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  • NF-κB inducing kinase, NIK mediates cigarette smoke/TNFα-induced histone acetylation and inflammation through differential activation of IKKs. 21887257

    Nuclear factor (NF)-κB inducing kinase (NIK) is a central player in the non-canonical NF κB pathway, which phosphorylates IκB kinase α (IKKα) resulting in enhancement of target gene expression. We have recently shown that IKKα responds to a variety of stimuli including oxidants and cigarette smoke (CS) regulating the histone modification in addition to its role in NF-κB activation. However, the primary signaling mechanism linking CS-mediated oxidative stress and TNFα with histone acetylation and pro-inflammatory gene transcription is not well understood. We hypothesized that CS and TNFα increase NIK levels causing phosphorylation of IKKα, which leads to histone acetylation.To test this hypothesis, we investigated whether NIK mediates effects of CS and TNFα on histone acetylation in human lung epithelial cells in vitro and in lungs of mouse exposed to CS in vivo. CS increased the phosphorylation levels of IKKα/NIK in lung epithelial cells and mouse lungs. NIK is accumulated in the nuclear compartment, and is recruited to the promoters of pro-inflammatory genes, to induce posttranslational acetylation of histones in response to CS and TNFα. Cells in which NIK is knocked down using siRNA showed partial attenuation of CSE- and TNFα-induced acetylation of histone H3 on pro-inflammatory gene promoters. Additional study to determine the role of IKKβ/NF-κB pathway in CS-induced histone acetylation suggests that the canonical pathway does not play a role in histone acetylation particularly in response to CS in mouse lungs.Overall, our findings provide a novel role for NIK in CS- and TNFα-induced histone acetylation, especially on histone H3K9.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • Epstein-Barr virus latent infection membrane protein 1 TRAF-binding site induces NIK/IKK alpha-dependent noncanonical NF-kappaB activation. 14691250

    Epstein-Barr virus (EBV) latent infection membrane protein 1 (LMP1)-induced NF-kappaB activation is important for infected cell survival. LMP1 activates NF-kappaB, in part, by engaging tumor necrosis factor (TNF) receptor-associated factors (TRAFs), which also mediate NF-kappaB activation from LTbetaR and CD40. LTbetaR and CD40 activation of p100/NF-kappaB2 is now known to be NIK/IKKalpha-dependent and IKKbeta/IKKgamma independent. In the experiments described here, we found that EBV LMP1 induced p100/NF-kappaB2 processing in human lymphoblasts and HEK293 cells. LMP1-induced p100 processing was NIK/IKKalpha dependent and IKKbeta/IKKgamma independent. Furthermore, the LMP1 TRAF-binding site was required for p100 processing and p52 nuclear localization, whereas the LMP1 death domain-binding site was not. Moreover, the LMP1 TRAF-binding site preferentially caused RelB nuclear accumulation. In murine embryo fibroblasts (MEFs), IKKbeta was essential for LMP1 up-regulation of macrophage inflammatory protein (MIP)-2, TNFalpha, I-TAC, ELC, MIG, and CXCR4 RNAs. Interestingly, in IKKalpha knockout MEFs, LMP1 hyperinduced MIP-2, TNFalpha, and I-TAC expression, consistent with a role for IKKalpha in down-modulating canonical IKKbeta activation or its effects. In contrast, LMP1 failed to up-regulate CXCR4 and MIG RNA in IKKalpha knockout MEFs, indicating a dependence on noncanonical IKKalpha activation. Furthermore, LMP1 up-regulation of MIP-2 RNA in MEFs was both IKKbeta- and IKKgamma-dependent, whereas LMP1 upregulation of MIG and I-TAC RNA was fully IKKgamma independent. Thus, LMP1 induces typical canonical IKKbeta/IKKgamma-dependent, atypical canonical IKKbeta-dependent/IKKgamma-independent, and noncanonical NIK/IKKalpha-dependent NF-kappaB activations; NIK/IKKalpha-dependent NF-kappaB activation is principally mediated by the LMP1 TRAF-binding site.
    Document Type:
    Reference
    Product Catalog Number:
    06-413
    Product Catalog Name:
    Anti-NFκB p52 Antibody

  • Inhibition of MicroRNA-23b Attenuates Immunosuppression in Late Sepsis through NIK, TRAF1 and XIAP. 29506272

    microRNA-23b (miR-23b) is a multiple functional miRNA. We hypothesize that miR-23b plays a role in the pathogenesis of sepsis. Our study investigated the effect of miR-23b on sepsis induced immunosuppression.Mice were treated with miR-23b inhibitors by tail vein injection 2 days after cecal ligation puncture (CLP)-induced sepsis. Apoptosis in spleens and apoptotic signals were detected, meanwhile survival was monitored. T cell immunoreactivities were examined in late sepsis. NF-κB-inducing kinase (NIK), TNF-receptor associated factor-1 (TRAF1) and X-linked inhibitor of apoptosis protein (XIAP), as the putative targets of miR-23b, were identified by dual luciferase reporter assay.miR-23b expression is upregulated and sustained during sepsis. The activation of TLR4/9/p38/STAT3 signal pathway contributes to the production of miR-23b in CLP-induced sepsis. miR-23b inhibitor decreased TUNEL positive cells in spleen and improved survival. MiR-23b inhibitor restored the immunoreactivity by alleviating the development of T cell exhaustion and producing smaller amounts of immunosuppressive IL-10 and IL-4 in late sepsis. We demonstrated that miR-23b mediated immunosuppression in late sepsis by inhibiting non-canonical NF-κB signal and promoting pro-apoptotic signal pathway via targeting NIK, TRAF1 and XIAP.Inhibition of miR-23b reduces late sepsis-induced immunosuppression and improves survival. miR-23b might be a target for immunosuppression.
    Document Type:
    Reference
    Product Catalog Number:
    17-371
    Product Catalog Name:
    EZ-ChIP™

  • APPL1 regulates basal NF-κB activity by stabilizing NIK. 22685329

    APPL1 is a multifunctional adaptor protein that binds membrane receptors, signaling proteins and nuclear factors, thereby acting in endosomal trafficking and in different signaling pathways. Here, we uncover a novel role of APPL1 as a positive regulator of transcriptional activity of NF-κB under basal but not TNFα-stimulated conditions. APPL1 was found to directly interact with TRAF2, an adaptor protein known to activate canonical NF-κB signaling. APPL1 synergized with TRAF2 to induce NF-κB activation, and both proteins were necessary for this process and function upstream of the IKK complex. Although TRAF2 was not detectable on APPL endosomes, endosomal recruitment of APPL1 was required for its function in the NF-κB pathway. Importantly, in the canonical pathway, APPL1 appeared to regulate the proper spatial distribution of the p65 subunit of NF-κB in the absence of cytokine stimulation, since its overexpression enhanced and its depletion reduced the nuclear accumulation of p65. By analyzing the patterns of gene transcription upon APPL1 overproduction or depletion we found altered expression of NF-κB target genes that encode cytokines. At the molecular level, overexpressed APPL1 markedly increased the level of NIK, the key component of the noncanonical NF-κB pathway, by reducing its association with the degradative complex containing TRAF2, TRAF3 and cIAP1. In turn, high levels of NIK triggered nuclear translocation of p65. Collectively, we propose that APPL1 regulates basal NF-κB activity by modulating the stability of NIK, which affects the activation of p65. This places APPL1 as a novel link between the canonical and noncanonical machineries of NF-κB activation.
    Document Type:
    Reference
    Product Catalog Number:
    05-419
    Product Catalog Name:
    Anti-Myc Tag Antibody, clone 9E10

  • IkappaB kinase-beta: NF-kappaB activation and complex formation with IkappaB kinase-alpha and NIK. 9346485

    Activation of the transcription factor nuclear factor kappa B (NF-kappaB) by inflammatory cytokines requires the successive action of NF-kappaB-inducing kinase (NIK) and IkappaB kinase-alpha (IKK-alpha). A widely expressed protein kinase was identified that is 52 percent identical to IKK-alpha. IkappaB kinase-beta (IKK-beta) activated NF-kappaB when overexpressed and phosphorylated serine residues 32 and 36 of IkappaB-alpha and serines 19 and 23 of IkappaB-beta. The activity of IKK-beta was stimulated by tumor necrosis factor and interleukin-1 treatment. IKK-alpha and IKK-beta formed heterodimers that interacted with NIK. Overexpression of a catalytically inactive form of IKK-beta blocked cytokine-induced NF-kappaB activation. Thus, an active IkappaB kinase complex may require three distinct protein kinases.
    Document Type:
    Reference
    Product Catalog Number:
    AB16528
    Product Catalog Name:
    Anti-NIK Antibody, CT

  • The zinc fingers of human poly(ADP-ribose) polymerase are differentially required for the recognition of DNA breaks and nicks and the consequent enzyme activation. Other ... 2123876

    The recognition of double-stranded DNA breaks and single-stranded nicks by human poly(ADP-ribose) polymerase and the consequent enzymic activation were examined using derivatives of the enzyme expressed in Escherichia coli. The N-terminal 162 residues encompass two zinc fingers. Deletion or mutation of the first finger results in a loss of activation by DNA with either single-stranded or double-stranded damage. Destruction of the second finger reduces activation by double-stranded DNA breaks only slightly, but eliminates activation by single-stranded DNA nicks. These data suggest that activation by single-stranded DNA nicks requires two zinc fingers, but activation by double-stranded DNA breaks requires only the finger closer to the N terminus. Variant proteins that lack both zinc fingers are enzymically inactive but still exhibit weak DNA binding, which is independent of DNA damage. Thus, other regions are also capable of binding intact DNA, but the recognition of a strand nick or break which occasions the synthesis of poly(ADP-ribose) specifically requires the zinc fingers.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple

  • Proliferating potential and apoptosis in the development of secondary hyperparathyroidism: a study based on Ki-67 immunohistochemical staining and the terminal dUTP nick- ... 18789120

    Secondary hyperparathyroidism (SHPT) is a common complication in hemodialysis (HD) patients. SHPT progresses from initial diffuse hyperplasia (diffuse) to early nodularity (early), then to multinodular hyperplasia (nodular), and finally to a single nodule (single) consisting of uniform parenchymal cells. We analyzed the roles of proliferation and apoptosis in SHPT progression. Seventy-four parathyroid glands from 36 HD patients with SHPT, and 10 parathyroid glands from 10 non-HD patients without SHPT were used for analysis. The former were classified as diffuse (N = 17), early (N = 22), nodular (N = 20), and single (N = 15); the latter were classified as normal (N = 10). To analyze proliferating cells we used Ki-67, and to detect apoptotic cells, we used the terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick-end labeling (TUNEL) assay. Concerning the Ki-67 labeling index (LI), the incremental order was single, nodular, early, diffuse, and normal. Oxyphilic cells and around the central portion of each lesion were distinctly stained by Ki-67. Concerning the TUNEL LI, the incremental order was early, diffuse, nodular, single, and normal. Chief cells and around the peripheral portion of each lesion were distinctly stained by TUNEL. In the progression from early to nodular, for oxyphilic cells, the Ki-67 LI increased and the TUNEL LI decreased; for chief cells, the Ki-67 LI decreased and the TUNEL LI showed no significant change. We considered that proliferative activity increases and that the apoptosis rate decreases as SHPT progresses from diffuse to single. Moreover, the specific differences in the rate of proliferation and apoptosis between oxyphilic and chief cells might be associated with SHPT progression.
    Document Type:
    Reference
    Product Catalog Number:
    S7101
    Product Catalog Name:
    ApopTag® Plus Peroxidase In Situ Apoptosis Kit

  • Developmental toxicity of glyceryl trinitrate in quail embryos. 21472843

    Although glyceryl trinitrate (GTN) is used extensively to treat angina and heart failure, little is known about its effects on the conceptus during organogenesis. The goal of these studies was to investigate the effects of GTN in a model organism, the quail (Coturnix coturnix japonica) embryo.
    Document Type:
    Reference
    Product Catalog Number:
    S7100
    Product Catalog Name:
    ApopTag® Peroxidase In Situ Apoptosis Detection Kit

  • Intracavernous delivery of synthetic angiopoietin-1 protein as a novel therapeutic strategy for erectile dysfunction in the type II diabetic db/db mouse. 20584113

    Patients with erectile dysfunction (ED) associated with type II diabetes often have impaired endothelial function and tend to respond poorly to oral phosphodiesterase type 5 inhibitors. Therefore, neovascularization is a promising strategy for curing diabetic ED.
    Document Type:
    Reference
    Product Catalog Number:
    S7160
    Product Catalog Name:
    ApopTag® Fluorescein Direct In Situ Apoptosis Detection Kit

  • Murine Glut-1 transporter haploinsufficiency: postnatal deceleration of brain weight and reactive astrocytosis. 19591936

    Glucose transporter type 1 (Glut-1) facilitates glucose flux across the blood-brain-barrier. In humans, Glut-1 deficiency causes acquired microcephaly, seizures and ataxia, which are recapitulated in our Glut-1 haploinsufficient mouse model. Postnatal brain weight deceleration and development of reactive astrogliosis were significant by P21 in Glut-1(+/-) mice. The brain weight differences remained constant after P21 whereas the reactive astrocytosis continued to increase and peaked at P90. Brain immunoblots showed increased phospho-mTOR and decreased phospho-GSK3-beta by P14. After fasting, the mature Glut-1(+/-) females showed a trend towards elevated phospho-GSK3-beta, a possible neuroprotective response. Lithium chloride treatment of human skin fibroblasts from control and Glut-1 DS patients produced a 45% increase in glucose uptake. Brain imaging of mature Glut-1(+/-) mice revealed a significantly decreased hippocampal volume. These subtle immunochemical changes reflect chronic nutrient deficiency during brain development and represent the experimental correlates to the human neurological phenotype associated with Glut-1 DS.
    Document Type:
    Reference
    Product Catalog Number:
    S7110
    Product Catalog Name:
    ApopTag® Fluorescein In Situ Apoptosis Detection Kit