilp2, dilp3 and dilp5) with subsequent effects on insulin signaling to modulate gene expression in peripheral tissues (e.g. tobi and pepck transcripts). In the gut, a strong increase in transcript levels of cytokines upd2, upd3 and downstream target socs36e of the JAK/STAT signaling pathway in the gut indicate an important role for this signaling pathway when TOR is inhibited.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Longevidade/genética , Transdução de Sinais/genética , Células-Tronco/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Animais , Drosophila/fisiologia , Proteínas de Drosophila/genética , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Glicogênio/metabolismo , Insulinas/metabolismo , Janus Quinases/metabolismo , Longevidade/fisiologia , Neuropeptídeos/metabolismo , Estresse Oxidativo , Interferência de RNA , Fatores de Transcrição STAT/metabolismo , Inanição/genética , Inanição/metabolismo , Inanição/fisiopatologia , Células-Tronco/fisiologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Serina-Treonina Quinases TOR/genética , Triglicerídeos/metabolismo
6.
Endocrinology ; 161(2)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31875887

RESUMO

The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway has cell-specific functions. Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of JAK-STAT signaling. STAT5 plays a significant role in adipocyte development and function, and bromodomain and extraterminal (BET) proteins may be involved in STAT5 transcriptional activity. We treated 3T3-L1 adipocytes with the BET inhibitor JQ1 and observed that growth hormone (GH)-induced expression of 2 STAT5 target genes from the SOCS family, Socs3 and Cish, were inversely regulated (increased and decreased, respectively) by BET inhibition. Chromatin immunoprecipitation analyses revealed that changes in STAT5 binding did not correlate with gene expression changes. GH promoted the recruitment of the BET protein BRD2 to the Cish, but not Socs3, promoter. JQ1 treatment ablated this effect as well as the GH-induced binding of ribonucleic acid polymerase II (RNA Pol II) to the Cish transcription start site. BRD2 knockdown also suppressed GH induction of Cish, further supporting the role of BRD2 in Cish transcriptional activation. In contrast, JQ1 increased the binding of activated Pol II to the Socs3 coding region, suggesting enhanced messenger RNA (mRNA) elongation. Our finding that JQ1 transiently reduced the interaction between the positive transcription elongation factor (P-TEFb) and its inhibitor hexamethylene bis-acetamide inducible 1 (HEXIM1) is consistent with a previously described off-target effect of JQ1, whereby P-TEFb becomes more available to be recruited by genes that do not depend on BET proteins for activating transcription. These results demonstrate substantially different transcriptional regulation of Socs3 and Cish and suggest distinct roles in adipocytes for these 2 closely related proteins.


Assuntos
Adipócitos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Proteínas Nucleares/antagonistas & inibidores , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Animais , Azepinas , Camundongos , Fator B de Elongação Transcricional Positiva/metabolismo , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Triazóis
7.
Med Sci Monit ; 25: 10122-10128, 2019 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-31884511

RESUMO

BACKGROUND MicroRNA (miR)-106a was involved in the tumorigenesis and highly expressed in gastric cancer. Required apatinib resistance greatly limits its efficacy in patients. Thus, the aim of the present study was to investigate the potential role of miR-106a-3p in gastric cancer cells with apatinib-resistance. MATERIAL AND METHODS The expression of miR-106a-3p was quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Cell Counting Kit-8 (CCK-8) assay was performed to analyze the sensitivity of gastric cancer cells to apatinib. The expression of relevant drug-resistant proteins was detected by western blot. We searched Targetscan6.2 to find out the target gene of miR-106a-3p. Luciferase reporter assay was used to analyze whether miR-106a-3p bound to relevant gene of SOCS family. The SOCS2, SOCS4, and SOCS5 were qualified by western blot, and their mRNA levels were detected by RT-qPCR. Further, JAK2, STAT3, and their phosphorylation levels were detected by western blot. RESULTS The results showed that the expression of miR-106a-3p was increased in apatinib­resistant gastric cancer, while miR-106a-3p inhibitor reduced the drug-resistance of SGC-7901-AP cells to apatinib. Dual luciferase reporter gene assay suggested that SOCS2, SOCS4, and SOCS5 were target genes of miR-106a-3p. The relevant SOCS genes silencing reversed the effects of miR-106a-3p inhibitor on decreasing the apatinib resistance of SGC-7901-AP cells, while the phosphorylation level of JAK and STAT reduced by miR-106a-3p inhibitor were increased. CONCLUSIONS miR-106a-3p induces apatinib resistance and activates JAK2/STAT3 by targeting SOCS system in gastric cancer. miR-106a-3p/SOCS plays a potent role in gastric cancer cell resistance to apatinib.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Janus Quinase 2/metabolismo , MicroRNAs/metabolismo , Piridinas/farmacologia , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Sequência de Bases , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/genética , Fosforilação/efeitos dos fármacos , Neoplasias Gástricas/patologia , Proteínas Supressoras da Sinalização de Citocina/genética
8.
Mediators Inflamm ; 2019: 1769374, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772499

RESUMO

Intraperitoneal adhesion is a common complication after abdominal surgery, which seriously affects the quality of life of patients. HuoXueTongFu Formula (HXTF) plays an important role in the prevention and treatment of intraperitoneal adhesions. However, the molecular-related mechanisms are still not fully known. In this study, the model of Intrapetitoneal adhesion was established by cecum abrasion and treated with HXTF for one week. RAW264.7 cells were given LPS, IFN-γ, IL-4, HXTF-medicated serum, and PPAR-γ agonist/antagonist, respectively. Histopathology, flow cytometry, ELISA, real-time PCR, and Western blotting were used to further detect the related protein, M1/M2 polarization tendency, and PPAR-γ nuclear translocation. The deposition of collagen fibres reduced in the local area of rats after the operation with HXTF treatment. Similar to IL-4, HXTF induced a tendency for macrophages to polarize toward M2 and promoted peroxisome proliferator-activated receptor-gamma (PPAR-γ) nuclear translocation. Furthermore, the use of HXTF and PPAR-γ agonists downregulated macrophage M1 polarization-related factors IL-1, IL-6, and TNF-alpha and upregulated M2 polarization-related factors IL-4, IL-10, and TGF-beta 1. Meanwhile, the use of HXTF and PPAR-γ agonists downregulated the SOCS3/JAK2/STAT1 pathway and activated the SOCS1/STAT6/PPAR-γ pathway. These results show that HXTF may reduce intraperitoneal adhesion by inducing macrophage M2 polarization and regulating the SOCS/JAK2/STAT/PPAR-γ pathway.


Assuntos
Janus Quinase 2/metabolismo , Macrófagos/metabolismo , PPAR gama/metabolismo , Extratos Vegetais/farmacologia , Fator de Transcrição STAT1/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Western Blotting , Polaridade Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citometria de Fluxo , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-4/metabolismo , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Qualidade de Vida , Células RAW 264.7 , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775389

RESUMO

Dendritic cells (DCs) regulate immunity and inflammation and respond to various stimuli, including cytokines. IL-1ß is a key cytokine in the course of both acute and chronic inflammatory responses, making it indispensable for protection of the host, but also linking it to several diseases. Thus, IL-1ß signaling must be tightly regulated. As suppressor of cytokine signaling (SOCS) proteins effectively control immune responses, we investigated the role of SOCS2 in IL-1ß-induced DC activation. Human monocyte-derived DCs were stimulated with IL-1ß, and SOCS2 mRNA and protein levels were measured. DC activation was assessed by cytokine secretion and surface marker expression. For functional analysis, small interfering RNA (siRNA)-based SOCS2 silencing was performed. SOCS2 expression was also analyzed in a curated NCBI GEO dataset of myeloid leukemia patients. We found IL-1ß to be a potent inducer of SOCS2 expression. By silencing SOCS2, we showed that SOCS2 specifically limits IL-1ß-induced IL-8 secretion. Moreover, our analysis revealed that SOCS2 levels are significantly increased in patients with acute and chronic myeloid leukemia, two hematological malignancies where disease progression is closely linked to IL-1ß. This study identifies SOCS2 as a novel IL-1ß-inducible target gene and points toward a potential role of SOCS2 in IL-1ß-mediated DC activation.


Assuntos
Células Dendríticas/imunologia , Interleucina-1beta/farmacologia , Ativação Linfocitária/imunologia , Monócitos/imunologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Humanos , Ativação Linfocitária/efeitos dos fármacos , Monócitos/citologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/genética
10.
Int J Mol Sci ; 20(21)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31653116

RESUMO

: Non-alcoholic fatty liver disease (NAFLD) is a major public health problem in many countries. In this study, the ability of Grifola frondosa heteropolysaccharide (GFP) to ameliorate NAFLD was investigated in rats fed a high-fat diet (HFD). The molecular mechanisms modulating the expression of specific gene members related to lipid synthesis and conversion, cholesterol metabolism, and inflammation pathways were determined. The components of the intestinal microflora in rats were analyzed by high-throughput next-generation 16S rRNA gene sequencing. Supplementation with GFP significantly increased the proportions of Allobaculum, Bacteroides, and Bifidobacterium and decreased the proportions of Acetatifactor, Alistipes, Flavonifractor, Paraprevotella, and Oscillibacter. In addition, Alistipes, Flavonifractor, and Oscillibacter were shown to be significant cecal microbiota according to the Spearman's correlation test between the gut microbiota and biomedical assays (|r| > 0.7). Histological analysis and biomedical assays showed that GFP treatments could significantly protect against NAFLD. In addition, Alistipes, Flavonifractor, and Oscillibacter may play vital roles in the prevention of NAFLD. These results suggest that GFP could be used as a functional material to regulate the gut microbiota of NAFLD individuals.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Grifola/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Polissacarídeos/farmacologia , Animais , Bacteroides/genética , Bacteroides/isolamento & purificação , Bacteroidetes/genética , Bacteroidetes/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Polissacarídeos/uso terapêutico , RNA Ribossômico 16S/metabolismo , Ratos , Ratos Wistar , Esteroide 12-alfa-Hidroxilase/genética , Esteroide 12-alfa-Hidroxilase/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo
11.
Shanghai Kou Qiang Yi Xue ; 28(3): 237-240, 2019 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-31489408

RESUMO

PURPOSE: To investigate the protective effect and mechanism of resveratrol on oxidative stress of MC3T3-E1. METHODS: The levels of reactive oxygen species in the cells were observed by fluorescence microscope and flow cytometry. The expression of SOCS-1 protein was detected by Western blot. SOCS-1 transient transfected cell line was established, and the levels of reactive oxygen species in transfected cells were observed by fluorescence microscopy and flow cytometry. The data were analyzed using SPSS22.0 software package. RESULTS: The level of ROS in LPS group was significantly higher than that in the blank group and LPS+RES group (P<0.05). The expression level of SOCS-1 protein was increased after LPS stimulation for 30 min (P<0.05). The level of ROS in the siSOCS-1+LPS+RES group was significantly higher than that in the untransfected group (P<0.05). CONCLUSIONS: Resveratrol may counteract LPS-mediated oxidative stress in MC3T3E1 cells by modulating SOCS-1 protein.


Assuntos
Estresse Oxidativo , Resveratrol , Estilbenos , Proteínas Supressoras da Sinalização de Citocina , Linhagem Celular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio , Resveratrol/farmacologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo
12.
Transpl Immunol ; 56: 101228, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31398463

RESUMO

Suppressor of cytokine signaling (SOCS) proteins have acknowledged roles in regulation of immune responses. Moreover, their role in the evolution of allograft rejection is being elucidated. In the current investigation, we measured transcript levels of SOCS1-4 in the peripheral blood of a group of renal transplant recipients including both rejected and non-rejected allografts. Expression analyses showed that relative expression of SOCS2 was significantly higher in transplant-rejected male patients compared to non-rejected group. However, such significant difference was not detected between female subjects. Expression of SOCS2 was significantly higher in T-cell-mediated rejection group compared with non-rejected individuals with creatinine rise (Relative expression difference [95% CrI] =6.74 [0.94, 12.65], P = 0.043). Conversely, SOCS4 expression was significantly lower in T-cell-mediated rejection group compared with non-rejected individuals with creatinine rise (Relative expression difference [95% CrI] = -0.35 [-0.63, -0.1], P = 0.008). Patterns of correlations between expression levels of SOCS genes were different in non-rejected group. The obtained results indicate the role SOCS genes in development of allograft rejection.


Assuntos
Rejeição de Enxerto/genética , Sobrevivência de Enxerto/genética , Transplante de Rim , Rim/fisiologia , Proteínas Supressoras da Sinalização de Citocina/genética , Linfócitos T/imunologia , Adulto , Creatinina/urina , Feminino , Regulação da Expressão Gênica , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Transplante Homólogo , Adulto Jovem
13.
PLoS One ; 14(7): e0219989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31344133

RESUMO

Hepatitis C virus (HCV) replication involves many viral and host factors. Host factor SPRY domain- and SOCS box-containing protein 2(SPSB2) belongs to SPSB family, and it recruits target proteins by the SPRY domain and forms E3 ubiquitin ligase complexes by the SOCS box. As an adaptor protein, it can regulate the host's response to infection, but little is known about whether SPSB2 plays a role in HCV replication. In the present study, we found that HCV infection significantly upregulated the mRNA and protein levels of SPSB2 in HCVcc-infected cells. Exogenous expression of SPSB2 in hepatoma cells decreased HCV RNA and protein levels which depended on the SOCS box, while knockdown of endogenous SPSB2 increased HCV RNA and protein levels. Additionally, we demonstrated that SPSB2 interacted with HCV structural protein E1 and nonstructural protein protein 5A (NS5A) via the C-terminal portion of the SPSB2 SPRY domain. Furthermore, SPSB2 induced NS5A ubiquitination and mediated NS5A degradation. Collectively, this study discovered host factor SPSB2 significantly inhibits HCV replication by interacting and degrading NS5A.


Assuntos
Hepacivirus/fisiologia , Hepatite C/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Células HEK293 , Hepatite C/genética , Humanos , Ligação Proteica , Proteólise , Proteínas Supressoras da Sinalização de Citocina/química , Proteínas Supressoras da Sinalização de Citocina/genética , Ubiquitinação , Regulação para Cima , Replicação Viral
14.
Skelet Muscle ; 9(1): 19, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31230596

RESUMO

BACKGROUND: Sexually dimorphic growth has been attributed to the growth hormone (GH)/insulin-like growth factor 1 (IGF1) axis, particularly GH-induced activation of the intracellular signal transducer and activator of transcription 5B (STAT5B), because deletion of STAT5B reduces body mass and the mass of skeletal muscles in male mice to that in female mice. However, it remains unclear why these effects are sex- and species-specific, because the loss of STAT5B retards growth in girls, but not in male mice. Our objectives were to determine whether sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice and investigate the mechanisms by which STAT5B regulates sexually dimorphic growth. METHODS: Blood and skeletal muscle were harvested from male and female STAT5B-/- mice and their wild-type littermates from the onset of puberty to adulthood. RESULTS: Growth of the skeleton and skeletal muscles was retarded in both sexes of STAT5B-/- mice, but more so in males. Although reduced, sexually dimorphic growth of skeletal muscle persisted in STAT5B-/- mice with an oxidative shift in the composition of myofibres in both sexes. Concentrations of IGF1 in blood and skeletal muscle were reduced in male STAT5B-/- mice at all ages, but only in female STAT5B-/- mice at the onset of puberty. Expression of androgen receptor (AR) and oestrogen receptor alpha (ERα) mRNA and protein was reduced in skeletal muscles of male and female STAT5B-/- mice, respectively. Loss of STAT5B abolished the sexually dimorphic expression of myostatin protein and Igf1, Ar, Erα, suppressor of cytokine signalling 2 (Socs2), and cytokine-inducible SH2-containing protein (Cis) mRNA in skeletal muscle. CONCLUSIONS: STAT5B appears to mediate GH signalling in skeletal muscles of male mice at all ages, but only until puberty in female mice. STAT5B also appears to mediate the actions of androgens and oestrogens in both male and female mice, but sexually dimorphic growth persists in STAT5B-/- mice.


Assuntos
Desenvolvimento Muscular/fisiologia , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Fator de Transcrição STAT5/metabolismo , Fatores Etários , Animais , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Desenvolvimento Muscular/genética , Miostatina/genética , Miostatina/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fator de Transcrição STAT5/deficiência , Fator de Transcrição STAT5/genética , Caracteres Sexuais , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo
15.
Acta Crystallogr F Struct Biol Commun ; 75(Pt 6): 412-418, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31204687

RESUMO

The SPRY domain-containing SOCS box protein 2 (SPSB2) is one of four mammalian SPSB proteins that are characterized by a C-terminal SOCS box and a central SPRY/B30.2 domain. SPSB2 interacts with inducible nitric oxide synthase (iNOS) via the SPRY domain and polyubiquitinates iNOS, resulting in its proteasomal degradation. Inhibitors that can disrupt SPSB2-iNOS interaction and augment NO production may serve as novel anti-infective and anticancer agents. The previously determined murine SPSB2 structure may not reflect the true apo conformation of the iNOS-binding site. Here, the crystal structure of human SPSB2 SPRY domain in the apo state is reported at a resolution of 1.9 Å. Comparison of the apo and ligand-bound structures reveals that the iNOS-binding site is highly preformed and that major conformational changes do not occur upon ligand binding. Moreover, the C-terminal His6 tag of the recombinant protein binds to a shallow pocket adjacent to the iNOS-binding site on a crystallographically related SPSB2 molecule. These findings may help in structure-based and fragment-based SPSB2 inhibitor design in the future.


Assuntos
Apoproteínas/química , Apoproteínas/metabolismo , Modelos Moleculares , Óxido Nítrico Sintase Tipo II/metabolismo , Proteínas Supressoras da Sinalização de Citocina/química , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Sequência de Aminoácidos , Domínio B30.2-SPRY , Cristalografia por Raios X , Humanos , Óxido Nítrico Sintase Tipo II/química , Conformação Proteica
16.
Biochemistry (Mosc) ; 84(4): 329-345, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31228925

RESUMO

The review describes functional and structural features of different isoforms of prolactin receptor, mechanisms of signaling pathway activation, and molecular messengers involved in the transmission and termination of signal from the prolactin receptor isoforms. Changes in the ratio between prolactin receptor isoforms, key mediators of prolactin signal transduction and termination in various organs and tissues, are analyzed. Special attention is given to the role of molecular mediators and the ratio between the isoforms in normal physiological functions and pathologies. Approaches for therapeutic correction of prolactin signaling impairments are discussed.


Assuntos
Prolactina/metabolismo , Receptores da Prolactina/metabolismo , Animais , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Inibidoras de STAT Ativados/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores da Prolactina/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Proteínas Supressoras da Sinalização de Citocina/metabolismo
17.
Life Sci ; 231: 116549, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200002

RESUMO

BACKGROUND: Long non-coding RNA (lncRNA) is emerging as an important regulator in various physiological and pathological processes. Recently, it was found that lncRNA long non-coding RNA tumor suppressor candidate 7 (TUSC7) could play tumor suppressive roles in several cancers. However, the function and underlying regulatory mechanism of lncRNA TUSC7 in endometrial carcinoma (EC) remains largely unclear. METHODS: The expression levels of TUSC7 and microRNAs-616 (miR-616) were analyzed by real-time PCR and in situ hybridization. Cell cycle and cell metastasis associated protein expressions were determined by western blotting. Cell proliferation, cycle and metastasis were determined by CCK-8 cell viability, colony formation, flow cytometer, wound scratch and transwell assays respectively in vitro. RNA pull-down, luciferase and western blotting assays were used to examine the target relationship between TUSC7 and miR-616 or that between miR-616 and suppressors of cytokine signaling 4 (5) (SOCS4 (SOCS5)). The functional effects of TUSC7 through sponging miR-616 were further examined using a xenograft tumor mouse model in vivo. RESULTS: TUSC7 was downexpressed in EC tissues and cell lines, and TUSC7 upregulation could remarkably inhibit cell proliferation, cycle progression and metastasis in EC cells. Mechanistic investigations demonstrated that TUSC7 can interact with miR-616 and decrease its expression, thereby upregulating the expression of miR-616's targets SOCS4 (SOCS5). Additionally, in vivo experiments using a xenograft tumor mouse model revealed that TUSC7 can serve as a tumor suppressor through sponging miR-616, and upregulating SOCS4 (SOCS5) in EC. CONCLUSIONS: In this study, a newly identified regulatory mechanism of lncRNA TUSC7/miR-616/ SOCS4 (SOCS5) axis was systematically studied, which may hold promise as a promising target for EC treatment.


Assuntos
Neoplasias do Endométrio/genética , Neoplasias do Endométrio/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Animais , Apoptose , Técnicas de Cultura de Células , Ciclo Celular , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Neoplasias do Endométrio/patologia , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Invasividade Neoplásica , RNA Longo não Codificante/biossíntese , RNA Longo não Codificante/genética , Proteínas Supressoras da Sinalização de Citocina/genética
18.
Int J Biol Sci ; 15(5): 1080-1090, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31182927

RESUMO

Up-regulation of ASB6 has been previously associated with late-stage and poor prognosis of oral squamous cell carcinoma (OSCC) patients. To explore the cellular and molecular basis of how ASB6 enhances the malignancy of OSCC, we employed the clonogenicity and migration assays, murine pulmonary metastasis model, Western blot, and immunofluorescence microscopy to characterize the phenotypes of OSCC cells with lentiviral-based stable overexpression or knockdown of ASB6. We found that ASB6 overexpression increases, whereas ASB6 knockdown decreases, the potential of tumor-sphere formation, colony formation, and expression of Oct-4 and Nanog. While knockdown of ASB6 decreases cell migration in vitro and lung metastasis in mice, the migratory potential was however not promoted by ASB6 overexpression. ASB6 knockdown down-regulates the level of vimentin, and the loss of filopodia formation became more prominent following CRISPR/Cas9-directed knockout of ASB6. Moreover, ASB6 was up-regulated when cells were grown in selective condition featured with a collateral effect of enhancing intracellular stress, and the level of endoplasmic reticulum (ER) stress was further increased by knockdown of ASB6. Thus, ASB6 may attenuate ER stress that would otherwise accumulate and subsequently impede the potential of cells to acquire or sustain the stemness properties and metastatic capacity, thereby enhancing the malignancy of OSCC by increasing the population of cancer stem or stem-like cells.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Animais , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma de Células Escamosas , Linhagem Celular Tumoral , Movimento Celular/genética , Movimento Celular/fisiologia , Estresse do Retículo Endoplasmático/genética , Estresse do Retículo Endoplasmático/fisiologia , Imunofluorescência , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , Microscopia Confocal , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo
19.
Artif Cells Nanomed Biotechnol ; 47(1): 2098-2106, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31144533

RESUMO

Periodontitis refers to the inflammation of gums and the surrounding structures and caused by a bacterial infection. The infection occurs owing to poor oral hygiene and could destroy the bone and the gum over time if left untreated. The present study identified the involvement of a key long noncoding RNA (lncRNA), i.e. FGD5-AS1, in the pathogenesis of periodontitis by assessing its expression in the gingival tissues of patients diagnosed with chronic periodontitis (CP). Overexpression of FGD5-AS1 in primary human periodontal ligament cells (PDLCs) significantly reduced the lipopolysaccharide (LPS)-induced periodontitis, whereas its suppression aggravated this injury. Moreover, the miR-142-3p was markedly expressed in the gingival samples of patients diagnosed with CP and LPS-induced PDLCs. We found that the FGD5-AS1-mediated reduction in the inflammation was mediated through downside regulation of miR-142-3p, as evident from the upregulation of SOCS6, a target gene of miR-142-3p. Furthermore, the association between FGD5-AS1 and NF-κB pathway was detected. FGD5-AS1 was found to protect against LPS-stimulated PDLC injury through restraining the NF-κB signals. Based on these findings, we conclude that up-regulation of lncRNA FGD5-AS1 could protect against periodontitis via regulating the miR-142-3p/SOCS6/NF-κB signals. Therefore, the FGD5-AS1/miR-142-3p/SOCS6 axis may act as an important indicator in explaining the pathogenesis of periodontitis.


Assuntos
Regulação da Expressão Gênica , MicroRNAs/metabolismo , NF-kappa B/metabolismo , Periodontite/genética , Periodontite/metabolismo , RNA Longo não Codificante/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Estudos de Casos e Controles , Gengiva/metabolismo , Gengiva/patologia , Humanos , MicroRNAs/genética , Periodontite/patologia , Transdução de Sinais/genética , Regulação para Cima
20.
Fish Shellfish Immunol ; 90: 102-108, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048038

RESUMO

The suppressor of cytokine signaling (SOCS) family members play crucial roles in regulating immune signal pathways by acting as inhibitors of cytokine receptor signaling. In this study, 10 SOCS genes were identified in soiny mullet (Liza haematocheila), an economically important aquaculture mugilid species in China and other Asian countries. Sequence comparison showed that the sequence identity between mullet SOCSs and their counterparts from other vertebrates ranged from 38.2% to 92.5%. All mullet SOCS genes were constitutively expressed in tissues examined, but their expression patterns were different. Further, following Streptococcus dysgalactiae infection, all mullet SOCS genes exhibited distinct expression patterns in tissues. These results suggest that SOCSs are involved in immune response to bacterial infection and provide the basis for understanding the complex cytokine regulatory network of teleosts.


Assuntos
Doenças dos Peixes/imunologia , Proteínas de Peixes/genética , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Smegmamorpha/genética , Proteínas Supressoras da Sinalização de Citocina/genética , Animais , Proteínas de Peixes/metabolismo , Perfilação da Expressão Gênica/veterinária , Análise de Sequência de DNA/veterinária , Análise de Sequência de Proteína/veterinária , Smegmamorpha/metabolismo , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus/fisiologia , Proteínas Supressoras da Sinalização de Citocina/metabolismo
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