Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 27
Filtrar
1.
Circ Res ; 125(9): 834-846, 2019 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-31495264

RESUMO

RATIONALE: Pathogenic variations in the lamin gene (LMNA) cause familial dilated cardiomyopathy (DCM). LMNA insufficiency caused by LMNA pathogenic variants is believed to be the basic mechanism underpinning LMNA-related DCM. OBJECTIVE: To assess whether silencing of cardiac Lmna causes DCM and investigate the role of Yin Yang 1 (Yy1) in suppressing Lmna DCM. METHODS AND RESULTS: We developed a Lmna DCM mouse model induced by cardiac-specific Lmna short hairpin RNA. Silencing of cardiac Lmna induced DCM with associated cardiac fibrosis and inflammation. We demonstrated that upregulation of Yy1 suppressed Lmna DCM and cardiac fibrosis by inducing Bmp7 expression and preventing upregulation of Ctgf. Knockdown of upregulated Bmp7 attenuated the suppressive effect of Yy1 on DCM and cardiac fibrosis. However, upregulation of Bmp7 alone was not sufficient to suppress DCM and cardiac fibrosis. Importantly, upregulation of Bmp7 together with Ctgf silencing significantly suppressed DCM and cardiac fibrosis. Mechanistically, upregulation of Yy1 regulated Bmp7 and Ctgf reporter activities and modulated Bmp7 and Ctgf gene expression in cardiomyocytes. Downregulation of Ctgf inhibited TGF-ß (transforming growth factor-ß)/Smad signaling in DCM hearts. Regulation of both Bmp7 and Ctgf further suppressed TGFß/Smad signaling. In addition, co-modulation of Bmp7 and Ctgf reduced CD3+ T cell numbers in DCM hearts. CONCLUSIONS: Our findings demonstrate that upregulation of Yy1 or co-modulation of Bmp7 and Ctgf offer novel therapeutic strategies for the treatment of DCM caused by LMNA insufficiency.


Assuntos
Proteína Morfogenética Óssea 7/biossíntese , Cardiomiopatias/metabolismo , Cardiomiopatias/prevenção & controle , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Fator de Transcrição YY1/biossíntese , Animais , Proteína Morfogenética Óssea 7/genética , Cardiomiopatias/genética , Fator de Crescimento do Tecido Conjuntivo/genética , Endotélio Vascular/metabolismo , Fibrose/genética , Fibrose/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição YY1/genética
2.
J Immunol ; 203(3): 627-638, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31227579

RESUMO

The promyelocytic leukemia zinc-finger transcription factor (PLZF) is essential for nearly all of the unique, innate-like functions and characteristics of NKT cells. It is not known, however, if the activity of PLZF is regulated by other factors. In this article, we show that the function of PLZF is completely dependent on the transcription factor Yin Yang 1 (YY1). Mouse NKT cells expressing wild-type levels of PLZF, but deficient for YY1, had developmental defects, lost their characteristic "preformed" mRNA for cytokines, and failed to produce cytokine protein upon primary activation. Immunoprecipitation experiments showed that YY1 and PLZF were coassociated. Taken together, these biochemical and genetic data show that the broadly expressed transcription factor, YY1, is required for the cell-specific "master regulator" functions of PLZF.


Assuntos
Células T Matadoras Naturais/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica/metabolismo , Fator de Transcrição YY1/genética , Animais , Citocinas/biossíntese , Citocinas/genética , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/biossíntese , Fator de Transcrição YY1/biossíntese
3.
Drug Resist Updat ; 30: 28-38, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28363333

RESUMO

Several gene products have been postulated to mediate inherent and/or acquired anticancer drug resistance and tumor metastasis. Among these, the metastasis suppressor and chemo-immuno-sensitizing gene product, Raf Kinase Inhibitor Protein (RKIP), is poorly expressed in many cancers. In contrast, the metastasis inducer and chemo-immuno-resistant factor Yin Yang 1 (YY1) is overexpressed in many cancers. This inverse relationship between RKIP and YY1 expression suggests that these two gene products may be regulated via cross-talks of molecular signaling pathways, culminating in the expression of different phenotypes based on their targets. Analyses of the molecular regulation of the expression patterns of RKIP and YY1 as well as epigenetic, post-transcriptional, and post-translational regulation revealed the existence of several effector mechanisms and crosstalk pathways, of which five pathways of relevance have been identified and analyzed. The five examined cross-talk pathways include the following loops: RKIP/NF-κB/Snail/YY1, p38/MAPK/RKIP/GSK3ß/Snail/YY1, RKIP/Smurf2/YY1/Snail, RKIP/MAPK/Myc/Let-7/HMGA2/Snail/YY1, as well as RKIP/GPCR/STAT3/miR-34/YY1. Each loop is comprised of multiple interactions and cascades that provide evidence for YY1's negative regulation of RKIP expression and vice versa. These loops elucidate potential prognostic motifs and targets for therapeutic intervention. Chiefly, these findings suggest that targeted inhibition of YY1 by specific small molecule inhibitors and/or the specific induction of RKIP expression and activity are potential therapeutic strategies to block tumor growth and metastasis in many cancers, as well as to overcome anticancer drug resistance. These strategies present potential alternatives for their synergistic uses in combination with low doses of conventional chemo-immunotherapeutics and hence, increasing survival, reducing toxicity, and improving quality of life.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias/tratamento farmacológico , Proteína de Ligação a Fosfatidiletanolamina/biossíntese , Fator de Transcrição YY1/biossíntese , Apoptose , Humanos , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
4.
Biochem Biophys Res Commun ; 460(4): 996-1001, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25839654

RESUMO

Hepcidin is a peptide hormone secreted in the liver and plays a key role in maintaining iron homeostasis. Here, we demonstrate that B-cell translocation gene 2 (BTG2) is a key player in hepatic hepcidin regulation via induction of Yin Yang 1 (YY1). Hepatic hepcidin gene expression significantly enhanced by fasting states and glucagon exposure led to induction of gluconeogenic gene expression, and elevated serum hepcidin production in mice. Notably, overexpression of BTG2 using adenoviral system (Ad-BTG2) significantly elevated serum hepcidin levels via a significant induction of YY1 gene transcription. Immunoprecipitation studies demonstrated that BTG2 physically interacted with YY1 and recruited on the hepcidin gene promoter. Finally, ablation of hepatic BTG2 gene by gene silencing markedly attenuated the elevation of serum hepcidin production along with YY1 and hepcidin mRNA expression in fasting state. Likewise, forskolin (FSK)-stimulated hepcidin promoter activity was dramatically disrupted by endogenous BTG2 knockdown. Overall, our current study provides a novel molecular mechanism of BTG2-mediated induction of hepcidin gene expression, thereby contributing to a better understanding of the hepatic hepcidin production involved in iron homeostasis.


Assuntos
Hepcidinas/biossíntese , Proteínas Imediatamente Precoces/fisiologia , Proteínas Supressoras de Tumor/fisiologia , Fator de Transcrição YY1/biossíntese , Animais , Sequência de Bases , Linhagem Celular Transformada , Primers do DNA , Gluconeogênese , Hepcidinas/genética , Proteínas Imediatamente Precoces/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética
5.
Biomolecules ; 11(2)2021 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-33498722

RESUMO

The HPC-1/syntaxin 1A (Stx1a) gene, which is involved in synaptic transmission and neurodevelopmental disorders, is a TATA-less gene with several transcription start sites. It is activated by the binding of Sp1 and acetylated histone H3 to the -204 to +2 core promoter region (CPR) in neuronal cell/tissue. Furthermore, it is depressed by the association of class 1 histone deacetylases (HDACs) to Stx1a-CPR in non-neuronal cell/tissue. To further clarify the factors characterizing Stx1a gene silencing in non-neuronal cell/tissue not expressing Stx1a, we attempted to identify the promoter region forming DNA-protein complex only in non-neuronal cells. Electrophoresis mobility shift assays (EMSA) demonstrated that the -183 to -137 OL2 promoter region forms DNA-protein complex only in non-neuronal fetal rat skin keratinocyte (FRSK) cells which do not express Stx1a. Furthermore, the Yin-Yang 1 (YY1) transcription factor binds to the -183 to -137 promoter region of Stx1a in FRSK cells, as shown by competitive EMSA and supershift assay. Chromatin immunoprecipitation assay revealed that YY1 in vivo associates to Stx1a-CPR in cell/tissue not expressing Stx1a and that trichostatin A treatment in FRSK cells decreases the high-level association of YY1 to Stx1a-CPR in default. Reporter assay indicated that YY1 negatively regulates Stx1a transcription. Finally, mass spectrometry analysis showed that gene silencing factors, including HDAC1, associate onto the -183 to -137 promoter region together with YY1. The current study is the first to report that Stx1a transcription is negatively regulated in a cell/tissue-specific manner by YY1 transcription factor, which binds to the -183 to -137 promoter region together with gene silencing factors, including HDAC.


Assuntos
Regulação da Expressão Gênica , Inativação Gênica , Histona Desacetilases/genética , Regiões Promotoras Genéticas , Sintaxina 1/biossíntese , Fator de Transcrição YY1/biossíntese , Animais , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Inibidores de Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Espectrometria de Massas , Ratos , Proteínas Repressoras/metabolismo
6.
Int J Biol Sci ; 17(7): 1629-1643, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994849

RESUMO

Long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) plays important roles in the pathogenesis and progression of cancers. However, the role of SNHG12 in the metastasis of gastric cancer (GC) has not yet been thoroughly investigated. In the present study, we demonstrated that SNHG12 was upregulated in GC tissues and cell lines. In addition, the expression level of SNHG12 in GC samples was significantly related to tumor invasion depth, TNM stage and lymph node metastasis and was associated with disease-free survival (DFS) and overall survival (OS) in GC patients. In vivo and in vitro assays indicated that SNHG12 promotes GC metastasis and epithelial-mesenchymal transition (EMT). Bioinformatics and mechanistic analyses revealed that SNHG12 can directly target miR-218-5p to regulate YWHAZ mRNA, forming an SNHG12/miR-218-5p/YWHAZ axis and decreasing the ubiquitination of ß-catenin. In addition, SNHG12 stabilizes CTNNB1 mRNA by binding with HuR, thus activating the ß-catenin signaling pathway. Further analysis also revealed that the transcription factor YY1 negatively modulates SNHG12 transcription. In conclusion, SNHG12 is a potential prognostic marker and therapeutic target for GC. Negatively modulated by YY1, SNHG12 promotes GC metastasis and EMT by regulating the miR-218-5p/YWHAZ axis and stabilizing CTNNB1 via activation of the ß-catenin signaling pathway.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/genética , Regulação para Cima , Fator de Transcrição YY1/genética , Idoso , Apoptose , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , RNA Longo não Codificante/biossíntese , RNA Neoplásico/genética , Estudos Retrospectivos , Transdução de Sinais , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/secundário , Fator de Transcrição YY1/biossíntese
7.
Neurotoxicology ; 86: 94-103, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34310962

RESUMO

Dysregulation of the astrocytic glutamate transporter excitatory amino acid transporter 2 (EAAT2) is associated with several neurological disorders, including Parkinson's disease, Alzheimer's disease, and manganism, the latter induced by chronic exposure to high levels of manganese (Mn). Mechanisms of Mn-induced neurotoxicity include impairment of EAAT2 function secondary to the activation of the transcription factor Yin Yang 1 (YY1) by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). However, the upstream mechanisms by which Mn-induced NF-κB activates YY1 remain to be elucidated. In the present study, we used the H4 human astrocyte cell line to test if Mn activates YY1 through the canonical NF-κB signaling pathway, leading to EAAT2 repression. The results demonstrate that Mn exposure induced phosphorylation of the upstream kinase IκB kinase (IKK-ß), leading to NF-κB p65 translocation, increased YY1 promoter activity, mRNA/protein levels, and consequently repressed EAAT2. Results also demonstrated that Mn-induced oxidative stress and subsequent TNF-α production were upstream of IKK-ß activation, as antioxidants attenuated Mn-induced TNF-α production and IKK-ß activation. Moreover, TNF-α inhibition attenuated the Mn-induced activation of IKK-ß and YY1. Taken together, Mn-induced oxidative stress and TNF-α mediates activation of NF-κB signaling and YY1 upregulation, leading to repression of EAAT2. Thus, targeting reactive oxygen species (ROS), TNF-α and IKK-ß may attenuate Mn-induced YY1 activation and consequent EAAT2 repression.


Assuntos
Astrócitos/metabolismo , Transportador 2 de Aminoácido Excitatório/biossíntese , Quinase I-kappa B/metabolismo , Manganês/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição YY1/biossíntese , Astrócitos/efeitos dos fármacos , Células Cultivadas , Transportador 2 de Aminoácido Excitatório/antagonistas & inibidores , Humanos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologia
8.
J Cancer Res Clin Oncol ; 147(3): 755-765, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33315124

RESUMO

PURPOSE: The transcription factors YY1 and CP2 have been associated with tumor promotion and suppression in various cancers. Recently, simultaneous expression of both markers was correlated with negative prognosis in cancer. The aim of this study was to explore the expression of YY1 and CP2 in head and neck squamous cell carcinoma (HNSCC) patients and their association with survival. METHODS: First, we analyzed mRNA expression and copy number variations (CNVs) of YY1 and CP2 using "The Cancer Genome Atlas" (TCGA) with 510 HNSCC patients. Secondly, protein expression was investigated via immunohistochemistry in 102 patients, who were treated in the Vienna General Hospital, utilizing a tissue microarray. RESULTS: The median follow-up was 2.9 years (1.8-4.6) for the TCGA cohort and 10.3 years (6.5-12.8) for the inhouse tissue micro-array (TMA) cohort. The median overall survival of the TCGA cohort was decreased for patients with a high YY1 mRNA expression (4.0 vs. 5.7 years, p = 0.030, corr. p = 0.180) and high YY1-CNV (3.53 vs. 5.4 years, p = 0.0355, corr. p = 0.213). Furthermore, patients with a combined high expression of YY1 and CP2 mRNA showed a worse survival (3.5 vs. 5.4 years, p = 0.003, corr. p = 0.018). The mortality rate of patients with co-expression of YY1 and CP2 mRNA was twice as high compared to patients with low expression of one or both (HR 1.99, 95% CI 1.11-3.58, p = 0.021). Protein expression of nuclear YY1 and CP2 showed no association with disease outcome in our inhouse cohort. CONCLUSION: Our data indicate that simultaneous expression of YY1 and CP2 mRNA is associated with shorter overall survival. Thus, combined high mRNA expression might be a suitable prognostic marker for risk stratification in HNSCC patients. However, since we could not validate this finding at genomic or protein level, we hypothesize that unknown underlying mechanisms which regulate mRNA transcription of YY1 and CP2 are the actual culprits leading to a worse survival.


Assuntos
Proteínas de Ligação a DNA/genética , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição/genética , Fator de Transcrição YY1/genética , Biomarcadores Tumorais , Proteínas de Ligação a DNA/biossíntese , Bases de Dados Genéticas , Feminino , Dosagem de Genes , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Análise Serial de Tecidos , Fatores de Transcrição/biossíntese , Fator de Transcrição YY1/biossíntese
9.
Breast Cancer Res ; 11(6): R90, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20025767

RESUMO

INTRODUCTION: Candidacy for anti-HER2 adjuvant therapy in breast cancer is assessed using tumour HER2 status but recently it has been proposed that the transcription factors AP-2alpha and YY1 may cause Her2 protein overexpression independently of gene amplification. METHODS: We characterised AP-2alpha/beta, AP-2alpha and YY1 with HER2 gene and protein expression, other relevant biomarkers, and clinical outcome using tissue microarrays (TMAs) and immunohistochemistry in a large (n = 1,176) clinically annotated series of early stage operable breast cancer. The associations and prognostic independence of AP-2 and YY1 was assessed in all patients and an oestrogen receptor negative subgroup. RESULTS: Nuclear expression of AP-2alpha/beta, AP-2alpha and YY1 was detected in 23%, 44% and 33% of cases respectively. AP-2alpha/beta significantly correlated with YY1 and both markers were increased in luminal oestrogen receptor (ER) positive tumours of small size and low grade but only AP-2alpha/beta correlated with good prognosis breast cancer specific survival and disease free interval (BCSS and DFI). These characteristics were lost in oestrogen receptor negative patients. AP-2alpha also correlated with luminal-type tumours but not with YY1 expression or good prognosis. AP-2alpha and YY1 showed a significant correlation with Her2 protein expression and in addition, YY1 correlated with HER2 gene expression. Discordant HER2 gene and protein expression was identified in six cases (0.71% of the study group) with four of these showing AP-2alpha but absence of AP-2alpha/beta and YY1 expression. CONCLUSIONS: AP-2alpha/beta and YY1 are markers of good prognosis principally due to their association with oestrogen receptor but are not independent predictors. Discordant HER2 protein/gene expression is a rare event that is not always explained by the actions of AP-2 and YY1.


Assuntos
Neoplasias da Mama/genética , Receptor ErbB-2/genética , Fator de Transcrição AP-2/biossíntese , Fator de Transcrição YY1/biossíntese , Adulto , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Análise em Microsséries , Pessoa de Meia-Idade , Isoformas de Proteínas , Receptor ErbB-2/biossíntese , Receptores de Estrogênio/biossíntese , Fator de Transcrição AP-2/genética , Transcrição Gênica , Fator de Transcrição YY1/genética
10.
Cancer Res ; 67(10): 4816-26, 2007 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-17510411

RESUMO

HLJ1 is a novel tumor and invasion suppressor that inhibits tumorigenesis and cancer metastasis. However, the mechanism of HLJ1 activation is currently unclear. Here, we identify an enhancer segment in the HLJ1 gene at -2,125 to -1,039 bp upstream of the transcription start site. A 50-bp element between -1,492 and -1,443 bp is the minimal enhancer segment, which includes the activator protein 1 (AP-1) site (-1,457 to -1,451 bp), an essential regulatory domain that binds the transcriptional factors FosB, JunB, and JunD. Chromatin immunoprecipitation assays confirm that these AP-1 family members bind to a specific site in the HLJ1 enhancer segment in vivo. Overexpression of either YY1 at promoter or AP-1 at enhancer results in a 3-fold increase in the transcriptional activity of HLJ1. We propose a novel mechanism whereby expression of the tumor suppressor, HLJ1, is up-regulated via enhancer AP-1 binding to promoter YY1 and the coactivator, p300, through DNA bending and multiprotein complex formation. The combined expression of AP-1 and YY1 enhances HLJ1 expression by more than five times and inhibits in vitro cancer cell invasion. Elucidation of the regulatory mechanism of HLJ1 expression may facilitate the development of personalized therapy by inhibiting cancer cell proliferation, angiogenesis, and metastasis.


Assuntos
Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Proteínas de Choque Térmico HSP40/genética , Fator de Transcrição AP-1/genética , Fator de Transcrição YY1/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Sequência de Bases , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Elementos Facilitadores Genéticos , Proteínas de Choque Térmico HSP40/biossíntese , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-jun/biossíntese , Proteínas Proto-Oncogênicas c-jun/genética , Fator de Transcrição AP-1/metabolismo , Ativação Transcricional , Transfecção , Regulação para Cima , Fator de Transcrição YY1/biossíntese , Fator de Transcrição YY1/metabolismo
11.
Biochimie ; 157: 184-194, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30481541

RESUMO

Long noncoding RNAs (lncRNAs) are frequently implicated in various cancers. However, the significances of lncRNAs in nasopharyngeal carcinoma (NPC) are largely unclear. In this study, we identified a novel lncRNA nasopharyngeal carcinoma copy number amplified transcript-1 (NPCCAT1), whose expression is increased in NPC tissues compared with nasopharyngeal normal tissues. Furthermore, we found the genomic copy number of NPCCAT1 is amplified in NPC, which contributes to the upregulation of NPCCAT1 in NPC. Functional experiments demonstrated that overexpression of NPCCAT1 promotes NPC cell growth and migration in vitro and NPC tumor growth in vivo. Knockdown of NPCCAT1 suppresses NPC cell grow and migration. Mechanistically, we found that NPCCAT1 directly binds YY1 mRNA 5'UTR, promotes YY1 mRNA translation, and upregulates YY1 protein level. Gain-of-function and loss-of-function assays revealed that YY1 promoted NPC cell proliferation and migration. Moreover, rescue assays showed that depletion of YY1 attenuated the roles of NPCCAT1 overexpression in promoting NPC cell growth and migration in vitro and NPC tumor growth in vivo. Overall, our study identified NPCCAT1 as an oncogenic lncRNA which promotes NPC progression via upregulating YY1, and suggested that lncRNA NPCCAT1 may be a promising therapeutic target for NPC.


Assuntos
Regulação Neoplásica da Expressão Gênica , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Neoplasias/biossíntese , RNA Longo não Codificante/metabolismo , RNA Neoplásico/metabolismo , Regulação para Cima , Fator de Transcrição YY1/biossíntese , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteínas de Neoplasias/genética , RNA Longo não Codificante/genética , RNA Neoplásico/genética , Fator de Transcrição YY1/genética
12.
Arthritis Res Ther ; 21(1): 134, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159863

RESUMO

BACKGROUND: We previously found that high-mobility group box protein 1 (HMGB1) promoted cell proliferation, migration, invasion, and autophagy in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), but little is known about its regulatory mechanism. The aim of this study was to investigate the regulatory mechanism of HMGB1 at the posttranscription level. METHODS: Real-time qPCR, CCK-8 cell proliferation assay, transwell cell migration assay, enzyme-linked immunosorbent assay (ELISA), and western blotting were used in this study. The targeting relationship between miRNA and mRNA was presented by the luciferase reporter assay. RESULTS: MiR-449a was downregulated in RA synovial tissue and inhibited RA-FLS proliferation, migration, and IL-6 production. MiR-449a directly targeted HMGB1 and inhibited its expression. Yin Yang 1(YY1) negatively regulated miR-449a expression and formed a mutual inhibition loop in RA-FLS. MiR-449a inhibited TNFα-mediated HMGB1 and YY1 overexpression and IL-6 production. CONCLUSIONS: Our results reveal the regulatory mechanism of HMGB1 in RA and demonstrate that miR-449a is a crucial molecule in RA pathogenesis and a suitable candidate for miRNA replacement therapies in RA.


Assuntos
Artrite Reumatoide/genética , Regulação da Expressão Gênica , Proteína HMGB1/genética , Inflamação/genética , MicroRNAs/genética , Sinoviócitos/patologia , Fator de Transcrição YY1/genética , Idoso , Apoptose , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Western Blotting , Movimento Celular , Proliferação de Células , Células Cultivadas , Ensaio de Imunoadsorção Enzimática , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteína HMGB1/biossíntese , Humanos , Inflamação/metabolismo , Inflamação/patologia , Masculino , MicroRNAs/biossíntese , Pessoa de Meia-Idade , RNA/genética , Sinoviócitos/metabolismo , Fator de Transcrição YY1/biossíntese
13.
Metabolism ; 96: 33-45, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31028762

RESUMO

BACKGROUND: Renal fibrosis promotes the development of diabetic nephropathy (DN). A growing number of studies have reported that Yin Yang 1 (YY1), which is involved in cellular proliferation and differentiation, plays a crucial role in the pathogenesis of many diseases, such as pulmonary fibrosis, hepatic steatosis and cancer. METHODS: We detected the expression of YY1 under various glucose concentration and time gradient conditions. Rapamycin was used to verify the mTORC1/p70S6K/YY1 signaling pathway in HK-2 cells. We used db/db mice to examine the connection between renal fibrosis and YY1. A luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to identify whether YY1 directly regulated α-SMA by binding to the α-SMA promoter. RNA silencing and overexpression were performed by using a YY1 expression/knockdown plasmid to investigate the function of YY1 in renal fibrosis of DN. RESULTS: YY1 expression and subsequent nuclear translocation were upregulated in a glucose- and time-dependent manner via the mTORC1/p70S6K signaling pathway in HK-2 cells. YY1 expression and nuclear translocation was significantly upregulated in db/db mice. Furthermore, YY1 upregulated α-SMA expression and activity in high-glucose-cultured HK-2 cells. Overexpression of YY1 promoted renal fibrosis in db/m mice mainly by upregulating α-SMA expression and inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Finally, downregulation of YY1 reversed renal fibrosis by improving EMT in vivo and in vitro. CONCLUSIONS: These results reveal that upregulation of YY1 plays a critical role in HG-induced deregulation of EMT-associated protein expression, which finally results in renal fibrosis of DN. Therefore, decreasing YY1 expression might represent a new therapeutic target for diabetic nephropathy-induced renal fibrosis.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Fator de Transcrição YY1/efeitos dos fármacos , Actinas/metabolismo , Animais , Linhagem Celular , Nefropatias Diabéticas/complicações , Nefropatias Diabéticas/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Fibrose , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Glucose/farmacologia , Humanos , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/efeitos dos fármacos , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Transporte Proteico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição YY1/biossíntese , Fator de Transcrição YY1/genética
14.
Breast Cancer Res ; 10(1): R9, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18218085

RESUMO

INTRODUCTION: Overexpression of the ERBB2 oncogene is observed in about 20% of human breast tumors and is the consequence of increased transcription rates frequently associated with gene amplification. Several studies have shown a link between activator protein 2 (AP-2) transcription factors and ERBB2 gene expression in breast cancer cell lines. Moreover, the Yin Yang 1 (YY1) transcription factor has been shown to stimulate AP-2 transcriptional activity on the ERBB2 promoter in vitro. In this report, we examined the relationships between ERBB2, AP-2alpha, and YY1 both in breast cancer tissue specimens and in a mammary cancer cell line. METHODS: ERBB2, AP-2alpha, and YY1 protein levels were analyzed by immunohistochemistry in a panel of 55 primary breast tumors. ERBB2 gene amplification status was determined by fluorescent in situ hybridization. Correlations were evaluated by a chi2 test at a p value of less than 0.05. The functional role of AP-2alpha and YY1 on ERBB2 gene expression was analyzed by small interfering RNA (siRNA) transfection in the BT-474 mammary cancer cell line followed by real-time reverse transcription-polymerase chain reaction and Western blotting. RESULTS: We observed a statistically significant correlation between ERBB2 and AP-2alpha levels in the tumors (p < 0.01). Moreover, associations were found between ERBB2 protein level and the combined high expression of AP-2alpha and YY1 (p < 0.02) as well as between the expression of AP-2alpha and YY1 (p < 0.001). Furthermore, the levels of both AP-2alpha and YY1 proteins were inversely correlated to ERBB2 gene amplification status in the tumors (p < 0.01). Transfection of siRNAs targeting AP-2alpha and AP-2gamma mRNAs in the BT-474 breast cancer cell line repressed the expression of the endogenous ERBB2 gene at both the mRNA and protein levels. Moreover, the additional transfection of an siRNA directed against the YY1 transcript further reduced the ERBB2 protein level, suggesting that AP-2 and YY1 transcription factors cooperate to stimulate the transcription of the ERBB2 gene. CONCLUSION: This study highlights the role of both AP-2alpha and YY1 transcription factors in ERBB2 oncogene overexpression in breast tumors. Our results also suggest that high ERBB2 expression may result either from gene amplification or from increased transcription factor levels.


Assuntos
Neoplasias da Mama/metabolismo , Genes erbB-2/genética , Fator de Transcrição AP-2/biossíntese , Fator de Transcrição YY1/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Fator de Transcrição AP-2/genética , Fator de Transcrição YY1/genética
15.
Eur Rev Med Pharmacol Sci ; 21(15): 3377-3383, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28829505

RESUMO

OBJECTIVE: It has been well-established that microRNAs (miRNAs), a class of short non-coding RNA molecules, play an important role in the development of gastric cancer. In the present study, we focused on miR-105, a novel miRNA not previously linked to gastric cancer. PATIENTS AND METHODS: 36 paired surgically resected gastric cancer tissues and matched adjacent normal tissues were used to detect the expression of miR-105. AGS cells were used to overexpress or silence of miR-105 and to determine its effect on several tumorigenic properties. A cell proliferation enzyme-linked immunosorbent assay was used to analyze the incorporation of BrdU during DNA synthesis of AGS cells. Total cDNA from AGS cells was used to amplify the 3'-UTR of YY1 by PCR and luciferase activity was determined using the Dual-Luciferase Reporter Assay System RESULTS: We found that expression of miR-105 was reduced in gastric cancer tissues, compared with adjacent normal tissues, due to hypermethylation at its promoter region. Overexpression of miR-105 suppressed, whereas its inhibition promoted cell viability and proliferation. We further identified Yin Yang 1 (YY1) as a direct target of miR-105, by which miR-105 exerted its anti-proliferative role. Moreover, we found that DNMT3A was responsible for the down-regulation of miR-105 in gastric cancer cells. CONCLUSIONS: Our data demonstrate that miR-105 inhibits gastric cancer cell proliferation and progression, which might provide a therapeutical target for cancer therapy.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , MicroRNAs/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regiões 3' não Traduzidas/genética , Linhagem Celular Tumoral , Proliferação de Células , DNA Metiltransferase 3A , Regulação para Baixo/genética , Inativação Gênica , Genes p53/genética , Humanos , Fator de Transcrição YY1/biossíntese , Fator de Transcrição YY1/genética
16.
Mol Med Rep ; 15(5): 2433-2442, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28447715

RESUMO

Multiple organ dysfunction (MOD) is a lethal complication in children with sepsis. Apoptosis of several cell types is involved in this process, and it is associated with increased Fas cell surface death receptor (Fas) expression. As YY1 transcription factor (YY1) negatively regulates the expression of Fas in cancer models, and is associated with the clinical outcome, it may be important in MOD. The present study aimed to determine the association between the expression of Fas, YY1 and apoptosis in children with sepsis, and its association with MOD, these factors were analyzed in 30 pediatric patients that had been diagnosed with sepsis. Peripheral blood mononuclear cells were purified from patients, and YY1 and Fas protein expression was assessed by immunocytochemistry. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick­end labeling. Sepsis was monitored using clinical parameters, pediatric logistic organ dysfunction (PELOD) score and the pediatric mortality index. The results demonstrated that Fas expression was directly correlated with apoptosis levels and the expression of YY1 was inversely correlated with apoptosis levels. Patients with high levels of apoptosis exhibited increased disease severity and poor clinical outcome. Notably, the findings of the present study demonstrated that there were higher survival rates in patients with high YY1 expression, compared with those with low YY1 expression. Additionally, patients with MOD exhibited lower proportions of apoptotic cells compared with sepsis patients without MOD. Furthermore, the PELOD score was positively correlated with Fas and inversely correlated with YY1 expression. Finally, high apoptosis and low YY1 expression were prognostic factors associated with poor survival rates. These data suggested that YY1 may be important for apoptosis induction via the regulation of Fas during sepsis. Therefore, Fas may be a potential therapeutic target to prevent MOD through regulation of YY1 expression. Furthermore, YY1 and Fas expression in PBMCs may be used to as prognostic markers.


Assuntos
Apoptose , Regulação da Expressão Gênica , Leucócitos Mononucleares/metabolismo , Insuficiência de Múltiplos Órgãos/sangue , Sepse/sangue , Fator de Transcrição YY1/biossíntese , Receptor fas/biossíntese , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Leucócitos Mononucleares/patologia , Masculino , Insuficiência de Múltiplos Órgãos/mortalidade , Insuficiência de Múltiplos Órgãos/patologia , Sepse/mortalidade , Sepse/patologia
17.
Oncotarget ; 8(15): 24389-24400, 2017 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-28412749

RESUMO

Recent studies have demonstrated an oncogenic role of the transcription factor (TF) CP2c in hepatocellular carcinoma (HCC) based on a strong correlation between CP2c expression, tumor grade, and aggressiveness. We recently found that CP2c directly interacts with another TF, YY1, which is also overexpressed in multiple cancers, including HCC. To evaluate if these proteins are co-regulated in carcinogenesis, we analyzed the expression of CP2c and YY1 in HCC (n = 136) tissues and examined the correlation between their expression and clinicopathological characteristics of HCC. Receiver operating characteristic analysis exhibited the validity of CP2c and nuclear YY1 expression as a diagnostic factor in HCC tissues. High expression of CP2c was significantly correlated with patient age, and higher histological grade, American Joint Committee on Cancer (AJCC) stage, and small and large vessel invasion in HCC tissues, whereas high expression of nuclear YY1 was significantly associated with higher AJCC stage and small vessel invasion. In univariate and multivariate analyses, high expression of CP2c was significantly correlated with disease free survival (DFS), indicating that CP2c expression is an independent prognostic factor for DFS in HCC patients. Patients with high expression of both CP2c and nuclear YY1 usually had a shorter median survival time and worse DFS prognosis than other patients, suggesting that combined detection of CP2c and nuclear YY1 is a useful prognostic marker in HCC patients.


Assuntos
Carcinoma Hepatocelular/metabolismo , Proteínas de Ligação a DNA/biossíntese , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição/biossíntese , Fator de Transcrição YY1/biossíntese , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Transcrição/genética , Fator de Transcrição YY1/genética
18.
Biotechnol J ; 10(7): 1019-28, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25612069

RESUMO

Transient gene expression (TGE) in CHO cells is utilized to produce material for use in early stage drug development. These systems typically utilize the cytomegalovirus (CMV) promoter to drive recombinant gene transcription. In this study, we have mechanistically dissected CMV-mediated TGE in CHO cells in order to identify the key regulators of this process. An in silico analysis of the promoter composition of transcription factor regulatory elements (TFREs) and the CHO cell repertoire of transcription factors identified eight TFREs as likely effectors of CMV activity. We determined the regulatory function of these elements by preventing their cognate transcription factors from binding at the CMV promoter. This was achieved by both scrambling promoter binding site sequences and using decoy molecules to sequester intracellular transcription factors. We determined that the vast majority of CMV activity is mediated by just two discrete TFREs, showing that simultaneous inhibition of NF-κB and CRE-mediated transactivation reduced CMV-driven transient secreted alkaline phosphatase (SEAP) production by over 75%. Further, we identified a mechanism by which CMV-mediated TGE is negatively regulated in CHO cells, showing that inhibition of YY1-mediated transrepression increased SEAP production 1.5-fold. This work enables optimization and control of CMV-mediated TGE in CHO cells, in order to improve transient protein production yields.


Assuntos
Fosfatase Alcalina/biossíntese , Células CHO , NF-kappa B/genética , Transcrição Gênica , Fator de Transcrição YY1/genética , Fosfatase Alcalina/genética , Animais , Sítios de Ligação , Cricetinae , Cricetulus , Citomegalovirus/genética , Descoberta de Drogas , Expressão Gênica , Integrases/genética , Regiões Promotoras Genéticas , Fator de Transcrição YY1/biossíntese
19.
Oncol Rep ; 34(1): 311-7, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25954903

RESUMO

Esophageal squamous cell carcinoma (ESCC), one of the most common gastrointestinal tumors, is known for its high mortality rate. microRNAs (miRNAs) have been reported to play important regulatory roles in cancer metastasis and progression. miR-34a has been demonstrated to be associated with the development of and metastasis in certain types of cancer via various target genes, but its function and targets in ESCC are unknown. The aim of this study was to examine whether the expression of miR-34a was significantly decreased in ESCC tissues, compared with normal esophageal tissues using RT-PCR and western blot analysis. The results showed that miR-34a overexpression increased apoptosis and decreased clonogenic formation, but inhibited invasion and migration in ESCC cells by suppressing MMP-2 and -9 expression. Yin Yang-1 (YY1), a widely distributed transcription factor that belongs to the GLI-Kruppel class of zinc finger proteins, was found to be a direct target of miR-34a in ESCC cell lines. Rescue experiments indicated that the suppressive effect of miR-34a on invasion and migration was mediated by activating YY1 expression. Results of the present study showed that miR-34a is associated with ESCC migration and provides a potential therapeutic and diagnostic target for ESCC.


Assuntos
Carcinoma de Células Escamosas/genética , Proliferação de Células/genética , Neoplasias Esofágicas/genética , MicroRNAs/genética , Fator de Transcrição YY1/genética , Apoptose , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , MicroRNAs/metabolismo , Invasividade Neoplásica/genética , Fator de Transcrição YY1/biossíntese
20.
Curr Cancer Drug Targets ; 15(2): 145-57, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25817371

RESUMO

Yin Yang 1 (YY1) is a multifunctional protein regulating both gene transcription and protein modifications. Recent studies reveal a proliferative role of YY1 in oncogenesis. Consistently, YY1 overexpression has been observed in various human malignancies and its levels correlate with poor prognoses of many types of cancers. In this review, we focus on the signaling pathways and regulatory proteins that YY1 modulates to promote tumor cell growth, proliferation, migration and metastasis. We also discuss the signals and molecules that regulate YY1 expression and function in cancer-related context. Based on the expression feature and regulatory activities in tumor cells, YY1 possesses a great potential as a biomarker for many cancers and can serve as a therapeutic target clinically to impede cancer development and progression or sensitize cancer cells to anticancer drugs.


Assuntos
Antineoplásicos/administração & dosagem , Carcinogênese/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/metabolismo , Fator de Transcrição YY1/biossíntese , Animais , Biomarcadores/metabolismo , Carcinogênese/efeitos dos fármacos , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Fator de Transcrição YY1/antagonistas & inibidores
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA