nfkb1 - nuclear factor of kappa light polypeptide enhancer in B-cells
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Publication
Journal: European journal of human genetics : EJHG
January/25/2019
Abstract
Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.
Publication
Journal: Journal of exercise rehabilitation
January/18/2019
Abstract
The progression of ischemic stroke is associated with inflammatory response, in which the nuclear factor kappa B subunit 1 (NFKB1) plays an important role. The aim of present study was to determine whether promoter single nucleotide polymorphism (SNP) in the NFKB1 gene was contributed to susceptibility of ischemic stroke. One hundred twenty-one Korean adult patients with ischemic stroke (65.7±12.1 years in age) and 291 Korean healthy controls (63.0±9.3 years in age) were recruited. We genotyped a promoter SNP (rs11940017, -1727, C/T) of NFKB1 gene using direct sequencing in 121 Korean ischemic stroke patients and 291 control subjects. The T/C genotype of rs11940017 SNP in the codominant model (vs. the T/T genotype) (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.15-0.92; P=0.032) and the genotype containing C allele (T/C and C/C) in the dominant model (vs. the T/T genotype) (OR, 0.33; 95% CI, 0.14-0.81; P=0.0068) were associated with a decreased risk of ischemic stroke. The frequency of C allele was decreased in ischemic stroke patients, compared with control subjects (OR, 0.31; 95% CI, 0.13-0.74; P=0.008). These results suggest that the promoter SNP (rs11940017, -1727, C/T) of NFKB1 gene may affect ischemic stroke susceptibility in Korean population.
Publication
Journal: Neurological research
January/16/2017
Abstract
OBJECTIVE
This study aims to investigate gene expression changes in rat dorsal horns after sciatic nerve injury (SNI).
METHODS
The GSE18803 microarray data collected from young and adult rats were downloaded from GEO. After preprocessing, differentially expressed genes (DEGs) between SNI and sham-operated groups were selected using Limma package, in young and adult group, respectively, followed by Venn analysis. Then, enrichment analyses were performed for these DEGs using DAVID. The STRING database was used to identify protein-protein interactions (PPIs) among these DEGs, and the module network was further extracted using plugin ClusterONE. Finally, protein domain enrichment analysis of DEGs in each module was performed using InterPro database.
RESULTS
Totally, 210 and 50 DEGs were identified in adult and young group, respectively. Among them, 160 were specific in adult group (e.g. CCL2, NF-κB1 and RAC2); 9 were specific in young group (e.g. ILF3 and LYVE1); and 41 were common in both two groups (e.g. FCER1G, C1QA, C1QB and C1QC). The up-regulated DEGs were mostly enriched in immune response-related biological processes, as well as 15 immune- and inflammation-related pathways. Then, two modules were identified in PPI network. CCL2 and NF-κB1 had high connectivity degrees in module 1, and RAC2, FCER1G and CD68 in module 2.
CONCLUSIONS
CCL2, NF-κB1, RAC2, FCER1G and C1Q may contribute to the generation of neuropathic pain after SNI via immune and defense pathways. Among the five genes, the first three are specific in adult population, while the latter two are age-independent. They all might function through involvement of these immune or inflammatory pathways.
Publication
Journal: Seminars in cancer biology
September/20/2016
Abstract
Malignancies of mature B cells are quite distinctive in originating from well-differentiated cells. Hence, it is not paradoxical that, similar to their normal counterparts, most mature B cell lymphoma subtypes are critically dependent on microenvironmental cues. Such external signals are sensed by various receptors present on the malignant cells, including the Toll-like receptors (TLRs), eliciting a range of cellular responses, including proliferation but also anergy and apoptosis, often with disease-specific patterns. Critically, the TLR signaling pathways are intertwined with other receptor pathways in malignant B cells, most notably the B-cell receptor pathway, and converge on NF-κB, leading to its activation. In the present review, we summarize the literature on TLR expression and functionality and its impact on NF-κB activation in different B cell malignancies including chronic lymphocytic leukemia where TLR9 induces activation, cell proliferation and chemoresistance in a proportion of patients while apoptosis can be induced in others. Additionally, we also discuss the therapeutic potential of strategies targeting TLR signaling in lymphoma.
Publication
Journal: Cellular signalling
July/15/2016
Abstract
Follistatin-like 1 (FSTL1) functions as a pivotal modulator of inflammation and is implicated in many inflammatory diseases such as rheumatoid arthritis. Here, we report that FSTL1 is strongly upregulated and secreted during osteoclast differentiation of bone marrow-derived macrophages (BMMs) and that FSTL1 positively regulates osteoclast formation induced by RANKL and M-CSF. The overexpression of FSTL1 or treatment with recombinant FSTL1 (rFSTL1) in BMMs enhances the formation of multinuclear osteoclasts and the induction of c-Fos and NFATc1, transcription factors important for osteoclastogenesis. Conversely, knockdown of FSTL1 using a small hairpin RNA suppresses osteoclast formation and the expression of these transcription factors. While FSTL1 does not affect RANKL-stimulated activation of p38 MAPK, phosphorylation of IκBα, JNK, and ERK were increased by overexpression or addition of rFSTL1. Furthermore, rFSTL1 increased RANKL-induced NF-κB transcriptional activity in a dose-dependent manner. In addition to its role in osteoclastogenesis, FSTL1 promotes proliferation of osteoclast precursors by increasing M-CSF-induced ERK activation, which in turn leads to accelerated osteoclast formation. Together, our findings demonstrate that FSTL1 is a secreted osteoclastogenic factor that plays a critical role in osteoclast formation via the NF-κB and MAPKs signaling pathways.
Publication
Journal: PLoS pathogens
November/18/2017
Abstract
At the crossroad between the NF-κB and the MAPK pathways, the ternary complex composed of p105, ABIN2 and TPL2 is essential for the host cell response to pathogens. The matrix protein (M) of field isolates of rabies virus was previously shown to disturb the signaling induced by RelAp43, a NF-κB protein close to RelA/p65. Here, we investigated how the M protein disturbs the NF-κB pathway in a RelAp43-dependant manner and the potential involvement of the ternary complex in this mechanism. Using a tandem affinity purification coupled with mass spectrometry approach, we show that RelAp43 interacts with the p105-ABIN2-TPL2 complex and we observe a strong perturbation of this complex in presence of M protein. M protein interaction with RelAp43 is associated with a wide disturbance of NF-κB signaling, involving a modulation of IκBα-, IκBβ-, and IκBε-RelAp43 interaction and a favored interaction of RelAp43 with the non-canonical pathway (RelB and p100/p52). Monitoring the interactions between host and viral proteins using protein-fragment complementation assay and bioluminescent resonance energy transfer, we further show that RelAp43 is associated to the p105-ABIN2-TPL2 complex as RelAp43-p105 interaction stabilizes the formation of a complex with ABIN2 and TPL2. Interestingly, the M protein interacts not only with RelAp43 but also with TPL2 and ABIN2. Upon interaction with this complex, M protein promotes the release of ABIN2, which ultimately favors the production of RelAp43-p50 NF-κB dimers. The use of recombinant rabies viruses further indicates that this mechanism leads to the control of IFNβ, TNF and CXCL2 expression during the infection and a high pathogenicity profile in rabies virus infected mice. All together, our results demonstrate the important role of RelAp43 and M protein in the regulation of NF-κB signaling.
Publication
Journal: Molecular neurobiology
November/7/2017
Abstract
Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor, protects neurons against ischemic stroke insult by reducing oxidative stress. NADPH oxidase (NOX) activation, a major driving force in ROS generation in the setting of reoxygenation/reperfusion, constitutes an important pathogenetic mechanism of ischemic brain damage. In the present study, both transient in vitro oxygen-glucose deprivation and in vivo middle cerebral artery (MCA) occlusion-reperfusion experimental paradigms of ischemic neuronal death were used to investigate the interaction between PPAR-γ and NOX. With pharmacological (PPAR-γ antagonist GW9662), loss-of-function (PPAR-γ siRNA), and gain-of-function (Ad-PPAR-γ) approaches, we first demonstrated that 15-deoxy-∆(12,14)-PGJ2 (15d-PGJ2), via selectively attenuating p22phox expression, inhibited NOX activation and the subsequent ROS generation and neuronal death in a PPAR-γ-dependent manner. Secondly, results of promoter analyses and subcellular localization studies further revealed that PPAR-γ, via inhibiting hypoxia-induced NF-κB nuclear translocation, indirectly suppressed NF-κB-driven p22phox transcription. Noteworthily, postischemic p22phox siRNA treatment not only reduced infarct volumes but also improved functional outcome. In summary, we report a novel transrepression mechanism involving PPAR-γ downregulation of p22phox expression to suppress the subsequent NOX activation, ischemic neuronal death, and brain infarct. Identification of a PPAR-γ → NF-κB → p22phox neuroprotective signaling cascade opens a new avenue for protecting the brain against ischemic insult.
Publication
Journal: Aging cell
July/31/2017
Abstract
Older adults universally suffer from sarcopenia and approximately 60-70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging-related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFκB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases (e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFκB pathway would protect against aging-related sarcopenia and insulin resistance. Aged mice with muscle-specific overexpression of a super-repressor IκBα mutant (MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild-type mice. In MISR mice, NFκB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy (e.g., myostatin). We conclude that the mechanism behind aging-induced sarcopenia is NFκB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFκB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function.
Publication
Journal: Scientific reports
July/18/2017
Abstract
NFκB is a central mediator of inflammation. Present inhibitors of NFκB are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NFκB enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NFκB activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NFκB. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NFκB itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NFκB enhanceosome offers a promising target for useful anti-inflammatory agents.
Publication
Journal: Oncotarget
February/19/2017
Abstract
Changes in the DNA methylation (DNAm) landscape have been implicated in aging and cellular senescence. To unravel the role of specific DNAm patterns in late-life survival, we performed genome-wide methylation profiling in nonagenarians (n=111) and determined the performance of the methylomic predictors and conventional risk markers in a longitudinal setting. The survival model containing only the methylomic markers was superior in terms of predictive accuracy compared with the model containing only the conventional predictors or the model containing conventional predictors combined with the methylomic markers. At the 2.55-year follow-up, we identified 19 mortality-associated (false-discovery rate <0.5) CpG sites that mapped to genes functionally clustering around the nuclear factor kappa B (NF-κB) complex. Interestingly, none of the mortality-associated CpG sites overlapped with the established aging-associated DNAm sites. Our results are in line with previous findings on the role of NF-κB in controlling animal life spans and demonstrate the role of this complex in human longevity.
Publication
Journal: Nature
January/1/2014
Publication
Journal: The open virology journal
August/28/2013
Abstract
HIV exploits the T-cell signaling network to gain access to downstream cellular components, which serves as effective tools to break the cellular barriers. Multiple host factors and their interaction with viral proteins contribute to the complexity of HIV-1 pathogenesis and disease progression. HIV-1 proteins gp120, Nef, Tat and Vpr alter the T-cell signaling pathways by activating multiple transcription factors including NF-ĸB, Sp1 and AP-1. HIV-1 evades the immune system by developing a multi-pronged strategy. Additionally, HIV-1 encoded proteins influence the apoptosis in the host cell favoring or blocking T-cell apoptosis. Thus, T-cell signaling hijacked by viral proteins accounts for both viral persistence and immune suppression during HIV-1 infection. Here, we summarize past and present studies on HIV-1 T-cell signaling with special focus on the possible role of T cells in facilitating viral infection and pathogenesis.
Publication
Journal: Journal of molecular medicine (Berlin, Germany)
September/21/2017
Abstract
MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family was also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b, and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB, and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, and CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways.
Expression of the miR-29 family is regulated in cartilage during osteoarthritis. SOX9 represses expression of the miR-29 family in chondrocytes. The miR-29 family is regulated by TGF-β1 and IL-1 in chondrocytes. The miR-29 family negatively regulates Smad, NFκB, and canonical Wnt signalling. Several Wnt-related genes are direct targets of the miR-29 family.
Publication
Journal: Current eye research
July/16/2017
Abstract
Nuclear factor-kappa B (NF-κB) has been proposed as a therapeutic target for the treatment of cataracts. The authors investigated the relationship between nuclear factor of activated T cells 5 (NFAT5) and NF-κB in ultraviolet B (UVB)-irradiated human lens epithelial (HLE) cells.
Human lens epithelial B-3 (HLE-B3) cells were exposed to UVB light at a dose of 10 mJ/cm2 and then incubated for 24 h. Cell viability was assessed by using the Cell Counting Kit-8 (CCK-8) assay. Gene expression level of NFAT5 was determined using real-time quantitative polymerase chain reaction (qPCR). Protein expression levels of NFAT5, NF-κB p65, and α-smooth muscle actin (α-SMA) and the association of NFAT5 with the NF-κB p65 subunit were measured by Western blot analysis and a co-immunoprecipitation assay, respectively. The cellular distribution of NFAT5 and NF-κB p65 was examined by triple immunofluorescence staining.
At 24 h after UVB exposure, cell viability significantly decreased in a dose-dependent manner, and UVB light (15 and 20 mJ/cm2) significantly increased the ROS generation. UVB irradiation increased NFAT5 mRNA and protein levels and increased phosphorylation of NF-κB in HLE-B3 cells. α-SMA protein levels were increased in the irradiated cells. In addition, NFAT5 and NF-κB translocated from the cytoplasm to the nucleus, and binding between the p65 subunit and NFAT5 was increased.
Exposure to UVB radiation induces nuclear translocation and stimulates binding between NFAT5 and NF-κB proteins in HLE-B3 cells. These interactions may form part of the biochemical mechanism of cataractogenesis in UVB-irradiated HLECs.
Publication
Journal: Oncotarget
May/26/2017
Abstract
Conventional high-recurrence risk factors are not sufficient to predict post-operative risk of tumor recurrence or sensitivity to 5-fluorouracil (5-FU)-based chemotherapy for stage II colon cancer. DDA1, an evolutionarily conserved gene located at 19p13.11, may be involved in the activation of nuclear factor kappaB (NFκB). This study aimed to investigate whether DDA1 contributes to tumorigenesis and progression of stage II colon cancer via activation of the NFκB pathway. We found that positive expression of DDA1 alone or in combination with p65 nuclear translocation correlated with increased risk of tumor recurrence in patients with stage IIB-IIC colon cancer. DDA1 overexpression in colon cancer lines promoted cell proliferation, facilitated cell cycle progression, inhibited 5-FU-induced apoptosis, enhanced invasion, and induced the epithelial-mesenchymal transition. Suppression of DDA1 inhibited tumor progression, and reduced tumor growth in vivo. We also demonstrated that DDA1-mediated tumor progression is associated with the activation of the NFκB/COP9 signalosome 2(CSN2)/glycogen synthase kinase3β (GSK3β) pathway. These results indicate that DDA1 promotes colon cancer progression through activation of NFκB/CSN2/GSK3β signaling. DDA1, together with NFκB activation status, may serve as a sensitive biomarker for tumor recurrence risk and prognosis in patients with stage IIB-IIC colon cancers.
Publication
Journal: Oncotarget
April/2/2017
Abstract
Hepatocyte growth factor activator inhibitor type 1 (HAI-1), encoded by the Spint1 gene, is a membrane-bound serine protease inhibitor expressed on the epithelial cell surface. We have previously reported that the intestine-specific Spint1-deleted ApcMin/+ mice showed accelerated formation of intestinal tumors. In this study, we focused on the role of nuclear factor-κB (NF-κB) signaling in the HAI-1 loss-induced tumor susceptibility. In the HAI-1-deficient intestine, inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, were upregulated in normal mucosa. Furthermore, increased nuclear translocation of NF-κB was observed in both normal mucosa and tumor tissues of HAI-1-deficient ApcMin/+ intestines, and an NF-κB target gene, such as urokinase-type plasminogen activator, was upregulated in the HAI-1-deficient tumor tissues. Thus, we investigated the effect of dehydroxymethylepoxyquinomicin (DHMEQ), a synthetic inhibitor of NF-κB, on intestinal HAI-1-deficient ApcMin/+ mice. Treatment with DHMEQ reduced the formation of intestinal tumors compared with vehicle control in the HAI-1-deficient ApcMin/+ mice. These results suggested that insufficient HAI-1 function promotes intestinal carcinogenesis by activating NF-κB signaling.
Publication
Journal: Reproductive sciences (Thousand Oaks, Calif.)
July/1/2014
Abstract
We aimed to investigate whether the surgical removal of endometrioma alters the nuclear factor-kappa B1 (NF-kB1; p50/105) and NF-kB p65 (Rel A) expression in the eutopic endometrium of infertile women with endometrioma before and after laparoscopic removal of the ovarian endometrioma during the mid-secretory phase. Infertile women with endometrioma (n = 15) were enrolled. Infertile patients with nonendometriotic ovarian cyst (n = 10) and healthy fertile women (n = 10) were recruited as controls. Endometrial samples were obtained before and 3 months after the laparoscopic cystectomy. The NF-kB1 (p50/105) levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in the endometrium of all groups before and after laparoscopic ovarian cystectomy during implantation window. Expression of NF-kB1 (p50/105) in eutopic endometrium was significantly higher in infertile women with endometrioma compared to nonendometriotic cyst and fertile controls (P < .05). Laparoscopic cystectomy resulted in a significant decrease in NF-kB1 expression in women with endometrioma. The NF-kB p65 (Rel A) immunoreactivity of eutopic endometrium decreased significantly subsequent to the surgical removal of the endometrioma. In conclusion, increased endometrial NF-kB expression may contribute to endometriosis-associated infertility.
Publication
Journal: Diabetes
June/5/2011
Abstract
OBJECTIVE
To investigate the role of epigenetic regulation of the manganese superoxide dismutase gene (sod2) in the development of diabetic retinopathy and the metabolic memory phenomenon associated with its continued progression after hyperglycemia is terminated.
METHODS
Streptozotocin-induced diabetic rats were maintained in poor glycemic control (PC, GHb ∼12%) or in good glycemic control (GC, GHb ~7.0%) for 4 months, or were allowed to maintain PC for 2 months, followed by GC for 2 additional months (PC-Rev). For experimental galactosemia, a group of normal rats were fed a 30% galactose diet for 4 months or for 2 months, followed by a normal diet for 2 additional months. Trimethyl histone H4 lysine 20 (H4K20me3), acetyl histone H3 lysine 9 (H3K9), and nuclear transcriptional factor NF-κB p65 and p50 at the retinal sod2 promoter and enhancer were examined by chromatin immunoprecipitation.
RESULTS
Hyperglycemia (diabetes or galactosemia) increased H4K20me3, acetyl H3K9, and NF-κB p65 at the promoter and enhancer of retinal sod2, upregulated protein and gene expression of SUV420h2, and increased the interactions of acetyl H3K9 and NF-κB p65 to H4K20me3. Reversal of hyperglycemia failed to prevent increases in H4K20me3, acetyl H3K9, and NF-κB p65 at sod2, and sod2 and SUV420h2 continued to be abnormal. Silencing SUV420h2 by its small interfering RNA in retinal endothelial cells prevented a glucose-induced increase in H4K20me3 at the sod2 enhancer and a decrease in sod2 transcripts.
CONCLUSIONS
Increased H4K20me3 at sod2 contributes to its downregulation and is important in the development of diabetic retinopathy and in the metabolic memory phenomenon. Targeting epigenetic changes may serve as potential therapeutic targets to retard the development and progression of diabetic retinopathy.
Publication
Journal: PloS one
October/21/2008
Abstract
BACKGROUND
The Rel/NF-kappaB transcription factors are often activated in solid or hematological malignancies. In most cases, NF-kappaB activation is found in malignant cells and results from activation of the canonical NF-kappaB pathway, leading to RelA and/or c-Rel activation. Recently, NF-kappaB activity in inflammatory cells infiltrating solid tumors has been shown to contribute to solid tumor initiation and progression. Noncanonical NF-kappaB activation, which leads to RelB activation, has also been reported in breast carcinoma, prostate cancer, and lymphoid leukemia.
RESULTS
Here we report a novel role for RelB in stromal cells that promote T-cell leukemogenesis. RelB deficiency delayed leukemia onset in the TEL-JAK2 transgenic mouse model of human T acute lymphoblastic leukemia. Bone marrow chimeric mouse experiments showed that RelB is not required in the hematopoietic compartment. In contrast, RelB plays a role in radio-resistant stromal cells to accelerate leukemia onset and increase disease severity.
CONCLUSIONS
The present results are the first to uncover a role for RelB in the crosstalk between non-hematopoietic stromal cells and leukemic cells. Thus, besides its previously reported role intrinsic to specific cancer cells, the noncanonical NF-kappaB pathway may also play a pro-oncogenic role in cancer microenvironmental cells.
Publication
Journal: Oncotarget
February/23/2017
Abstract
Phosphatase and tensin homolog (PTEN) is a major tumor suppressor and usually silenced via the deletion, insertion and mutation. We previously discovered its inactivation via aberrant CpG island methylation. Here, we provide further evidence that EBV latent membrane protein 1(LMP1) can induce a higher intensity of DNA methylation at PTEN CpG islands, inactivating PTEN at the cellular and molecular level. Initially, increased methylation intensity of PTEN CpG islands was observed in EBV-infected nasopharyngeal carcinoma (NPC) cells, accompanied by decreased PTEN expression. In NPC tissue samples showing the methylation at PTEN promoter, LMP1 was highly expressed in higher methylation intensity group relative to lower intensity group, and DNA methyltransferase 3b (DNMT3b) expression was positively correlated with LMP1 expression. Moreover, transfection of LMP1 gene into EBV-negative NPC cells demonstrated that LMP1 up-regulated DNMT3b expression, leading to a higher intensity of PTEN CpG island methylation. Mechanistically, computational prediction and luciferase reporter assay identified a functional NF-κB binding site on DNMT3b promoter and the mutated NF-κB binding site abolished LMP1-mediated DNMT3b activation. Chromatin immunoprecipitation displayed that NF-κB p65 subunit constitutively bound to DNMT3b promoter, supporting the activation of DNMT3b by EBV LMP1 via NF-κB signaling. Furthermore, the expression level of DNMT3b was observed to be increased in the nuclei of LMP1-expressing NPC cells, and a NF-κB inhibitor, PDTC, counteracted LMP1-mediated DNMT3b overexpression. Thus, this study first reports that LMP1-mediated NF-κB can up-regulate DNMT3b transcription, thereby leading to relatively higher methylation intensity at PTEN CpG islands, and ultimately silencing major tumor suppressor PTEN.
Publication
Journal: The Journal of biological chemistry
August/27/2015
Abstract
The NF-κB transcriptional response is tightly regulated by a number of processes including the phosphorylation, ubiquitination, and subsequent proteasomal degradation of NF-κB subunits. The IκB family protein BCL-3 stabilizes a NF-κB p50 homodimer·DNA complex through inhibition of p50 ubiquitination. This complex inhibits the binding of the transcriptionally active NF-κB subunits p65 and c-Rel on the promoters of NF-κB target genes and functions to suppress inflammatory gene expression. We have previously shown that the direct interaction between p50 and BCL-3 is required for BCL-3-mediated inhibition of pro-inflammatory gene expression. In this study we have used immobilized peptide array technology to define regions of BCl-3 that mediate interaction with p50 homodimers. Our data show that BCL-3 makes extensive contacts with p50 homodimers and in particular with ankyrin repeats (ANK) 1, 6, and 7, and the N-terminal region of Bcl-3. Using these data we have designed a BCL-3 mimetic peptide based on a region of the ANK1 of BCL-3 that interacts with p50 and shares low sequence similarity with other IκB proteins. When fused to a cargo carrying peptide sequence this BCL-3-derived peptide, but not a mutated peptide, inhibited Toll-like receptor-induced cytokine expression in vitro. The BCL-3 mimetic peptide was also effective in preventing inflammation in vivo in the carrageenan-induced paw edema mouse model. This study demonstrates that therapeutic strategies aimed at mimicking the functional activity of BCL-3 may be effective in the treatment of inflammatory disease.
Publication
Journal: Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
September/24/1995
Abstract
The mouse Rab geranylgeranyl transferase beta subunit has been cloned from a mouse E8.5 embryonic cDNA library. Sequence comparison reveals 97.4% sequence identity at the amino acid level to the rat clone isolated from an adult rat brain cDNA library. This gene, given a gene symbol of Rabggtb, is mapped in the distal region of mouse chromosome 3. It is ubiquitously expressed in adult animals but displays an interesting pattern of expression during a specific time of embryonic development. The expression of this gene can be detected in the whole embryos during early embryonic stages and is specifically concentrated in the developing brain, heart, and liver between gestation stages of E11.5 and E13.5. In addition, the expression of this gene is induced by retinoic acid in a mouse embryonal carcinoma cell line, P19.
Publication
Journal: Disease markers
November/27/2019
Abstract
Mechanical stress-induced cardiac remodeling that results in heart failure is characterized by transcriptional reprogramming of gene expression. However, a systematic study of genomic changes involved in this process has not been performed to date. To investigate the genomic changes and underlying mechanism of cardiac remodeling, we collected and analyzed DNA microarray data for murine transverse aortic constriction (TAC) and human aortic stenosis (AS) from the Gene Expression Omnibus database and the European Bioinformatics Institute.The differential expression genes (DEGs) across the datasets were merged. The Venn diagrams showed that the number of intersections for early and late cardiac remodeling was 74 and 16, respectively. Gene ontology and protein-protein interaction network analysis showed that metabolic changes, cell differentiation and growth, cell cycling, and collagen fibril organization accounted for a great portion of the DEGs in the TAC model, while in AS patients' immune system signaling and cytokine signaling displayed the most significant changes. The intersections between the TAC model and AS patients were few. Nevertheless, the DEGs of the two species shared some common regulatory transcription factors (TFs), including SP1, CEBPB, PPARG, and NFKB1, when the heart was challenged by applied mechanical stress.This study unravels the complex transcriptome profiles of the heart tissues and highlighting the candidate genes involved in cardiac remodeling induced by mechanical stress may usher in a new era of precision diagnostics and treatment in patients with cardiac remodeling.
Publication
Journal: Frontiers in physiology
June/19/2019
Abstract
Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disorder of the colon, characterized by continuous mucosal inflammation. Recently, some studies have considered it as part of an inflammatory bowel disease-based global network. Herein, with the aim of identifying the underlying potential genetic mechanisms involved in the development of UC, multiple algorithms for weighted correlation network analysis (WGCNA), principal component analysis (PCA), and linear models for microarray data algorithm (LIMMA) were used to identify the hub genes. The map of platelet activation, ligand-receptor interaction, calcium signaling pathway, and cAMP signaling pathway showed significant links with UC development, and the hub genes CCR7, CXCL10, CXCL9, IDO1, MMP9, and VCAM1, which are associated with immune dysregulation and tumorigenesis in biological function, were found by multiple powerful bioinformatics methods. Analysis of The Cancer Genome Atlas (TCGA) also showed that the low expression of CCR7, CXCL10, CXCL9, and MMP9 may be correlated with a poor prognosis of overall survival (OS) in colorectal cancer (CRC) patients (all p < 0.05), while no significance detected in both of IDO1 and VCAM1. In addition, low expression of CCR7, CXCL10, CXCL9, MMP9, and IDO1 may be associated with a poor prognosis in recurrence free survival (RFS) time (all p < 0.05), but no significant difference was identified in VCAM1. Moreover, the NFKB1, FLI1, and STAT1 with the highest enrichment score were detected as the master regulators of hub genes. In summary, these results indicated the central role of the hub genes of CCR7, CXCL10, CXCL9, IDO1, VCAM1, and MMP9, in response to UC progression, as well as the development of UC to CRC, thus shedding light on the molecular mechanisms involved and assisting with drug target validation.
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