Their results further identified NFKB signaling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease. Carmody et al. By blocking ubiquitination of p50, Bcl3 stabilizes a p50 complex that inhibits gene transcription. As a consequence, Bcl3-deficient mice and cells were found to be hypersensitive to TLR activation and unable to control responses to lipopolysaccharides.
Kravchenko et al. The consequence is specific repression of stimulus-mediated induction of NFKB-responsive genes encoding inflammatory cytokines and other immune regulators. Zhang et al. Several interventional models were developed showing that aging retardation and life span extension were achieved in mice by preventing aging-related hypothalamic or brain IKK-beta and NF-kappa-B activation. Dying cells initiate adaptive immunity by providing antigens and apoptotic stimuli for dendritic cells, which in turn activate CD8-positive T cells through antigen cross-priming.
Yatim et al. They found that release of inflammatory mediators, such as damage-associated molecular patterns, was not sufficient for CD8-positive T-cell cross-priming. Lack of NFKB signaling in necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity.
NFκB-RE-luc | Mouse Models | Taconic Biosciences
Ozes et al. Most proliferating cells are programmed to undergo apoptosis unless specific survival signals are provided. Platelet-derived growth factor PDGF; promotes cellular proliferation and inhibits apoptosis. In this pathway, NFKB1 does not induce c-myc and apoptosis, but instead induces putative antiapoptotic genes. Aliprantis et al.
Thus, TLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms. The tumor suppressor p53 inhibits cell growth through activation of cell cycle arrest and apoptosis. Most cancers lack active p53, suggesting a therapeutic intervention. The NFKB transcription factor can protect from or contribute to apoptosis. Ryan et al. In cells without NFKB activity, pinduced apoptosis is abrogated.
In addition to its role as a kidney cytokine regulating hematopoiesis, erythropoietin is also produced in the brain after oxidative or nitrosative stress. The transcription factor HIF1 upregulates erythropoietin following hypoxic stimuli. Digicaylioglu and Lipton demonstrated that preconditioning with erythropoietin protects neurons in models of ischemic and degenerative damage due to excitotoxins and consequent generation of free radicals, including nitric oxide.
Transfection of cerebrocortical neurons with a dominant interfering form of JAK2 or an I-kappa-B-alpha superrepressor blocks erythropoietin-mediated prevention of neuronal apoptosis. Thus, neuronal erythropoietin receptors activate a neuroprotective pathway that is distinct from previously well characterized JAK and NFKB functions. Moreover, this erythropoietin effect may underlie neuroprotection mediated by hypoxic-ischemic preconditioning.
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Baek et al. These genes are exemplified by the tetraspanin KAI1 , which regulates membrane receptor function. KAI1 is also directly activated by a ternary complex, dependent on the acetyltransferase activity of TIP60, that consists of the presenilin-dependent C-terminal cleavage product of the beta amyloid precursor protein APP; , FE65 , and TIP60, identifying a specific in vivo gene target of an APP-dependent transcription complex in the brain.
Zhong et al.
Waterfield et al. P exerted this signaling function by controlling the stability and function of an upstream kinase, Tpl2 In mouse macrophages, Tpl2 formed a stable and inactive complex with p, and activation of Tpl2 involved its dissociation from p and subsequent degradation. The authors concluded that p functions as a physiologic partner and inhibitor of TPL2, providing an example of how a transcription factor component regulates upstream signaling events.
By affinity purification in HeLa cells, Lang et al. Lang et al. Anest et al. Consistent with this, chromatin immunoprecipitation assays revealed that IKKA was recruited to the promoter regions of NF-kappa-B-regulated genes on stimulation with tumor necrosis factor-alpha Notably, NF-kappa-B-regulated gene expression was suppressed by the loss of IKKA, and this correlated with a complete loss of gene-specific phosphorylation of histone H3 see on serine, a modification previously associated with positive gene expression.
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Furthermore, Anest et al. Yamamoto et al. Brummelkamp et al. Trompouki et al. Loss of the deubiquitinating activity of CYLD correlated with tumorigenesis. Smahi et al. Using an integrated approach comprising tandem affinity purification, liquid chromatography tandem mass spectrometry, network analysis, and directed functional perturbation studies using RNA interference or loss-of-function analysis, Bouwmeester et al.
Sigala et al. These cells were also not protected from apoptosis in response to cytokines. Wertz et al. They also provided an example of a protein containing separate ubiquitin ligase and deubiquitinating domains, both of which participate in mediating a distinct regulatory effect. Covert et al. Lipopolysaccharide binding to Toll-like receptor-4 TLR4; causes activation of NK-kappa-B that requires 2 downstream pathways, each of which when isolated exhibits damped oscillatory behavior.
Computational modeling of the 2 TLR4-dependent signaling pathways suggests that 1 pathway requires a time delay to establish early antiphase activation of NF-kappa-B by the 2 pathways. Morlon et al.
Wu et al. Medeiros et al. Using mice lacking Ikbkb in different cell types, Rius et al. Ikbkb was essential for Hif1a accumulation in macrophages experiencing a bacterial infection. Ashall et al. Tay et al. They found that, in contrast to population-level studies with bulk assays, the activation was heterogeneous and was a digital process at the single-cell level with fewer cells responding at lower doses.
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Cells also encoded a subtle set of analog parameters, including NF-kappa-B peak intensity, response time, and number of oscillations, to modulate the outcome. Bivona et al. Genetic or pharmacologic inhibition of NF-kappa-B enhanced erlotinib-induced apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant lung cancer models.
Using proteomic analysis, Toubiana et al. MYOD regulates skeletal muscle differentiation and is essential for repair of damaged tissue. NFKB is activated by the cytokine tumor necrosis factor TNF; , a mediator of skeletal muscle wasting in cachexia. Guttridge et al.
In studies using a highly bone-metastatic human breast cancer cell line, Park et al. A key target of NFKB was CSF2 , which mediated osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Park et al. In studies involving bone marrow progenitor cells and T-cell acute lymphoblastic leukemia T-ALL cell lines, Vilimas et al. The NFKB pathway was highly active in establishing human T-ALL, and inhibition of the pathway efficiently restricted tumor growth both in vitro and in vivo.
Vilimas et al. Meylan et al. Concomitant loss of p53 and expression of oncogenic Kras containing the G12D mutation Conversely, in lung tumor cell lines expressing Kras G12D and lacking p53, p53 restoration led to NF-kappa-B inhibition.