Nuclear factor-kappa B (NF-κB) is a ubiquitous transcription factor that is involved in inflammatory and immune responses, as well as in regulation of expression of many other genes related to cell survival, proliferation, and differentiation. In mammals, NF-κB comprises five subunits that can bind to promoter regions of target genes as homodimers or heterodimers. The most common dimer is the p50/p65 heterodimer. The several combinations of dimers that can be formed contribute to the heterogeneous regulation of NF-κB target genes, and this heterogeneity is further increased by interactions of the NF-κB dimers with other transcription factors, such as steroid hormone receptors, activator protein-1 (AP-1), and cAMP response element binding protein (CREB). In the thyroid, several studies have demonstrated the involvement of NF-κB in thyroid autoimmunity, thyroid cancer, and thyroid-specific gene regulation. The role of NF-κB in thyroid autoimmunity was hypothesized more than 20 years ago, after the
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NF-kappa B is a widely used regulator of inducible and tissue-specific gene control. In the cytosol, when complexed to an inhibitory molecule, I kappa B, NF-kappa B is in an inactive form and cannot bind DNA. Activation of cells with appropriate stimuli results in the dissociation of NF-kappa B from I kappa B and its translocation to the nucleus as an active binding protein. We now demonstrate that NF-kappa B binding in vitro can be inhibited by agents that modify free sulfhydryls. Binding is eliminated after treatment with N-ethylmaleimide, an alkylating agent, and diamide, an oxidizing agent. The diamide effect can be reversed by 2-mercaptoethanol. Further, 2-mercaptoethanol acts synergistically with deoxycholate plus Nonidet P-40 in converting inactive cytosolic NF-kappa B to an active DNA-binding form. It is therefore possible that modulation of the redox state of NF-kappa B could represent a post-translational control mechanism for this factor.. ...
TY - JOUR. T1 - Nuclear Role of IκB Kinase-γ/NF-κB Essential Modulator (IKKγ/NEMO) in NF-κB-dependent Gene Expression. AU - Verma, Udit N.. AU - Yamamoto, Yumi. AU - Prajapati, Shashi. AU - Gaynor, Richard B.. PY - 2004/1/30. Y1 - 2004/1/30. N2 - The IκB kinase (IKK) complex, which is composed of the two kinases IKKα and IKKβ and the regulatory subunit IKKγ/nuclear factor-κB (NF-κB) essential modulator (NEMO), is important in the cytokine-induced activation of the NF-κB pathway. In addition to modulation of IKK activity, the NF-κB pathway is also regulated by other processes, including the nucleocytoplasmic shuttling of various components of this pathway and the post-translational modification of factors bound to NF-κB-dependent promoters. In this study, we explored the role of the nucleocytoplasmic shuttling of components of the IKK complex in the regulation of the NF-κB pathway. IKKγ/NEMO was demonstrated to shuttle between the cytoplasm and the nucleus and to interact with the ...
The transcription factor nuclear factor-kappa B (NF-κB) plays an essential role in epidermal appendage induction and morphogenesis. In the epidermis of mice lacking NF-κB activity, initiation of primary hair follicle pre-placode formation is observed, but these primitive structures fail to proliferate and generate placodes. NF-κB signaling is known to modulate activity of WNT and SHH signaling at early stages of hair follicle development, but these roles do not fully account for the phenotypes observed when this pathway is blocked. To identify additional NF-κB target genes we developed a novel method to isolate and transcriptionally profile primary hair follicle placodes with active NF-κB signaling. In parallel, we compared gene expression at the same developmental stage in embryos with compromised NF-κB signaling, and wild type littermate controls. In addition to corroborating established NF-κB functions, these analyses uncovered novel NF-κB target genes with potential roles in priming ...
The transcriptional nuclear factor (NF)-kappaB can be activated by diverse stimuli such as cytokines, mitogens, oxidative stress, and lipids, leading to the transactivation of several genes that play important roles in the development of atherosclerosis. Because oxidative stress may play a key role in the pathogenesis of diabetic vascular disease, we have examined whether culture of porcine vascular smooth muscle cells (PVSMCs) under high glucose (HG) conditions (25 mmol/l) to simulate the diabetic state can lead to the activation of NF-kappaB, and also whether cytokine- or growth factor-induced NF-kappaB activation is altered by HG culture. We observed that PVSMCs cultured in HG showed significantly greater activation of NF-kappaB in the basal state compared with cells cultured in normal glucose (NG) (5.5 mmol/l). Treatment of the cells with cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin-1beta, or with growth factors, such as platelet-derived growth factor, insulin-like ...
Todays study seeks to research the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-B) activation and excitotoxicity in rats striatal neurons. degradation and phosphorylation, adjustments in the degrees of IKK, p-IKK, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced lack of striatal neurons were inhibited by Z-FF-FMK […]. Read More ». ...
Todays study seeks to research the role of cathepsin L in glutamate receptor-induced transcription factor nuclear factor-kappa B (NF-B) activation and excitotoxicity in rats striatal neurons. degradation and phosphorylation, adjustments in the degrees of IKK, p-IKK, TP53, caspase-3, beclin1, p62, and LC3II/LC3I. The results show that QA-induced lack of striatal neurons were inhibited by Z-FF-FMK […]. Read More ». ...
Around 40,000 people die from sepsis in the UK each year. Although the Surviving Sepsis Campaign -a performance improvement effort by hospitals across Europe, South America and the United States- has improved outcomes, the mortality rate remains at 31% overall, and ,70% in patients who develop sepsis-induced multiple organ failure.. Oxidative stress in patients with sepsis has been consistently described over the last 20 years by us and others (reviewed in [2]). Oxidative stress initiates inflammatory responses via activation of the redox sensitive transcription factor nuclear factor kappa B (NFkB). Mitochondrial dysfunction initiated by oxidative stress is generally accepted as a playing a major role in sepsis induced organ failure.. Production of energy takes place in mitochondria resulting in production of reactive oxygen species (ROS) as by-products. Although ROS are damaging, they are essential in cell signalling and their activity is tightly regulated by a network of antioxidants. When ...
Objective-The activation of nuclear factor-kB (NF-kB) is a crucial step in the arterial walls response to injury. The identification and characterization of the NF-kB essential modulator- binding domain (NBD) peptide, which can block the activation of the IkB kinase complex, have provided an opportunity to selectively abrogate the inflammation-induced activation of NF-kB. The aim of the present study was to evaluate the effect of the NBD peptide on neointimal formation.,br,,/br, Methods and Results-In the rat carotid artery balloon angioplasty model, local treatment with the NBD peptide (300 microg/site) significantly reduced the number of proliferating cells at day 7 (by 40%; P,0.01) and reduced injury-induced neointimal formation (by 50%; P,0.001) at day 14. These effects were associated with a significant reduction of NF-kB activation and monocyte chemotactic protein-1 expression in the carotid arteries of rats treated with the peptide. In addition, the NBD peptide (0.01 to 1 micromol/L) ...
TY - JOUR. T1 - Cytosolic-DNA-mediated, STING-dependent proinflammatory gene induction necessitates canonical NF-kB activation through TBK1. AU - Abe, Takayuki. AU - Barber, Glen N.. PY - 2014. Y1 - 2014. N2 - STING (stimulator of interferon genes) is known to control the induction of innate immune genes in response to the recognition of cytosolic DNA species, including the genomes of viruses such as herpes simplex virus 1 (HSV-1). However, while STING is essential for protection of the host against numerous DNA pathogens, sustained STING activity can lead to lethal inflammatory disease. It is known that STING utilizes interferon regulatory factor 3 (IRF3) and nuclear factor kB (NF-kB) pathways to exert its effects, although the signal transduction mechanisms remain to be clarified fully. Here we demonstrate that in addition to the activation of these pathways, potent induction of the Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) pathway was similarly observed in ...
Fischer, J.G.; Glauert, H.P.; Yin, T., 2002: Moderate Iron Overload Enhances Lipid Peroxidation in Livers of Rats, but Does Not Affect NF-kB Activation Induced by the Peroxisome Proliferator, Wy-14,643
AIMS/HYPOTHESIS: The beta cell destruction and insulin deficiency that characterises type 1 diabetes mellitus is partially mediated by cytokines, such as IL-1beta, and by nitric oxide (NO)-dependent and -independent effector mechanisms. IL-1beta activates mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), p38 and c-Jun NH2-terminal kinase (JNK), and the nuclear factor kappa B (NFkappaB) pathway. Both pathways are required for expression of the gene encoding inducible nitric oxide synthase (iNOS) and for IL-1beta-mediated beta cell death. The molecular mechanisms by which these two pathways regulate beta cell Nos2 expression are currently unknown. Therefore, the aim of this study was to clarify the putative crosstalk between MAPK and NFkappaB activation in beta cells. MATERIALS AND METHODS: The MAPKs ERK, p38 and JNK were inhibited by SB203580, PD98059 or Tat-JNK binding domain or by cells overexpressing the JNK binding domain. The effects
Negative selection eliminates thymocytes bearing autoreactive T cell receptors (TCR) via an apoptotic mechanism. We have cloned an inhibitor of NF-kappa B, I kappa BNS, which is rapidly expressed upon TCR-triggered but not dexamethasone- or gamma irradiation-stimulated thymocyte death. The predicted protein contains seven ankyrin repeats and is homologous to I kappa B family members. In class I and class II MHC-restricted TCR transgenic mice, transcription of I kappa BNS is stimulated by peptides that trigger negative selection but not by those inducing positive selection (i.e., survival) or nonselecting peptides. I kappa BNS blocks transcription from NF-kappa B reporters, alters NF-kappa B electrophoretic mobility shifts, and interacts with NF-kappa B proteins in thymic nuclear lysates following TCR stimulation. Retroviral transduction of I kappa BNS in fetal thymic organ culture enhances TCR-triggered cell death consistent with its function in selection.. ...
en] The role of nuclear factor (NF)-kappa B in the regulation of apoptosis in normal and cancer cells has been extensively studied in recent years. Constitutive NF-kappa B activity in B lymphocytes as well as in Hodgkins disease and breast cancer cells protects these cells against apoptosis. It has also been reported that NF-kappa B activation by tumor necrosis factor (TNF)-alpha, chemotherapeutic drugs, or ionizing radiations can protect several cell types against apoptosis, suggesting that NF-kappa B could participate in resistance to cancer treatment. These observations were explained by the regulation of antiapoptotic gene expression by NF-kappa B. However, in our experience, inhibition of NF-kappa B activity in several cancer cell lines has a very variable effect on cell mortality, depending on the cell type, the stimulus, and the level of NF-kappa B inhibition. Moreover, in some experimental systems, NF-kappa B activation is required for the onset of apoptosis. Therefore, it is likely ...
Title: Molecular Mechanisms of Bcl10-Mediated NF-kappaB Signal Transduction Author: Felicia D. Langel, Ph.D., 2006 Directed by: Brian C. Schaefer, Ph.D., Assistant Professor, Department of Microbiology and Immunology Bcl10 is a key signaling intermediate in the TCR-to-NF-?B pathway in T lymphocytes. It is currently believed that, once activated, Bcl10 functions within a multiprotein signaling complex that activates the IKK complex. Bcl10 is thought to regulate this signaling complex, but how it transmits its signal through the complex is unknown. A thorough knowledge of Bcl10 biology is critical to understanding how Bcl10 functions and how it regulates its binding partners. In this study, we used mutational analysis, molecular imaging, biochemistry, and computer/bioinformatics modeling to elucidate a structure and function for Bcl10. From our data, we identified a novel binding site for MALT1 within the Bcl10 protein, hypothesized that this site is completely separate and distinct from the ...
The sequence and biochemical properties of the product of the cloned cDNA for the p65 subunit of nuclear factor kappa B (NF-kappa B) have been determined. The cDNA has an open reading frame of 549 amino acids capable of encoding a 60 kd protein. NF-kappa B p65 contains an amino-terminal region of 320 amino acids with extensive similarity to the oncogene c-rel and lesser similarity to NF-kappa B p50. In vitro translated p65 forms a DNA-binding complex with NF-kappa B p50, and the binding of this complex can be specifically inhibited by purified I kappa B. Progressive carboxy-terminal deletions of p65 show that, contrary to previous assumptions, p65 does include a DNA-binding domain that in vivo might become activated only through hetero-oligomerization with p50. DNA binding by truncated p65 is inhibited by I kappa B, thus mapping the I kappa B interaction domain to the rel-homologous region and suggesting that I kappa B exerts its inhibitory effect upon NF-kappa B primarily through interaction with p65.
In contrast, compared to NTG HF, TG HF hearts had markedly reduced (p , 0.01) NF-κB DNA activation, and significantly less (p , 0.05) LV dilatation (LVEDV 52 ± 20 μL) and systolic dysfunction (LVEF 61 ± 8 %), but a similar degree of hypertrophy as assessed by LV/TL and ANF expression. Moreover, as compared to TG sham, TG HF hearts exhibited no TNF, IL-1β, or IL-6 upregulation. Importantly, as compared to TG sham, TG HF showed only a mild increase in apoptotic rate (0.4 ± 0.3 %) that was not statistically significant (p = 0.45), suggesting that differences in the rate of cell loss between NTG and TG HF may account for comparable degrees of chamber hypertrophy despite differences in LV dilatation.. Conclusion: Persistent NF-κB activation imparts detrimental effects in post-infarction HF and worsens LV remodeling, related, at least in part, to augmentation of inflammatory cytokine expression and apoptosis. ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) refers to a protein complex functional in signaling pathways, particularly in response to stress stimuli. There are two signaling pathways leading to the activation of NF-kB signaling, known as the canonical (or classical) pathway, the non-canonical (or alternative) pathway.. In the canonical NF-kB pathway, NF-kB dimers such as p50/RelA are maintained in the cytoplasm by interaction with an independent Inhibitor of NF-kB (IkB) molecule. When the upstream signaling is active, an IkBa kinase (IKK) complex consisting of catalytic kinase subunits IKKa and/or IKKb and the scaffold protein NEMO will be recruited to the cytoplasmic adaptor of certain cell surface receptor and stay activated. Activation of IKK complex will consequently phosphorylate the IkB at two serine residues, which induce the proteasomal degradation of IkB. Released from IkB, NF-kB dimers then translocate into the nucleus and bind with a consensus sequence ...
In this review poster, we researched the function, regulation, and structure of NF-κB as it relates to carcinogenesis. Found in almost all animal cells, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a transcription factor that plays various roles in cellular proliferation, cell survival, inflammation, and T cell activation. There are two different NF-κB signaling pathways: the canonical pathway and the non-canonical pathway. NF-κB forms a p50/Rel A heterodimer in the canonical pathway and a p52/ Rel B heterodimer in the non-canonical pathway. NF-κB protein is normally sequestered in the cytoplasm as an inactive complex with a κB inhibitor (IκB) protein. Outside stimuli such as reactive oxygen species (ROS) and tumor necrosis factor alpha (TNF-α) activate cell surface receptors such as Toll-Like Receptors (TLRs) and Receptor Activators of NF-κB (RANK). These surface receptors, in turn, activate IκB kinase (IKK). IKK phosphorylates IκB, which causes ...
Being naturally curious necessitates spending time for more discovery. This statement holds true in the presence of the conduit and the means for gathering information. As I was curious reading about bee venom and its potential role in targeting tumors, I encountered NF-kB, which I already did encounter it long ago in my virology and immunology classes.. I needed a refresh, so I sought for papers that could help me with that.. What is NF-kB again? It is the nuclear factor kappa-light-chain-enhancer of activated B cells (thats mouthful). It has so many roles, namely in cellular growth, immunity, and oncogenesis. It is a transcription factor that upon activation through phosphorylation by the IKK (IkB kinase) protein, it will go into nucleus and bind to specific DNA sequence.. In its inactive state, it is sequestered in the cytoplasm of a cell. It is sequestered by having its nuclear localization signals masked by a protein called IkB. Thus activation of NF-kB is resulted from the degradation of ...
Previous investigations suggest that DL-3-n-butylphthalide (NBP) is a promising multifaceted drug for the treatment of stroke. It is not clear whether NBP can treat traumatic brain injury (TBI) and what could be the mechanisms of therapeutic benefits. To address these issues, TBI was induced by a controlled cortical impact in adult male mice. NBP (100 mg/kg) or saline was intraperitoneally administered within 5 min after TBI. One day after TBI, apoptotic events including caspase-3/9 activation, cytochrome c release from the mitochondria, and apoptosis-inducing factor (AIF) translocation into the nucleus in the pericontusion region were attenuated in NBP-treated mice compared to TBI-saline controls. In the assessment of the nuclear factor kappa-light-chain-enhancer of activated B (NF-κB) pathway, NBP ameliorated the p65 expression and the p-IκB-α/IκB-α ratio, indicating reduced NF-κB activation. Consistently, NBP reduced the upregulation of proinflammatory cytokines such as tumor ...
DNA transcription control. Computer model showing a molecule of the FP50 homodimer (green) from NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) bound to the DNA interferon regulatory factor (IRF) recognition sequence on a strand of DNA (deoxyribonucleic acid, orange). NF-kB is a protein complex that controls the transcription of DNA. IRFs are proteins that regulate the transcription of interferons, which are released in response to the presence of pathogens. - Stock Image C010/4990
Nuclear factor-kappa B (NF-kappa B) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF-kappa B (p50/p65) heterodimer complex in association with NF-kappa B inhibitor I kappa B alpha to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (similar to 2 million) and the Schrodingers medically relevant Glide fragments library (similar to 670) were used to create the e-pharmacophore models at the potential binding site which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP ...
Statement from paper: To test whether RIP3 and RIP4 have to be ubiquitinated by cIAP1/2 in order to mediate NF-kB activation, we compared RIP-mediated NF-kB luciferase reporter activity when ectopically expressed in HEK293T cells in the presence or absence of the IAP inhibitor BV6, a treatment that induces rapid auto-ubiquitination and degradation of endogenous cIAP1/2[41]. As shown in Figure 4A, BV6 treatment greatly impaired TNF and RIP1 RIP4-induced NF-kB activation but had no impact on TAK1-mediated NF-kB induction (Figure 4A). Those results, which indicate that cIAP1/2 act upstream of TAK1, are consistent with a role for cIAP1/2 as E3 ligases regulating RIP14-mediated activation of NF-kB. Expressed in LEGO: http://go-genkisugi.rhcloud.com/seed/model/gomodel:taxon_9606-5408ded30000003 previous recommendation RIP3: GO:0051092 positive regulation of NF-kappaB transcription factor activity: PMID:21931591: dependent_on(UniProtKB:Q13490 IAP2) Ruth comment: this highlights the problem of ...
Neuroinflammation is an essential defense response to pathogens or injury in the central nervous system, but might also contribute to the pathogenesis of neurological disorders. Astrocytes are glial cells that are implicated in neuroinflammation, but also in brain development and homeostasis. The NF-kappa B transcription factors are key regulators of inflammation that also regulate in cell proliferation, differentiation and survival. Previous studies suggested that NF-kappa B activation in astrocytes might indeed be critical for neuroinflammatory responses and its pathological consequences. In the present study a novel mouse model was characterized to further elucidate the role of astroglial NF-Kappa B signaling in neuroinflammation. This model conditionally expresses a constitutively active mutant of the NF-kappa B activating kinase IKK2 in astrocytes. This results in astroglial NF-kappa B activation, which is sufficient to induce a prominent neuroinflammatory response and impairs brain ...
Neuroinflammation is an essential defense response to pathogens or injury in the central nervous system, but might also contribute to the pathogenesis of neurological disorders. Astrocytes are glial cells that are implicated in neuroinflammation, but also in brain development and homeostasis. The NF-kappa B transcription factors are key regulators of inflammation that also regulate in cell proliferation, differentiation and survival. Previous studies suggested that NF-kappa B activation in astrocytes might indeed be critical for neuroinflammatory responses and its pathological consequences. In the present study a novel mouse model was characterized to further elucidate the role of astroglial NF-Kappa B signaling in neuroinflammation. This model conditionally expresses a constitutively active mutant of the NF-kappa B activating kinase IKK2 in astrocytes. This results in astroglial NF-kappa B activation, which is sufficient to induce a prominent neuroinflammatory response and impairs brain ...
The Tumor Necrosis Factor (TNF) Receptor Associated Factor 6 (TRAF6) is an intracellular signal transducers, being responsible for mediating many of the activation events initiated by TNF receptor (TNFR) and Toll-like/Interleukin-1 and 18 receptor (TIR) families, in which TRAF6 plays central roles in numerous biological processes including innate and adaptive immunity, osteoclastogenesis and bone development, CD40 signaling, neuronal cell development, and cancer cell progression. Acting as an E3 ubiquitin ligase, TRAF6 catalyzes lysine 63 linked poly-ubiquitination of itself and many other signal transducers upon association with upstream effectors possessing a short TRAF Interaction Motif (TIM) peptide sequence in the NF-KappaB signal transduction pathway. Ectopic over-expression of TRAF6 acts as a dominant-positive. However, the mechanism of TRAF6 activation by upstream activators or over-expression is unclear. This motivated our enthusiasm to study the role played by ubiquitination for TRAF6 in NF
Nuclear factor-kappa B (NF-kappaB) is an important transcription factor, involved in many immune and inflammatory responses. It is critical in HIV gene expression as it has kappa B binding sites in the HIV-1 long-terminal repeat. Hence, targeting NF-kappaB to prevent its DNA binding holds a signific …
The May laboratory investigates signal transduction pathways that lead to altered patterns of gene expression in immune and inflammatory responses. We are particularly interested in understanding how the loss of control of normal signaling contributes to the progression of diseases such as chronic inflammation and cancer. Our goal is to determine the specific molecular events underlying aberrant signals and to define realistic targets for selectively blocking abnormal, while maintaining physiologically normal responses. The focus of our work is the Nuclear Factor (NF)-kappa B transcription factor activation pathway that is critical for inflammation, innate and adaptive immunity and lymphocyte development. NF-kappa B activation is typically a rapid and transient response, however constitutive NF- kappa B activity occurs at sites of chronic inflammation and in various tumors, leukemias and lymphomas. We combine cellular, molecular and genetic approaches to determine the mechanisms that redirect ...
Increasing evidence from epidemiological, preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer. The molecular mechanism(s) by which chronic inflammation drives cancer initiation and promotion include increased production of pro-inflammatory mediators, such as cytokines, chemokines, reactive oxygen intermediates, increased expression of oncogenes, COX-2 (cyclo-oxygenase-2), 5-LOX (5-lipoxygenase) and MMPs (matrix metalloproteinases), and pro-inflammatory transcription factors such as NF-κB (nuclear factor κB), STAT3 (signal transducer and activator of transcription 3), AP-1 (activator protein 1) and HIF-1α (hypoxia-inducible factor 1α) that mediate tumour cell proliferation, transformation, metastasis, survival, invasion, angiogenesis, chemoresistance and radioresistance. These inflammation-associated molecules are activated by a number of environmental and lifestyle-related factors including ...
Danger signals activate Toll-like receptors (TLRs), thereby initiating inflammatory responses. Canonical TLR signalling, via Toll/Interleukin-1 receptor domain (TIR)-containing adaptors and proinflammatory transcription factors such as NF-κB, occurs in many cell types; however, additional mechanisms are required for specificity of inflammatory responses in innate immune cells. Here we show that SCIMP, an immune-restricted, transmembrane adaptor protein (TRAP), promotes selective proinflammatory cytokine responses by direct modulation of TLR4. SCIMP is a non-TIR-containing adaptor, binding directly to the TLR4-TIR domain in response to lipopolysaccharide. In macrophages, SCIMP is constitutively associated with the Lyn tyrosine kinase, is required for tyrosine phosphorylation of TLR4, and facilitates TLR-inducible production of the proinflammatory cytokines IL-6 and IL-12p40. Point mutations in SCIMP abrogating TLR4 binding also prevent SCIMP-mediated cytokine production. SCIMP is, therefore, an immune
Members of the NF-kappa B/Rel transcription factor family have been shown recently to be required for cellular transformation by oncogenic Ras and by other oncoproteins and to suppress transformation-associated apoptosis. Furthermore, NF-kappa B has been shown to be activated by several oncoproteins …
Among the many target genes of the transcription factor NF-kappaB are p53 and c-myc, both of which are involved in apoptosis. This prompted us to investigate the role of NF-kappaB in this process. We report that NF-kappaB is potently activated upon serum starvation, a condition leading to apoptosis in 293 cells. Similar to Bcl-2, a transdominant-negative mutant of the NF-kappaB p65 subunit partially inhibited apoptosis, indicating a direct involvement of the transcription factor in induction of cell death. As expected, the p65 mutant suppresses kappaB-dependent gene expression. Surprisingly, transiently or stably overexpressed Bcl-2 had the same effect. The transcription inhibitory activity of the two proteins correlated with their cell death protective potential. Like Bcl-2, the related protein Bcl-xL but not Bcl-xS was able to suppress kB-dependent transcription. Bcl-2 inhibited NF-kappaB activity by an unusual mechanism. It did not prevent the release of IkappaB in the cytoplasm but ...
Death receptor 6 (DR6, TNFRSF21) is a member of the death receptor family, which belongs to the superfamily of tumor necrosis factor receptors.
Tumour necrosis factor (p55 or p60) receptor (TNFR) 1 is the major receptor that activates pro-inflammatory signalling and induces gene expression in response to TNF. Consensus is lacking for the function of (p75 or p80) TNFR2 but experiments in mice have suggested neuro-, cardio- and osteo-protective and anti-inflammatory roles. It has been shown in various cell types to be specifically required for the induction of TNFR-associated factor-2 (TRAF2) degradation and activation of the alternative nuclear factor (NF)-kappaB pathway, and to contribute to the activation of mitogen-activated protein kinases (MAPK) and the classical NF-kappaB pathway. We have investigated the signalling functions of TNFR2 in primary human and murine macrophages. We find that in these cells TNF induces TRAF2 degradation, and this is blocked in TNFR2(-/-) macrophages. TRAF2 has been previously reported to be required for TNF-induced activation of p38 MAPK. However, TRAF2 degradation does not inhibit TNF-induced tolerance of p38
Cross-species comparison revealed that conservation of NF-κB family - related TFBS motifs is much higher in the Early genes group than in the Late genes group. The highest numbers of common DNA binding motifs considered were found in the locations where the adjusted promoter sequences were highly conserved. For almost all Early genes, the NF-κB-family related TFBS motifs were conserved between most pairs of species, with the exception of comparison between mouse and cattle in TNF. As we presumed the best promoter sequence conservation and interspecies conservation of TF binding motifs persisted between human and chimp, followed in many cases by that between human and cattle. In the case of two Early genes, REL and TNFAIP3 comparison, no conserved NF-κB-family related TFBS were found between chimpanzee or mouse and cattle. In human versus cattle comparison two single non-overlapping binding sites were found, but this is a low score in comparison with the number of conserved TFBS found in other ...
Phosphorylation of RELA plays a key role in regulating NF-κB activation and function. Subsequent to NF-κB nuclear translocation, RELA undergoes site-specific post-translational modifications to further enhance the NF-κB function as a transcription factor. RELA can either be phosphorylated in the RHD region or the TAD region, attracting different interaction partners. Triggered by lipopolysaccharide (LPS), protein kinase A (PKA) specifically phosphorylates serine 276 in the RHD domain in the cytoplasm, controlling NF-κB DNA-binding and oligomerization.[6] On the other hand, mitogen and stress-activated kinase 1 (MSK1) are also able to phosphorylate RELA at residue 276 under TNFα induction in the nucleus, increasing NF-κB response at the transcriptional level.[7] Phosphorylation of serine 311 by protein kinase C zeta type (PKCζ) serves the same purpose.[8] Two residues in the TAD region are targeted by phosphorylation. After IL-1or TNFα stimulation, serine 529 is phosphorylated by casein ...
The aim of the studies described in this thesis was to investigate the development of experimental hereditary hypertension and to persistently ameliorate the development of hypertension due brief interventions during early development (perinatal treatment). We used two different models of experimental hereditary hypertension, namely the spontaneously hypertensive rat (SHR) and ... read more the fawn-hooded hypertensive rat (FHH). SHR and FHH dams and their offspring were supplemented with five different treatments during pregnancy and lactation. We found that in both models the perinatal manipulation on the balance between nitric oxide (NO) and reactive oxygen species, with L-arginine and antioxidants, resulted in a persistent decrease in blood pressure and prevented renal injury in the FHH. A similar effect was found after perinatal inhibition of the inflammatory transcription factor NF-kappaB. With micoarray analysis we investigated the transcriptome throughout life in SHR and we developed a ...
PubMed comprises more than 30 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.
Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription ...
BACKGROUND: The zinc finger protein A20 is an ubiquitinating/deubiquitinating enzyme essential for the termination of inflammatory reactions through the inhibition of nuclear factor kappaB (NF-kappaB) signaling. Moreover, it also shows anti-apoptotic activities in some cell types and proapoptotic/pronecrotic effects in others. Although it is known that the regulation of inflammatory and cell death processes are critical in proper brain functioning and that A20 mRNA is expressed in the CNS, its role in the brain under physiological and pathological conditions is still unknown. METHODS: In the present study, we have evaluated the effects of A20 overexpression in mixed cortical cultures in basal conditions: the in vivo pattern of endogenous A20 expression in the control and N-methyl-d-aspartate (NMDA) excitotoxically damaged postnatal day 9 immature rat brain, and the post-injury effects of A20 overexpression in the same lesion model. RESULTS: Our results show that overexpression of A20 in mixed cortical
Nuclear factor kappa B (NF-κB) is a transcription factor that is associated with inflammation. Without stimulus, NF-κB is repressed by inhibitor of kappa B (IκB) proteins. Upon stimulation by TNF, IL-1, and/or pathogen-associated molecular patterns (e.g. LPS), adaptor proteins like MyD88 and TRAF will signal for the activation of inhibitor of kappa B kinase (IκBK), which goes on to phosphorylate either IκB (canonical pathway) or the p100 subunit of NF-κB (alternative pathway). The pathway of activation is dictated by the signal: TNF, IL-1 and TLR stimulation activate the classical pathway, while CD40L and BAFF activate the alternative pathway. In the classical pathway, phosphorylated IκB is ubiquitinated and then degraded, allowing for NF-κB to enter the nucleus and turn on transcription of genes for cytokines like TNFα and IL-1. The alternative pathway involves activation of the NF-κB-inducing kinase (NIK), which turns on IκB kinase-α (IKKα), leading to p100 phosphorylation.. Click ...
E3330 (APX-3330) is a direct, orally active AP endonuclease 1 (APE1; also known as REF-1) inhibitor, which suppresses NF-κB DNA-binding activity. E3330 (APX-3330) blocks TNF-α-induced activation of IL-8 production in liver cancer cell lines. E3330 (APX-3330) shows anticancer properties, such as inhibition of cancer cell growth and migration. - Mechanism of Action & Protocol.
Induction of apoptosis and NF-kB activation by Apaf-1/Nod1 family members and DD proteins (Inohara et al., 2000). The more recent study suggested that IKKgamma binds to the site in C-terminal regulatory region of IKKbeta which is located after the HLH motif. Images ...
PMID 15459013] Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. ...
The nuclear factor-kappaB (NF-kappaB) transcription factors have emerged as major regulators of programmed cell death (PCD) whether via apoptosis or necrosis. In this context, NF-kappaBs activity has important ramifications for normal tissue development, homoeostasis and the physiological functions of various cell systems including the immune, hepatic, epidermal and nervous systems. However, improper regulation of PCD by NF-kappaB can have severe pathologic consequences, ranging from neurodegeneration to cancer, where its activity often precludes effective therapy. Although NF-kappaB generally protects cells by inducing the expression genes encoding antiapoptotic and antioxidizing proteins, its role in apoptosis and necrosis can vary markedly in different cell contexts, and NF-kappaB can sensitize cells to death-inducing stimuli in some instances. This article describes our current knowledge of the role of NF-kappaB in apoptosis and necrosis, and focuses on the many advances since we last ...
Relative abundance of full-length and truncated FOXP1 isoforms is associated with differential NFkappaB activity in Follicular Lymphoma. Leuk Res. 2009 Dec; 33(12):1699-702 ...
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BACKGROUND: Unloading of skeletal muscle causes atrophy and loss of contractile function. In part, this response is believed to be mediated by the transcription factor nuclear factor-kappa B (NF-kappaB). Both curcumin, a component of the spice turmeric, and N-acetylcysteine (NAC), an antioxidant, inhibit activation of NF-kappaB by inflammatory stimuli, albeit by different mechanisms. In the present study, we tested the hypothesis that dietary curcumin or NAC supplementation would inhibit unloading-induced NF-kappaB activity in skeletal muscle and thereby protect muscles against loss of mass and function caused by prolonged unloading. METHODS: We used hindlimb suspension to unload the hindlimb muscles of adult mice. Animals had free access to drinking water or drinking water supplemented with 1% NAC and to standard laboratory diet or diet supplemented with 1% curcumin. For 11 days, half the animals in each dietary group were suspended by the tail (unloaded) and half were allowed to ambulate freely.
Humans are symbiotic organisms; our genome is populated with a substantial number of endogenous retroviruses (ERVs), some remarkably intact, while others are remnants of their former selves. Current research indicates that not all ERVs remain silent passengers within our genomes; re-activation of ERVs is often associated with inflammatory diseases. ERVK is the most recently endogenized and transcriptionally active ERV in humans, and as such may potentially contribute to the pathology of inflammatory disease. Here, we showcase the transcriptional regulation of ERVK. Expression of ERVs is regulated in part by epigenetic mechanisms, but also depends on transcriptional regulatory elements present within retroviral long terminal repeats (LTRs). These LTRs are responsive to both viral and cellular transcription factors; and we are just beginning to appreciate the full complexity of transcription factor interaction with the viral promoter. In this review, an exploration into the inflammatory transcription
Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mumol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-kappaB or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IkappaB-alpha protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, ...
NF-kappa B, a master regulator of several signaling cascades, is known to be actively transported in the nucleus in response to various stimuli. Here, we found that NF-kappa B is associated with polymeric tubulin and co-localized with microtubules in MCF-7 cells. Using TN16, a known microtubule targeting agent, we found that microtubule dynamics plays a critical role in NF-kappa B-microtubule interaction. Treatment of cells with low concentrations of TN16 (25 and 50 nM) that suppressed microtubule dynamics without visibly affecting microtubule organization enhanced the association of NF-kappa B with microtubules and facilitated nuclear translocation of NF-kappa B. Colchicine and vinblastine also produced similar nuclear translocation of NF-kappa B. Further, nuclear import of NF-kappa B activated apoptotic pathway in the cells that were blocked in mitosis by TN16 treatment suggesting that NF-kappa B acts as a pro-apoptotic protein in response to the suppression of microtubule dynamics. ...
Aspirin inhibits the activation of NF-kappa B, thus prevents the degradation of the NF-kappa B inhibitor, I kappa B, and therefore NF-kappa B is retained in the cytosol. Aspirin also inhibits NF-kappa B-dependent transcription from the Ig kappa enhancer and the human immunodeficiency virus (HIV) long terminal repeat (LTR) in transfected T cells. [1] Aspirin and salicylate are mediated in part by their specific inhibition of IKK-beta, thereby preventing activation by NF-kappaB of genes involved in the pathogenesis of the inflammatory response. [2] Aspirin is protective against neurotoxicity elicited by the excitatory amino acid glutamate in rat primary neuronal cultures and hippocampal slices. [3] Aspirin triggers transcellular biosynthesis of a previously unrecognized class of eicosanoidsduring coincubations of human umbilical vein endothelial cells (HUVEC) and neutrophils [polymorphonuclear leukocytes (PMN)]. Aspirin evokes a unique class of eicosanoids formed by acetylated PGHS-2 and ...
Early life adversity increases the risk for later infection. The febrile response is a potent mechanism to combat infection. We found that variations in maternal care influence the febrile response to 50µg/kg lipopolysaccharide (LPS) challenge in adult male rats. Offspring from low-licking/grooming (LG) mothers had an increased febrile response compared to offspring from high-LG mothers challenged with LPS. Low-LG offspring had reduced plasma IL-6 at one and two hours post challenge compared to high-LG offspring. IL-6 gene expression in the anterior hypothalamus was induced following LPS challenge in low-LG offspring but not in high-LG offspring at two hours post challenge. Occupancy of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) to the IL-6 promoter region in the anterior hypothalamus was greater in low-LG offspring treated with LPS than in high-LG offspring. These findings suggest greater activation of thermoregulatory neurons in the ...
I kappa B-alpha inhibits transcription factor NF-kappa B by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate I kappa B-alpha. This liberates NF-kappa B to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-kappa B correlates with phosphorylation of I kappa B-alpha and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 of I kappa B-alpha was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-kappa B could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-kappa B. ...
TY - JOUR. T1 - Various Mechanisms Involve the Nuclear Factor (Erythroid-Derived 2)-Like (NRF2) to Achieve Cytoprotection in Long-Term Cisplatin-Treated Urothelial Carcinoma Cell Lines. AU - Skowron, Margaretha A.. AU - Niegisch, Guenter. AU - Albrecht, Philipp. AU - van Koeveringe, Gommert. AU - Romano, Andrea. AU - Albers, Peter. AU - Schulz, Wolfgang A.. AU - Hoffmann, Michele J.. PY - 2017/8. Y1 - 2017/8. KW - urothelial carcinoma (UC). KW - cisplatin resistance. KW - nuclear factor (erythroid-derived 2)-like 2 (NRF2). KW - sequestosome 1 (p62. KW - SQSTM1). KW - Kelch-like ECH-associated protein 1 (KEAP1). KW - cytoprotection. KW - glutathione. KW - nuclear factor kappa-light-chain-enhancer of activated B cells (NF-B) pathway. KW - hippo pathway. KW - OVARIAN-CANCER CELLS. KW - BLADDER-CANCER. KW - OXIDATIVE STRESS. KW - SIGNALING PATHWAY. KW - CHEMOTHERAPEUTIC-AGENTS. KW - TRANSCRIPTION FACTORS. KW - ANTIOXIDANT RESPONSE. KW - CROSS-TALK. KW - BETA-TRCP. KW - RESISTANCE. U2 - ...
Exposure of mammalian cells to radiation triggers the ultraviolet (UV) response, which includes activation of activator protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B). This was postulated to occur by induction of a nuclear signaling cascade by damaged DNA. Recently, induction of AP-1 by UV was shown to be mediated by a pathway involving Src tyrosine kinases and the Ha-Ras small guanosine triphosphate-binding protein, proteins located at the plasma membrane. It is demonstrated here that the same pathway mediates induction of NF-kappa B by UV. Because inactive NF-kappa B is stored in the cytosol, analysis of its activation directly tests the involvement of a nuclear-initiated signaling cascade. Enucleated cells are fully responsive to UV both in NF-kappa B induction and in activation of another key signaling event. Therefore, the UV response does not require a signal generated in the nucleus and is likely to be initiated at or near the plasma membrane. ...
INTRODUCTION: To explore the effect of rosiglitazone on myocardial injury in septic rats through the nuclear factor kappa-light-chain-enhancer of
The NF-kappaB/Rel transcription factors participate in the activation of immune system regulatory genes and viral early genes including the human immunodeficiency virus type 1 long terminal repeat. NF-kappaB/Rel proteins are coupled to inhibitory molecules, collectively termed IkappaB, which are responsible for cytoplasmic retention of NF-kappaB. Cell activation leads to the phosphorylation and degradation of IkappaBalpha, permitting NG-kappaB/Rel translocation to the nucleus and target gene activation. To further characterize the signaling events that contribute to IkappaBalpha phosphorylation, a kinase activity was isolated from Jurkat T cells that specifically interacted with IkappaBalpha in an affinity chromatography step and phosphorylated IkappaBalpha with high specificity in vitro. By using an in-gel kinase assay with recombinant IkappaBalpha as substrate, two forms of the kinase (43 and 38 kDa) were identified. Biochemical criteria and immunological cross-reactivity identified the kinase ...
Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.
Acute psychosocial stress stimulates transient increases in circulating pro-inflammatory plasma cytokines, but little is known about stress effects on anti-inflammatory cytokines or underlying mechanisms. We investigated the stress kinetics and interrelations of pro- and anti-inflammatory measures on the transcriptional and protein level.,br /,,br /,Forty-five healthy men were randomly assigned to either a stress or control group. While the stress group underwent an acute psychosocial stress task, the second group participated in a non-stress control condition. We repeatedly measured before and up to 120 min after stress DNA binding activity of the pro-inflammatory transcription factor NF-κB (NF-κB-BA) in peripheral blood mononuclear cells, whole-blood mRNA levels of NF-κB, its inhibitor IκBα, and of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6, and the anti-inflammatory cytokine IL-10. We also repeatedly measured plasma levels of IL-1ß, IL-6, and IL-10.,br /,,br /,Compared ...
Intracranial aneurysms are associated with disturbed velocity patterns, and chronic inflammation, but the relevance for these findings are currently unknown. Here, we show that (disturbed) shear stress induced by vortices is a sufficient condition to activate the endothelial NF-kB pathway, possibly through a mechanism of mechanosensor de-activation. We provide evidence for this statement through in-vitro live cell imaging of NF-kB in HUVECs exposed to different flow conditions, stochastic modelling of flow induced NF-kB activation and induction of disturbed flow in mouse carotid arteries. Finally, CFD and immunofluorescence on human intracranial aneurysms showed a correlation similar to the mouse vessels, suggesting that disturbed shear stress may lead to sustained NF-kB activation thereby offering an explanation for the close association between disturbed flow and intracranial aneurysms.
Results (1) PAH specimens showed co-localisation of p65 within CD68+ macrophages in 75.4 (64.8-84.6)% of samples. Airway epithelium, neutrophils and lymphocytes were also positive for p65. (2) Pulmonary arterial medial thickness was increased in PAH compared to controls, at 33.7 (18.8-67.9)% in vessels 100-250 mm external diameter (E.D.) and 27.2 (14.8-44.2)% in vessels 250-500 mm ED, vs 17.7 (11.2-30.3)% and 14.9 (11.8-17.8)% in controls (p,0.0001 between groups). (3) Nuclear p65 was present in pulmonary artery endothelial cells (EC) but not other vascular cells including pulmonary artery smooth muscle cells in PAH: 53.9 (0-100)% of vessels 100-250 mm E.D. and 53.1 (0-100)% of those 250-500 mm E.D. scored EC p65 positivity in PAH compared to 7.5 (0-25.0)% in 100-250 mm ED and 4.7 (0-21.1)% in 250-500 mm ED in controls (p,0.0001 between groups) (Abstract P29 Figure 1). ...
Specific families of pattern recognition receptors are responsible for detecting microbial pathogens and generating innate immune responses. Toll-like receptors (TLRs) are membrane-bound receptors identified as homologs of Toll in Drosophila. Mammalian TLRs are expressed on innate immune cells, such as macrophages and dendritic cells, and respond to the membrane components of Gram-positive or Gram-negative bacteria. Pathogen recognition by TLRs provokes rapid activation of innate immunity by inducing production of proinflammatory cytokines and upregulation of costimulatory molecules. TLR signaling pathways are separated into two groups: a MyD88-dependent pathway that leads to the production of proinflammatory cytokines with quick activation of NF-{kappa}B and MAPK, and a MyD88-independent pathway associated with the induction of IFN-beta and IFN-inducible genes, and maturation of dendritic cells with slow activation of NF-{kappa}B and MAPK ...
Chemotherapy resistance of pancreatic cancer has been previously associated with hyperactivity of NF-κB [7, 11, 19, 33]. The discovery that GSK-3 regulates NF-κB [26], and that its inhibition has anti-inflammatory and growth inhibitory effects, holds promise to resolve the problem of drug resistance in cancers with inflammatory origin including pancreatic cancer [26, 28, 34]. In this paper, using a panel of six genetically distinct pancreatic cancer cell lines we confirmed previous reports that pharmacological inhibition of GSK-3 suppresses NF-κB transcriptional activity and is toxic to pancreatic cancer cells in a dose- and time-dependent manner [28]. We also show for the first time that GSK-3 inhibition potently reduces the clonogenic survival of pancreatic cancer cells. However, contrary to our hypothesis GSK-3/NF-κB inhibition did not sensitize to gemcitabine chemotherapy.. GSK-3 is a kinase involved in many cellular processes including energy metabolism, transcriptional regulation, cell ...
Vaccinia virus (VACV) protein N1 is an intracellular virulence factor and belongs to a family of VACV B-cell lymphoma (Bcl)-2-like proteins whose members inhibit apoptosis or activation of pro-inflammatory transcription factors, such as interferon (I
In vivo IkappaB alpha is a stronger inhibitor of NF-kappaB than is IkappaB beta. This difference is directly correlated with their varying abilities to inhibit NF-kappaB binding to DNA in vitro and in vivo. Moreover, IkappaB alpha, but not IkappaB beta, can remove NF-kappaB from functional preinitiation complexes in in vitro transcription experiments. Both IkappaBs function in vivo not only in the cytoplasm but also in the nucleus, where they inhibit NF-kappaB binding to DNA. The inhibitory activity of IkappaB beta, but not that of IkappaB alpha, is facilitated by phosphorylation of the C-terminal PEST sequence by casein kinase II and/or by the interaction of NF-kappaB with high-mobility group protein I (HMG I) on selected promoters. The unphosphorylated form of IkappaB beta forms stable ternary complexes with NF-kappaB on the DNA either in vitro or in vivo. These experiments suggest that IkappaB alpha works as a postinduction repressor of NF-kappaB independently of HMG I, whereas IkappaB beta ...
Background Nuclear factor kappa B (NF-B) is certainly a key nuclear transcription factor that controls the transcription of varied genes; and its own activation is certainly tightly managed by Inhibitor kappa B kinase (IKK). the data source size. Subsequently, recursive partitioning (RP) and docking filter systems were utilized to display screen the pharmacophore strikes. Finally, 29 substances were chosen for IKK enzyme inhibition assay to recognize a novel little molecule inhibitor of IKK em /em proteins. Conclusions In todays investigation, weve applied different computational versions sequentially to practically display screen the ChemDiv data source, and identified a little molecule which has an IC50 worth of 20.3 em /em M. This substance is certainly book among the known IKK em /em inhibitors. Further marketing from the strike substance can reveal a far more powerful anti-inflammatory agent. History Inhibitor kappa-B kinase em /em (IKK em /em ) is certainly a serine-threonine proteins ...
Prostate cancer (PCa) is the most frequently diagnosed cancer and the second most common cause of cancer deaths in men in the UK, despite the progress that has been made in PCa treatment. Nuclear Factor kappa B (NF-κB) regulates several genes involved in immune response, inflammation,proliferation and apoptosis. Overexpression of NF-κB has been shown to be involved in tumour progression and radiation therapy resistance of PCa. One potential approach in PCa cancer treatment therefore involves targeting IκBkinases (IKKs) which are key regulators of the NF-κB signaling pathway. Whilst IKKβ regulates the canonical NF-κB pathway involving degradation of IκB-α and phosphorylation of p65, IKKα regulates the non-canonical NF-κB pathway by mediating the processing of p100 to p52. Inhibition of NF-κB signaling by targeting IKKβ is a sub-optimal treatment choice as it has been shown to be associated with multiple serious toxicities. However, IKKα is of interest in PCa therapy as it has been ...
Background: Pulpitis is a complicated chronic inflammatory process which in a dynamic balance between damage and repair. Extracellular matrix plays an important regulatory role in wound healing and tissue repair. The aim of this study was to explore role of the epigenetic mark, enhancer of zes...
Inflammation is a beneficial mechanism that is usually triggered by injury or infection and is designed to return the body to homeostasis. However, uncontrolled or sustained inflammation can be deleterious and has been shown to be involved in the etiology of several diseases, including inflammatory bowel disorder and asthma. Therefore, effective anti-inflammatory signaling is important in the maintenance of homeostasis in the body. However, the inter-play between pro- and anti-inflammatory signaling is not fully understood. In the present study, we develop a mathematical model to describe integrated pro- and anti-inflammatory signaling in macrophages. The model incorporates the feedback effects of de novo synthesized pro-inflammatory (tumor necrosis factor alpha; TNF-a) and anti-inflammatory (interleukin-10; IL-10) cytokines on the activation of the transcription factor nuclear factor kappaB (NF-kB) under continuous lipopolysaccharide (LPS) stimulation (mimicking bacterial infection). In the ...
To investigate whether glutamine supplementation modulates intestinal nuclear factor kappa B (NF-kappaB) activity and pro-inflammatory cytokine expression after
Human pTECs are not only passive bystanders in the development of diabetic nephropathy, but they also respond actively to hyperglycemia and AGEs by inducing NF-κB activation and NF-κB-dependent gene expression in vitro and in vivo. One defined AGE generated by lipoxidation and glycoxidation in diabetic nephropathy is CML (44,52,61,70,114). The presence of CML-modified proteins in the urine of type 2 diabetic patients and the in vitro observation that CML is a potent inducer of sustained NF-κB activation in pTECs suggest that CML might play a role in the development of diabetes renal complications. In addition, the observation that type 2 diabetic patients demonstrated excretion of tubular cells that was positive for activated NF-κBp65 and IL-6 antigen implies that the AGE/CML-RAGE-mediated NF-κB activation is functionally significant.. Indirect evidence for the role of NF-κB activation in diabetic nephropathy has already been given from clinical studies in which an increase in oxidative ...
Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase II clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase 1 (TBK1)-interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and ∼750-fold increase in IFN-β mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor κB-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation ...
Our experiment showed that LIN28B was upregulated by inflammatory factor IKKβ and together with TCF7L2 sustained the stemness of cancer cells. Marotta and colleagues have demonstrated previously that the inflammatory transcription factor STAT3 was highly activated in the CD44+CD24− population (40). Recent reports analogously indicated that STAT3 phosphorylation was positively correlated with ALDH1 expression in cancer cell lines and human breast cancer samples (41). However, this study demonstrated a novel mechanism, indicating that activation of IKKβ, an inflammatory kinase in the NF-κB pathway, was strongly correlated with the expression of stemness genes, especially LIN28B in human breast cancer cell lines or tissues. Previous studies also showed that LIN28B promoted tumor cell transformation (23, 24) and had a functional role in the maintenance of CSCs (25, 26). Consistent with these findings, our experiment results showed that expression of LIN28B was highly positively correlated with ...
Introduction: We have previously reported that bacterial toxins, especially endotoxins such as lipopolysaccharides (LPS), might be important causative agents in the pathogenesis of rheumatoid arthritis (RA) in an in vitro model that simulates the potential effects of residing in damp buildings. Since numerous inflammatory processes are linked with the nuclear factor-kappa B (NF-kappa B), we investigated in detail the effects of LPS on the NF-kappa B pathway and the postulated formation of procollagen-endotoxin complexes. Methods: An in vitro model of human chondrocytes was used to investigate LPS-mediated inflammatory signaling. Results: Immunoelectron microscopy revealed that LPS physically interact with collagen type II in the extracellular matrix (ECM) and anti-collagen type II significantly reduced this interaction. BMS-345541 (a specific inhibitor of I kappa B kinase (IKK)) or wortmannin (a specific inhibitor of phosphatidylinositol 3-kinase (PI-3K)) inhibited the LPS-induced degradation of ...
Is predicted to contribute to IkappaB kinase activity. Involved in several processes, including epiboly involved in gastrulation with mouth forming second; negative regulation of I-kappaB kinase/NF-kappaB signaling; and somite specification. Predicted to localize to IkappaB kinase complex. Is expressed in several structures, including immature eye; nervous system; notochord; pectoral fin; and segmental plate. Human ortholog(s) of this gene implicated in fetal encasement syndrome and prostate cancer. Orthologous to human CHUK (component of inhibitor of nuclear factor kappa B kinase complex ...
Apoptosis induced by TNF-receptor I (TNFR1) is thought to proceed via recruitment of the adaptor FADD and caspase-8 to the receptor complex. TNFR1 signaling is also known to activate the transcription factor NF-kappa B and promote survival. The mechanism by which this decision between cell death and survival is arbitrated is not clear. We report that TNFR1-induced apoptosis involves two sequential signaling complexes. The initial plasma membrane bound complex (complex I) consists of TNFR1, the adaptor TRADD, the kinase RIP1, and TRAF2 and rapidly signals activation of NF-kappa B. In a second step, TRADD and RIP1 associate with FADD and caspase-8, forming a cytoplasmic complex (complex II). When NF-kappa B is activated by complex I, complex II harbors the caspase-8 inhibitor FLIP(L) and the cell survives. Thus, TNFR1-mediated-signal transduction includes a checkpoint, resulting in cell death (via complex II) in instances where the initial signal (via complex I, NF-kappa B) fails to be activated.
Antibodies for proteins involved in regulation of I-kappaB kinase/NF-kappaB signaling pathways, according to their Panther/Gene Ontology Classification
Pancreatic cancer is a major unsolved health problem because of its biological aggressiveness. In the last decade, traditional clinical cancer therapy regimens as surgical tumor resection, cytotoxic chemotherapy, and radiation therapy have been supplemented with individualized targeted therapies directed against molecular determinants of the tumor. In spite of improved multimodal therapeutic regimens, 5 year survival does not exceed 5 percent. Inherent or acquired resistance towards cytotoxic agents, ionizing radiation, or both, is one of the hallmarks of biological aggressiveness of pancreas cancer as a solid tumor. To develop a new chemotherapeutic agent is still a clinical major concern as well as the better understanding of etiopathogenesis and molecular biology of pancreatic cancer.. NF-kB is ubiquitous and can be detected in the cytoplasm of many cell types. Several researches have indicated that constitutive NF-kB activation may conduce to pancreatic tumorigenesis [15, 16]. Hence, the ...
Results: We observed no significant differences in tumour necrosis factor-alpha serum levels between the study groups. In the patient group, an increase in the tumour necrosis factor-alpha serum levels in patients carrying the tumour necrosis factor-alpha (-308 G/A) A allele compared to those without the A allele was found to be statistically significant. Additionally, an increase in the tumour necrosis factor-alpha serum levels in patients carrying tumour necrosis factor-alpha (-308 G/A) AA genotype compared with patients carrying the AG or GG genotypes was statistically significant. No significant differences were found in these 2 polymorphisms between the patient and control groups (p,0.05 ...
Abstract. The transcription factor NF kappa B (NF-κB) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune respo
COPD is associated with chronic inflammation predominantly affecting the lung parenchyma and peripheral airways, resulting in largely irreversible and progressive airflow limitation. This inflammation is characterized by increased levels of alveolar macrophages, neutrophils and T lymphocytes, which are recruited from the circulation. Oxidative stress is important in driving this inflammation (1). NF-κB is known to be critical in the regulation of proinflammatory molecules during cellular responses, particularly TNF-α, IL-6 and IL-8. When phosphorylated, IκB dissociates from the NF-κB-IκB complex, resulting in the translocation of NF-κB from the cytoplasm to the nucleus. Activation of NF-κB is regarded as an important initial event in the airway inflammatory response to a variety of stimuli, including infectious agents, toxins, cytokines, growth factors and oxidant stress (1,5,18). NF-κB may represent a link between inflammation and oxidative stress in chronic inflammatory diseases (19). ...
The small molecule inhibitor of the proteasome, bortezomib, promotes apoptosis;this effect appears to be due in part to prevention of NF-kB activation, but the...
1. Chen, Z., Luo, H. Y., Steinberg, M. H., and Chui, D. H. BCL11A represses HBG transcription in K562 cells. Blood Cells Mol Dis, 42: 144-149, 2009. 2. Konishi, E., Tabuchi, Y., and Yamanaka, A. A simple assay system for infection-enhancing and -neutralizing antibodies to dengue type 2 virus using layers of semi-adherent K562 cells. J Virol Methods, 163: 360-367. 3. Navarro, F., Gutman, D., Meire, E., Caceres, M., Rigoutsos, I., Bentwich, Z., and Lieberman, J. miR-34a contributes to megakaryocytic differentiation of K562 cells independently of p53. Blood, 114: 2181-2192, 2009. 4. Reuter, S., Charlet, J., Juncker, T., Teiten, M. H., Dicato, M., and Diederich, M. Effect of curcumin on nuclear factor kappaB signaling pathways in human chronic myelogenous K562 leukemia cells. Ann N Y Acad Sci, 1171: 436-447, 2009. 5. Salvatori, F., Cantale, V., Breveglieri, G., Zuccato, C., Finotti, A., Bianchi, N., Borgatti, M., Feriotto, G., Destro, F., Canella, A., Breda, L., Rivella, S., and Gambari, R. ...
Activator of Chk1/Cdc25C pathway; Inhibitor of the transforming growth factor beta-activated kinase-1-mediated NF-kappaB activation pathway; Antidiabetic
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Complete information for NFRKB gene (Protein Coding), Nuclear Factor Related To KappaB Binding Protein, including: function, proteins, disorders, pathways, orthologs, and expression. GeneCards - The Human Gene Compendium
This proposal describes the 5-year training program for the development of an academic career in molecular biology and Neonatology. The candidate is in his fina...
An increased level of the cytokine tumor necrosis factor alpha (TNFα) has been shown to be involved in the manifestation of both chronic pain and depression with respect to the hippocampus. Previous studies in this lab ...