Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 27

Publication Record

Connections

Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Chung L, Thiele Orberg E, Geis AL, Chan JL, Fu K, DeStefano Shields CE, Dejea CM, Fathi P, Chen J, Finard BB, Tam AJ, McAllister F, Fan H, Wu X, Ganguly S, Lebid A, Metz P, Van Meerbeke SW, Huso DL, Wick EC, Pardoll DM, Wan F, Wu S, Sears CL, Housseau F
(2018) Cell Host Microbe 23: 203-214.e5
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Bacterial Toxins, Bacteroides fragilis, Carcinogenesis, Cell Line, Tumor, Colon, Colorectal Neoplasms, Enzyme Activation, Epithelial Cells, Female, Gene Deletion, HT29 Cells, Humans, Inflammation, Interleukin-17, Male, Metalloendopeptidases, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Cells, Receptors, Interleukin-17, Receptors, Interleukin-8B, STAT3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 20, 2018
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using Apc mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.
Copyright © 2018 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
26 MeSH Terms
Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.
Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, Washington MK, Peek RM, Belkhiri A, El-Rifai WM
(2015) Cancer 121: 4348-58
MeSH Terms: Adenocarcinoma, Animals, Carcinogenesis, Chemokine CXCL5, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, I-kappa B Kinase, In Vitro Techniques, Inflammation, Interleukin-1beta, Mice, Mice, Knockout, Peptides, Phosphorylation, Real-Time Polymerase Chain Reaction, Receptors, Interleukin-4, Stomach, Stomach Neoplasms, Transcription Factor RelA, Trefoil Factor-1, Tumor Cells, Cultured, Tumor Necrosis Factor-alpha
Show Abstract · Added September 28, 2015
BACKGROUND - Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.
METHODS - For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.
RESULTS - The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.
CONCLUSIONS - These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.
© 2015 American Cancer Society.
0 Communities
3 Members
0 Resources
24 MeSH Terms
Differential role of an NF-κB transcriptional response element in endothelial versus intimal cell VCAM-1 expression.
Milstone DS, Ilyama M, Chen M, O'Donnell P, Davis VM, Plutzky J, Brown JD, Haldar SM, Siu A, Lau AC, Zhu SN, Basheer MF, Collins T, Jongstra-Bilen J, Cybulsky MI
(2015) Circ Res 117: 166-77
MeSH Terms: 5' Untranslated Regions, Animals, Atherosclerosis, Carotid Artery Injuries, Cells, Cultured, Chemotaxis, Leukocyte, Cholesterol, Dietary, E-Selectin, Endothelial Cells, Endothelium, Vascular, Humans, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Protein Interaction Mapping, RNA Polymerase II, Receptors, LDL, Response Elements, Transcription Factor RelA, Transcription, Genetic, Tunica Intima, Vascular Cell Adhesion Molecule-1
Show Abstract · Added September 6, 2016
RATIONALE - Human and murine Vcam1 promoters contain 2 adjacent nuclear factor-κB (NF-κB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown.
OBJECTIVE - Determine the role of the 5' NF-κB-binding element in expression of the endogenous Vcam1 gene.
METHODS AND RESULTS - Homologous recombination in embryonic stem cells was used to inactivate the 5' NF-κB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-κB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions.
CONCLUSIONS - This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-κB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries.
© 2015 American Heart Association, Inc.
0 Communities
1 Members
0 Resources
23 MeSH Terms
NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis.
Brown JD, Lin CY, Duan Q, Griffin G, Federation A, Paranal RM, Bair S, Newton G, Lichtman A, Kung A, Yang T, Wang H, Luscinskas FW, Croce K, Bradner JE, Plutzky J
(2014) Mol Cell 56: 219-231
MeSH Terms: Acetylation, Animals, Atherosclerosis, Azepines, Cell Adhesion, Cell Movement, Cells, Cultured, Chromatin, E-Selectin, Endothelial Cells, Endothelium, Vascular, Enhancer Elements, Genetic, Histones, Humans, Inflammation, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B p50 Subunit, Nuclear Proteins, Protein Binding, RNA Polymerase II, Regulatory Sequences, Nucleic Acid, SOXF Transcription Factors, Signal Transduction, Transcription Factor RelA, Transcription Factors, Transcription Initiation, Genetic, Transcription, Genetic, Triazoles, Tumor Necrosis Factor-alpha, Vascular Cell Adhesion Molecule-1
Show Abstract · Added September 6, 2016
Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
0 Communities
1 Members
0 Resources
33 MeSH Terms
Regulation of the Th1 genomic locus from Ifng through Tmevpg1 by T-bet.
Collier SP, Henderson MA, Tossberg JT, Aune TM
(2014) J Immunol 193: 3959-65
MeSH Terms: Animals, Cell Lineage, Enhancer Elements, Genetic, Epigenesis, Genetic, Genetic Loci, Interferon-gamma, Mice, Mice, Inbred BALB C, Proto-Oncogene Protein c-ets-1, RNA, Long Noncoding, Regulatory Sequences, Nucleic Acid, T-Box Domain Proteins, Th1 Cells, Transcription Factor RelA
Show Abstract · Added December 8, 2014
Long noncoding RNAs (lncRNAs), critical regulators of protein-coding genes, are likely to be coexpressed with neighboring protein-coding genes in the genome. How the genome integrates signals to achieve coexpression of lncRNA genes and neighboring protein-coding genes is not well understood. The lncRNA Tmevpg1 (NeST, Ifng-AS1) is critical for Th1-lineage-specific expression of Ifng and is coexpressed with Ifng. In this study, we show that T-bet guides epigenetic remodeling of Tmevpg1 proximal and distal enhancers, leading to recruitment of stimulus-inducible transcription factors, NF-κB and Ets-1, to the locus. Activities of Tmevpg1-specific enhancers and Tmevpg1 transcription are dependent upon NF-κB. Thus, we propose that T-bet stimulates epigenetic remodeling of Tmevpg1-specific enhancers and Ifng-specific enhancers to achieve Th1-lineage-specific expression of Ifng.
Copyright © 2014 by The American Association of Immunologists, Inc.
1 Communities
2 Members
0 Resources
14 MeSH Terms
PPM1A is a RelA phosphatase with tumor suppressor-like activity.
Lu X, An H, Jin R, Zou M, Guo Y, Su PF, Liu D, Shyr Y, Yarbrough WG
(2014) Oncogene 33: 2918-27
MeSH Terms: Animals, Cell Line, Tumor, Cell Movement, Cell Nucleus, Chemokine CCL2, Disease Models, Animal, Gene Expression, Heterografts, Humans, Male, Mice, NF-kappa B, Neoplasm Metastasis, Phosphoprotein Phosphatases, Phosphorylation, Prostatic Neoplasms, Protein Binding, Protein Phosphatase 2C, Protein Transport, Transcription Factor RelA, Transcription, Genetic, Tumor Necrosis Factor-alpha, Tumor Suppressor Proteins
Show Abstract · Added March 10, 2014
Nuclear factor-κB (NF-κB) signaling contributes to human disease processes, notably inflammatory diseases and cancer. NF-κB has a role in tumorigenesis and tumor growth, as well as promotion of metastases. Mechanisms responsible for abnormal NF-κB activation are not fully elucidated; however, RelA phosphorylation, particularly at serine residues S536 and S276, is critical for RelA function. Kinases that phosphorylate RelA promote oncogenic behaviors, suggesting that phosphatases targeting RelA could have tumor-inhibiting activities; however, few RelA phosphatases have been identified. Here, we identified tumor inhibitory and RelA phosphatase activities of the protein phosphatase 2C (PP2C) phosphatase family member, PPM1A. We show that PPM1A directly dephosphorylated RelA at residues S536 and S276 and selectively inhibited NF-κB transcriptional activity, resulting in decreased expression of monocyte chemotactic protein-1/chemokine (C-C motif) ligand 2 and interleukin-6, cytokines implicated in cancer metastasis. PPM1A depletion enhanced NF-κB-dependent cell invasion, whereas PPM1A expression inhibited invasion. Analyses of human expression data revealed that metastatic prostate cancer deposits had lower PPM1A expression compared with primary tumors without distant metastases. A hematogenous metastasis mouse model revealed that PPM1A expression inhibited bony metastases of prostate cancer cells after vascular injection. In summary, our findings suggest that PPM1A is a RelA phosphatase that regulates NF-κB activity and that PPM1A has tumor suppressor-like activity. Our analyses also suggest that PPM1A inhibits prostate cancer metastases and as neither gene deletions nor inactivating mutations of PPM1A have been described, increasing PPM1A activity in tumors represents a potential therapeutic strategy to inhibit NF-κB signaling or bony metastases in human cancer.
0 Communities
3 Members
0 Resources
23 MeSH Terms
Interactions between NF-κB and SP3 connect inflammatory signaling with reduced FGF-10 expression.
Carver BJ, Plosa EJ, Stinnett AM, Blackwell TS, Prince LS
(2013) J Biol Chem 288: 15318-25
MeSH Terms: Active Transport, Cell Nucleus, Animals, CHO Cells, Cell Nucleus, Cricetinae, Fetus, Fibroblast Growth Factor 10, Gene Expression Regulation, Humans, Immunity, Innate, Inflammation, Lipopolysaccharides, Lung, Mice, Response Elements, Sp3 Transcription Factor, Transcription Factor RelA
Show Abstract · Added March 7, 2014
Inflammation inhibits normal lung morphogenesis in preterm infants. Soluble inflammatory mediators present in the lungs of patients developing bronchopulmonary dysplasia disrupt expression of multiple genes critical for development. However, the mechanisms linking innate immune signaling and developmental programs are not clear. NF-κB activation inhibits expression of the critical morphogen FGF-10. Here, we show that interactions between the RELA subunit of NF-κB and SP3 suppress SP1-mediated FGF-10 expression. SP3 co-expression reduced SP1-mediated Fgf-10 promoter activity, suggesting antagonistic interactions between SP1 and SP3. Chromatin immunoprecipitation of LPS-treated primary mouse fetal lung mesenchymal cells detected increased interactions between SP3, RELA, and the Fgf-10 promoter. Expression of a constitutively active IκB kinase β mutant not only decreased Fgf-10 promoter activity but also increased RELA-SP3 nuclear interactions. Expression of a dominant-negative IκB, which blocks NF-κB nuclear translocation, prevented inhibition of FGF-10 by SP3. The inhibitory functions of SP3 required sequences located in the N-terminal region of the protein. These data suggested that inhibition of FGF-10 by inflammatory signaling involves the NF-κB-dependent interactions between RELA, SP3, and the Fgf-10 promoter. NF-κB activation may therefore lead to reduced gene expression by recruiting inhibitory factors to specific gene promoters following exposure to inflammatory stimuli.
1 Communities
2 Members
0 Resources
17 MeSH Terms
The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-κB.
Ziesché E, Kettner-Buhrow D, Weber A, Wittwer T, Jurida L, Soelch J, Müller H, Newel D, Kronich P, Schneider H, Dittrich-Breiholz O, Bhaskara S, Hiebert SW, Hottiger MO, Li H, Burstein E, Schmitz ML, Kracht M
(2013) Nucleic Acids Res 41: 90-109
MeSH Terms: Acetylation, Animals, Cell Line, Chemokine CXCL2, Down-Regulation, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Hydroxamic Acids, Interleukin-1, Interleukin-8, Mice, NF-kappa B, Phosphorylation, RNA Polymerase II, Signal Transduction, Transcription Factor RelA, Transcription, Genetic
Show Abstract · Added March 26, 2014
Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-κB p65 and its deacetylation at various lysines. NF-κB p65-deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-κB p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use.
2 Communities
1 Members
0 Resources
18 MeSH Terms
Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma.
Blix ES, Irish JM, Husebekk A, Delabie J, Forfang L, Tierens AM, Myklebust JH, Kolstad A
(2012) BMC Cancer 12: 478
MeSH Terms: CD40 Antigens, CD40 Ligand, CD79 Antigens, Cluster Analysis, Extracellular Signal-Regulated MAP Kinases, Flow Cytometry, Humans, Interleukins, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, B-Cell, Lymphoma, B-Cell, Marginal Zone, Models, Biological, Phospholipase C gamma, Phosphoproteins, Phosphorylation, Receptors, Antigen, B-Cell, STAT5 Transcription Factor, STAT6 Transcription Factor, Signal Transduction, T-Lymphocytes, Transcription Factor RelA
Show Abstract · Added February 15, 2013
BACKGROUND - Knowledge about signaling pathways in malignant cells may provide prognostic and diagnostic information in addition to identify potential molecular targets for therapy. B-cell receptor (BCR) and co-receptor CD40 signaling is essential for normal B cells, and there is increasing evidence that signaling via BCR and CD40 plays an important role in the pathogenesis of B-cell lymphoma. The aim of this study was to investigate basal and induced signaling in lymphoma B cells and infiltrating T cells in single-cell suspensions of biopsies from small cell lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) and marginal zone lymphoma (MZL) patients.
METHODS - Samples from untreated SLL/CLL and MZL patients were examined for basal and activation induced signaling by phospho-specific flow cytometry. A panel of 9 stimulation conditions targeting B and T cells, including crosslinking of the B cell receptor (BCR), CD40 ligand and interleukins in combination with 12 matching phospho-protein readouts was used to study signaling.
RESULTS - Malignant B cells from SLL/CLL patients had higher basal levels of phosphorylated (p)-SFKs, p-PLCγ, p-ERK, p-p38, p-p65 (NF-κB), p-STAT5 and p-STAT6, compared to healthy donor B cells. In contrast, anti-BCR induced signaling was highly impaired in SLL/CLL and MZL B cells as determined by low p-SFK, p-SYK and p-PLCγ levels. Impaired anti-BCR-induced p-PLCγ was associated with reduced surface expression of IgM and CD79b. Similarly, CD40L-induced p-ERK and p-p38 were also significantly reduced in lymphoma B cells, whereas p-p65 (NF-κB) was equal to that of normal B cells. In contrast, IL-2, IL-7 and IL-15 induced p-STAT5 in tumor-infiltrating T cells were not different from normal T cells.
CONCLUSIONS - BCR signaling and CD40L-induced p-p38 was suppressed in malignant B cells from SLL/CLL and MZL patients. Single-cell phospho-specific flow cytometry for detection of basal as well as activation-induced phosphorylation of signaling proteins in distinct cell populations can be used to identify aberrant signaling pathways.
1 Communities
1 Members
0 Resources
21 MeSH Terms
INK4a/ARF [corrected] inactivation with activation of the NF-κB/IL-6 pathway is sufficient to drive the development and growth of angiosarcoma.
Yang J, Kantrow S, Sai J, Hawkins OE, Boothby M, Ayers GD, Young ED, Demicco EG, Lazar AJ, Lev D, Richmond A
(2012) Cancer Res 72: 4682-95
MeSH Terms: Animals, Blotting, Western, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Hemangiosarcoma, Humans, I-kappa B Kinase, Interleukin-6, Mice, Mice, Knockout, NF-kappa B, Real-Time Polymerase Chain Reaction, Signal Transduction, Tissue Array Analysis, Transcription Factor RelA
Show Abstract · Added December 10, 2013
Although human angiosarcoma has been associated frequently with mutational inactivation of the tumor suppressor gene Ink4a/Arf, the underlying mechanisms have not been delineated. Here we report that malignant angiosarcoma is associated with high levels of RelA/NF-κB and IL-6 in contrast to normal vessels or benign hemagiomas. Studies of Ink4a/Arf deficient mice not only recapitulate genetic traits observed in human angiosarcoma, but also unveil a possible therapeutic link comprised of the NF-kB/IL-6/Stat3 signaling axis. In Ink4a/Arf(-/-) cells, NF-κB controlled Stat3 signaling by transcriptionally controlling the expression of IL-6, gp130, and Jak2. Further, IL-6 mediated Stat3 signaling through the sIL-6R. Inhibition of Ikkβ solely in myeloid cells was insufficient to block angiosarcoma development; in contrast, systemic inhibition of Ikkβ, IL-6, or Stat3 markedly inhibited angiosarcoma growth. Our findings offer clinical implications for targeting the NF-kB/IL-6/STAT3 pathway as a rational strategy to treat angiosarcoma.
2 Communities
5 Members
0 Resources
16 MeSH Terms