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Purified vascular endothelial cell (EC) growth factor receptor-2 (VEGFR2) auto-phosphorylates upon VEGF-A occupation in vitro, arguing that VEGR2 confers its mitotic and viability signaling in and of itself. Herein, we show that, in ECs, VEGFR2 function requires concurrent C3a/C5a receptor (C3ar1/C5ar1) and IL-6 receptor (IL-6R)-gp130 co-signaling. C3ar1/C5ar1 or IL-6R blockade totally abolished VEGFR2 auto-phosphorylation, downstream Src, ERK, AKT, mTOR and STAT3 activation, and EC cell cycle entry. VEGF-A augmented production of C3a/C5a/IL-6 and their receptors via a two-step p-Tyk2/p-STAT3 process. Co-immunoprecipitation analyses, confocal microscopy, ligand pulldown and bioluminescence resonance energy transfer assays all indicated that the four receptors are physically interactive. Angiogenesis in murine day 5 retinas and in adult tissues was accelerated when C3ar1/C5ar1 signaling was potentiated, but repressed when it was disabled. Thus, C3ar1/C5ar1 and IL-6R-gp130 joint activation is needed to enable physiological VEGFR2 function.
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Receptor gp130 de Citocinas/metabolismo , Receptor de Anafilatoxina C5a/metabolismo , Receptores de Complemento/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Animales , Proliferación Celular , Células Endoteliales/metabolismo , Interleucina-6/metabolismo , Ratones , Neovascularización Fisiológica , Transducción de Señal , Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: The prevalence of atopic dermatitis has increased over the last 10 years. Atopic dermatitis tends to run in families and commonly begins to manifest in childhood. The prevalence of atopic dermatitis is as high as 20% in children. Thus, early diagnosis and treatment of atopic dermatitis are important. Understanding its genetic basis is also needed to facilitate early detection. METHODS: To identify family-specific candidate genetic variants associated with early-onset atopic dermatitis in Koreans, we carried out whole-exome sequencing of three separate families with this condition. Additional validation was performed in 112 AD patients and 61 controls using Sanger sequencing. RESULTS: We focused on both common functional variants with a minor allele frequency higher than 1% and rare variants with a minor allele frequency less than 1%. The relevance of the respective variants was supported by a program that could predict whether the mutations resulted in damaged protein function. Fourteen overlapping genes were identified during exome sequencing. Three variants of the COL6A6 gene appeared in all three families and were in close proximity to atopic dermatitis-related loci on chromosome 3q21. The homozygous frequency for the rs16830494 minor allele (AA) and the rs59021909 (TT) allele and the rs200963433 heterozygous (CT) frequency were all higher in AD cases compared to controls in a population-based case-control study. CONCLUSION: Identifying family-specific COL6A6 polymorphisms and genetic variants of other candidate genes associated with AD using WES is a novel approach. Our study suggests that COL6A6 variants may be risk factors for atopic dermatitis. This study provides a genetic basis for early-onset AD diagnosis in Korean patients and the development of new therapies. TRIAL REGISTRATION: Trial registration number: IRB NO. C2008030 (133); Name of registry: The collection research of clinical data and patient blood to identify genetic and protein biomarker of atopic dermatitis; Date of registration: 09-July-2008. TRIAL REGISTRATION NUMBER: IRB NO. C2015258 (1716); Name of registry: The collection study of patient blood and clinical data for the development of the prognosis prediction and early diagnosis of atopic dermatitis; Date of registration: 15-jan-2016.
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Colágeno Tipo VI/genética , Dermatitis Atópica/genética , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN/métodos , Edad de Inicio , Exoma , Femenino , Predisposición Genética a la Enfermedad , Humanos , MasculinoRESUMEN
Epigallocatechin gallate (EGCG) is a major polyphenol in green tea that has beneficial effects in the prevention of cardiovascular disease. Autophagy is a cellular process that protects cells from stressful conditions. To determine whether the beneficial effect of EGCG is mediated by a mechanism involving autophagy, the roles of the EGCG-stimulated autophagy in the context of ectopic lipid accumulation were investigated. Treatment with EGCG increased formation of LC3-II and autophagosomes in primary bovine aortic endothelial cells (BAEC). Activation of calmodulin-dependent protein kinase kinase ß was required for EGCG-induced LC3-II formation, as evidenced by the fact that EGCG-induced LC3-II formation was significantly impaired by knockdown of calmodulin-dependent protein kinase kinase ß. This effect is most likely due to cytosolic Ca(2+) load. To determine whether EGCG affects palmitate-induced lipid accumulation, the effects of EGCG on autophagic flux and co-localization of lipid droplets and autophagolysosomes were examined. EGCG normalized the palmitate-induced impairment of autophagic flux. Accumulation of lipid droplets by palmitate was markedly reduced by EGCG. Blocking autophagosomal degradation opposed the effect of EGCG in ectopic lipid accumulation, suggesting the action of EGCG is through autophagosomal degradation. The mechanism for this could be due to the increased co-localization of lipid droplets and autophagolysosomes. Co-localization of lipid droplets with LC3 and lysosome was dramatically increased when the cells were treated with EGCG and palmitate compared with the cells treated with palmitate alone. Collectively, these findings suggest that EGCG regulates ectopic lipid accumulation through a facilitated autophagic flux and further imply that EGCG may be a potential therapeutic reagent to prevent cardiovascular complications.
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Autofagia/efectos de los fármacos , Catequina/análogos & derivados , Endotelio Vascular/efectos de los fármacos , Metabolismo de los Lípidos , Adenilato Quinasa/metabolismo , Animales , Secuencia de Bases , Proteínas Quinasas Dependientes de Calcio-Calmodulina/metabolismo , Catequina/farmacología , Bovinos , Células Cultivadas , Cartilla de ADN , Endotelio Vascular/citología , Endotelio Vascular/metabolismoRESUMEN
BACKGROUND: Amyloid-ß precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. Recently, the increased expression of APP in multiple types of cancers has been reported where it has significant correlation with the cancer cell proliferation. However, the function of APP in the pathogenesis of breast cancer has not previously been determined. In this study, we studied the pathological role of APP in breast cancer and revealed its potential mechanism. METHODS: The expression level of APP in multiple breast cancer cell lines was measured by Western blot analysis and the breast cancer tissue microarray was utilized to analyze the expression pattern of APP in human patient specimens. To interrogate the functional role of APP in cell growth and apoptosis, the effect of APP knockdown in MDA-MB-231 cells were analyzed. Specifically, multiple signal transduction pathways and functional alterations linked to cell survival and motility were examined in in vivo animal model as well as in vitro cell culture with the manipulation of APP expression. RESULTS: We found that the expression of APP is increased in mouse and human breast cancer cell lines, especially in the cell line possessing higher metastatic potential. Moreover, the analysis of human breast cancer tissues revealed a significant correlation between the level of APP and tumor development. Knockdown of APP (APP-kd) in breast cancer cells caused the retardation of cell growth in vitro and in vivo, with both the induction of p27(kip1) and caspase-3-mediated apoptosis. APP-kd cells also had higher sensitivity to treatment of chemotherapeutic agents, TRAIL and 5-FU. Such anti-tumorigenic effects shown in the APP-kd cells partially came from reduced pro-survival AKT activation in response to IGF-1, leading to activation of key signaling regulators for cell growth, survival, and pro-apoptotic events such as GSK3-ß and FOXO1. Notably, knock-down of APP in metastatic breast cancer cells limited cell migration and invasion ability upon stimulation of IGF-1. CONCLUSION: The present data strongly suggest that the increase of APP expression is causally linked to tumorigenicity as well as invasion of aggressive breast cancer and, therefore, the targeting of APP may be an effective therapy for breast cancer.
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Precursor de Proteína beta-Amiloide/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Movimiento Celular , Precursor de Proteína beta-Amiloide/genética , Animales , Apoptosis/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Supervivencia Celular/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Ratones , Estadificación de Neoplasias , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Obesity is characterized by a chronic proinflammatory state that leads to endothelial dysfunction. Saturated fatty acids (SFA) stimulate Toll-like receptors (TLR) that promote metabolic insulin resistance. However, it is not known whether TLR2 mediates impairment of vascular actions of insulin in response to high-fat diet (HFD) to cause endothelial dysfunction. siRNA knockdown of TLR2 in primary endothelial cells opposed palmitate-stimulated expression of proinflammatory cytokines and splicing of X box protein 1 (XBP-1). Inhibition of unfolding protein response (UPR) reduced SFA-stimulated expression of TNFα. Thus, SFA stimulates UPR and proinflammatory response through activation of TLR2 in endothelial cells. Knockdown of TLR2 also opposed impairment of insulin-stimulated phosphorylation of eNOS and subsequent production of NO. Importantly, insulin-stimulated vasorelaxation of mesenteric arteries from TLR2 knockout mice was preserved even on HFD (in contrast with results from arteries examined in wild-type mice on HFD). We conclude that TLR2 in vascular endothelium mediates HFD-stimulated proinflammatory responses and UPR that accompany impairment of vasodilator actions of insulin, leading to endothelial dysfunction. These results are relevant to understanding the pathophysiology of the cardiovascular complications of diabetes and obesity.
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Endotelio Vascular/fisiopatología , Resistencia a la Insulina/fisiología , Insulina/metabolismo , Obesidad/fisiopatología , Receptor Toll-Like 2/metabolismo , Animales , Glucemia/metabolismo , Células Endoteliales , Endotelio Vascular/metabolismo , Inmunohistoquímica , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Obesidad/metabolismo , Palmitatos/farmacología , Respuesta de Proteína Desplegada , Vasodilatación/efectos de los fármacos , Vasodilatación/inmunologíaRESUMEN
Objective: The objective of this study is to provide a comparative analysis of variant clusters and their relevance across Africa, America, Europe, and Asia, in order to understand the evolutionary patterns of the virus across different regions and to inform the development of targeted interventions and genomic surveillance eforts. Methods: The study analyzed the global lineage evolution pattern of 74, 075 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes from 32 countries across four continents, focusing on variant clusters and their relevance across regions. Variants were weighted according to their hierarchical level. The correlation between variants was visualized through Dimensionality reduction analysis and Pairwise Pearson's correlation. We presented a reconstructed phylogenetic tree based on correlation analysis and variant weights. Results: The analysis revealed that each continent had distinct variant clusters and different evolutionary patterns. The Americas had two clustered variants before lineage divergence and a downstream confluence lineage, Europe had bifurcation into two global lineages with an early occurrence of certain cluster while Asia had a downstream confluence of two large lineages diverging by two distinct clusters. Based on the cluster patterns of shared variants of the SARS-CoV-2 virus, Africa demonstrated a relatively clear distinction among three distinct regions. Conclusions: The study provides insights into the evolutionary patterns of SARS-CoV-2 and highlights the importance of international collaboration in tracking and responding to emerging variants. The study found that the global pandemic was driven by Omicron variants that evolved with significant differences between countries and regions, and with different patterns across continents.
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PURPOSES: Although clinical and radiological examinations can be used to diagnose oral cancer, and surgical pathology remains the gold standard, these conventional methods have limitations. We evaluated the feasibility of longitudinal next-generation sequencing-based liquid biopsy for oral squamous cell carcinoma surveillance. MATERIALS AND METHODS: Eleven patients were enrolled, and plasma and saliva were collected before, and 1, 3, and 6 months after surgery. Tumor-specific mutations were selected using paired, whole-exome analyses of tumor tissues and whole blood. Genes frequently mutated in head and neck cancer were identified using the Cancer Genome Atlas (TCGA) and Catalogue of Somatic Mutations in Cancer (COSMIC) databases to design targeted deep sequencing panels. RESULTS: In five of the six patients with recurrent cancer, circulating tumor DNA (ctDNA) was detected earlier with liquid biopsy than with conventional monitoring techniques. Moreover, patients without recurrence exhibited decreased ctDNA allele frequency post-treatment. CONCLUSIONS: Longitudinal liquid biopsy of plasma and saliva may be feasible for detecting somatic mutations associated with oral squamous cell carcinomas. It might be attributable to determine early tumor recurrence through genetic analysis of ctDNA.
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Carcinoma de Células Escamosas , ADN Tumoral Circulante/metabolismo , Biopsia Líquida/métodos , Neoplasias de la Boca , Anciano , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/diagnóstico , Neoplasias de la Boca/metabolismo , Recurrencia Local de Neoplasia , Saliva/metabolismoRESUMEN
Autophagy, an integral part of the waste recycling process, plays an important role in cellular physiology and pathophysiology. Impaired autophagic flux causes ectopic lipid deposition, which is defined as the accumulation of lipids in non-adipose tissue. Ectopic lipid accumulation is observed in patients with cardiometabolic syndrome, including obesity, diabetes, insulin resistance, and cardiovascular complications. Metformin is the first line of treatment for type 2 diabetes, and one of the underlying mechanisms for the anti-diabetic effect of metformin is mediated by the stimulation of AMP-activated protein kinase (AMPK). Because the activation of AMPK is crucial for the initiation of autophagy, we hypothesize that metformin reduces the accumulation of lipid droplets by increasing autophagic flux in vascular endothelial cells. Incubation of vascular endothelial cells with saturated fatty acid (SFA) increased the accumulation of lipid droplets and impaired autophagic flux. We observed that the accumulation of lipid droplets was reduced, and the autophagic flux was enhanced by treatment with metformin. The knock-down of AMPKα by using siRNA blunted the effect of metformin. Furthermore, treatment with SFA or inhibition of autophagy increased leukocyte adhesion, whereas treatment with metformin decreased the SFA-induced leukocyte adhesion. The results suggest a novel mechanism by which metformin protects vascular endothelium from SFA-induced ectopic lipid accumulation and pro-inflammatory responses. In conclusion, improving autophagic flux may be a therapeutic strategy to protect endothelial function from dyslipidemia and diabetic complications.
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Autofagia , Carnitina O-Palmitoiltransferasa/fisiología , Endotelio Vascular/efectos de los fármacos , Ácidos Grasos/toxicidad , Hipoglucemiantes/farmacología , Inflamación/tratamiento farmacológico , Metformina/farmacología , Proteínas Quinasas Activadas por AMP , Animales , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Resistencia a la Insulina , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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The adaptor protein TNF receptor-associated factor 6 (TRAF6) is a key mediator in inflammation. However, the molecular mechanisms controlling its activity and stability in cancer progression remain unclear. Here we show that death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK1) inhibits the proinflammatory signaling pathway by targeting TRAF6 for degradation, thereby suppressing inflammatory signaling-mediated tumor growth and metastasis in advanced cervical cancer cells. DRAK1 bound directly to the TRAF domain of TRAF6, preventing its autoubiquitination by interfering with homo-oligomerization, eventually leading to autophagy-mediated degradation of TRAF6. Depletion of DRAK1 in cervical cancer cells resulted in markedly increased levels of TRAF6 protein, promoting activation of the IL1ß signaling-associated pathway and proinflammatory cytokine production. DRAK1 was specifically underexpressed in metastatic cervical cancers and inversely correlated with TRAF6 expression in mouse xenograft model tumor tissues and human cervical tumor tissues. Collectively, our findings highlight DRAK1 as a novel antagonist of inflammation targeting TRAF6 for degradation that limits inflammatory signaling-mediated progression of advanced cervical cancer. SIGNIFICANCE: Serine/threonine kinase DRAK1 serves a unique role as a novel negative regulator of the inflammatory signaling mediator TRAF6 in cervical cancer progression.
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Proteínas Reguladoras de la Apoptosis/metabolismo , Autofagia , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias del Cuello Uterino/patología , Animales , Línea Celular Tumoral , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/inmunología , Ratones , Estadificación de Neoplasias , Unión Proteica/inmunología , Dominios Proteicos , Multimerización de Proteína/inmunología , Estabilidad Proteica , Proteolisis , Transducción de Señal/inmunología , Análisis de Matrices Tisulares , Ubiquitinación/inmunología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Targeting retinoid X receptor (RXR) has been proposed as one of the therapeutic strategies to treat individuals with metabolic syndrome, as RXR heterodimerizes with multiple nuclear receptors that regulate genes involved in metabolism. Despite numerous efforts, RXR ligands (rexinoids) have not been approved for clinical trials to treat metabolic syndrome due to the serious side effects such as hypertriglyceridemia and altered thyroid hormone axis. In this study, we demonstrate a novel rexinoid-like small molecule, UAB126, which has positive effects on metabolic syndrome without the known side effects of potent rexinoids. Oral administration of UAB126 ameliorated obesity, insulin resistance, hepatic steatosis, and hyperlipidemia without changes in food intake, physical activity, and thyroid hormone levels. RNA-sequencing analysis revealed that UAB126 regulates the expression of genes in the liver that are modulated by several nuclear receptors, including peroxisome proliferator-activated receptor α and/or liver X receptor in conjunction with RXR. Furthermore, UAB126 not only prevented but also reversed obesity-associated metabolic disorders. The results suggest that optimized modulation of RXR may be a promising strategy to treat metabolic disorders without side effects. Thus, the current study reveals that UAB126 could be an attractive therapy to treat individuals with obesity and its comorbidities.
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Dieta Alta en Grasa , Hígado Graso/tratamiento farmacológico , Hiperlipidemias/tratamiento farmacológico , Resistencia a la Insulina/fisiología , Hígado/efectos de los fármacos , Obesidad/tratamiento farmacológico , Receptores X Retinoide/agonistas , Animales , Hígado Graso/sangre , Hiperlipidemias/sangre , Lípidos/sangre , Masculino , Ratones , Obesidad/sangreRESUMEN
TrkC, a member of the tropomyosin-related kinase (Trk) family of neurotrophin receptors, is implicated in the growth and survival of human cancer tissues. TrkC is also a potent oncoprotein expressed in tumors derived from multiple cell lineages, and functions as an active protein tyrosine kinase by neurotrophin-3 (NT-3). We previously reported that TrkC plays an essential role in tumor growth and metastasis in a murine cancer cell line. Here, we report that expression of TrkC suppresses bone morphogenetic protein 2 (BMP-2)-induced Smad1 phosphorylation and transcriptional activation. In the highly metastatic CT26 murine colon cancer cell line, which expresses endogenous TrkC, silencing TrkC expression by small interfering RNA significantly enhanced BMP-2-induced Smad1 phosphorylation and restored BMP-2 growth inhibitory activity. In contrast, expression of TrkC in RIE-1 cells, in which TrkC is not expressed, completely suppressed BMP-2 transcriptional activation. Furthermore, we showed that TrkC directly binds to the BMP type II receptor (BMPRII), thereby preventing it from interacting with the BMPRI. This activity requires a functional TrkC protein tyrosine kinase, and the BMPRII seems to be a direct target of TrkC. Our findings provide evidence for a previously unknown mechanism by which TrkC, a neuronal receptor, can block BMP tumor-suppressor activity.
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Adenocarcinoma/metabolismo , Receptores de Proteínas Morfogenéticas Óseas de Tipo II/metabolismo , Proteínas Morfogenéticas Óseas/metabolismo , Neoplasias del Colon/metabolismo , Receptor trkC/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/patología , Animales , Anoicis/fisiología , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Línea Celular Tumoral , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Humanos , Ratones , Fosforilación , Unión Proteica , Receptor trkC/biosíntesis , Transducción de Señal , Proteína Smad1/metabolismo , Activación TranscripcionalRESUMEN
Metastatic breast cancers are aggressive tumors associated with high levels of epithelial-mesenchymal transition (EMT) markers, activation of IL6/JAK2/STAT3 and PI3K/AKT pathways for cell growth, mobility, invasion, metastasis, and CSC status. We identified a new molecular and functional network present in metastasis that regulates and coordinates with TrkC. Inhibition of SOCS3-mediated JAK2 degradation by TrkC increases total JAK2/STAT3 expression, and then leads to upregulation of Twist-1 through activation of JAK2/STAT3 cascade. Also, TrkC increases secretion and expression of IL-6, suggesting that this autocrine loop generated by TrkC maintains the mesenchymal state by continued activation of the JAK2/STAT3 cascade and upregulation of Twist expression. Moreover, TrkC interacts with the c-Src/Jak2 complex, which increases Twist-1 and Twist-2 levels via regulation of JAK2/STAT3 activation and JAK2/STAT3 expression. Furthermore, TrkC enhances metastatic potential of breast cancer via induction of EMT by upregulating Twist-1 and Twist-2. Additionally, TrkC significantly enhances the ability of breast cancer cells to form pulmonary metastases and primary tumor formation. Unexpectedly, we found that TrkC expression and clinical breast tumor pathological phenotypes show significant correlation. These findings suggest that TrkC plays a central role in tumorigenicity, metastasis, and self-renewal traits of metastatic breast cancer.
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Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti-oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions.
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Autofagia/efectos de los fármacos , Catequina/análogos & derivados , Regulación de la Expresión Génica/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Polifenoles/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Antioxidantes/química , Antioxidantes/farmacología , Señalización del Calcio/efectos de los fármacos , Catequina/química , Catequina/farmacología , Membrana Celular/efectos de los fármacos , AMP Cíclico/fisiología , GMP Cíclico/fisiología , Metilación de ADN/efectos de los fármacos , Humanos , Peróxido de Hidrógeno/metabolismo , Oxidantes/química , Oxidantes/farmacología , Oxidación-Reducción , Polifenoles/química , Té/química , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Transforming growth factor-ß1 (TGF-ß1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1ß must overcome the anti-inflammatory effects of TGF-ß to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1ß or Lipopolysaccharide (LPS) suppresses TGF-ß-induced anti-inflammatory signaling in a NF-κB-independent manner. TRAF6, a key molecule in IL-1ß signaling, mediates this suppressive effect through interaction with the type III TGF-ß receptor (TßRIII), which is TGF-ß-dependent and requires type I TGF-ß receptor (TßRI) kinase activity. TßRI phosphorylates TßRIII at residue S829, which promotes the TRAF6/TßRIII interaction and consequent sequestration of TßRIII from the TßRII/TßRI complex. Our data indicate that IL-1ß enhances the pro-inflammatory response by suppressing TGF-ß signaling through TRAF6-mediated sequestration of TßRIII, which may be an important contributor to the early stages of tumor progression.