Article

A cytokine responsive I B kinase that activates the transcription factor NF- B

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California at San Diego, La Jolla 92093-0636, USA.
Nature (Impact Factor: 41.46). 09/1997; 388(6642):548-54. DOI: 10.1038/41493
Source: PubMed

ABSTRACT

Nuclear transcription factors of the NF-kappaB/Rel family are inhibited by IkappaB proteins, which inactivate NF-kappaB by trapping it in the cell cytoplasm. Phosphorylation of IkappaBs marks them out for destruction, thereby relieving their inhibitory effect on NF-kappaB. A cytokine-activated protein kinase complex, IKK (for IkappaB kinase), has now been purified that phosphorylates IkappaBs on the sites that trigger their degradation. A component of IKK was molecularly cloned and identified as a serine kinase. IKK turns out to be the long-sought-after protein kinase that mediates the critical regulatory step in NF-kappaB activation.

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    • "Mass spectrometry analysis identified the existence of three isoforms of serine/threonine phosphatase PP1, PP1a, PP1b, and PP1g (Supplementary Table S1). PP1 has been reported to act on IKK dephosphorylation (DiDonato et al., 1997; Li et al., 2008), raising the possibility that hCINAP may deactivate IKK by recruiting PP1. To verify this possibility, we first examined the interactions between hCINAP and the three PP1 isoforms. "
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    ABSTRACT: Tight regulation of nuclear factor-κB (NF-κB) signaling is essential to maintain homeostasis in immune system in response to various stimuli, which has been studied extensively and deeply. However, the molecular mechanisms responsible for its negative regulation are not completely understood. Here we demonstrate that human coilin-interacting nuclear ATPase protein (hCINAP) is a novel negative regulator in NF-κB signaling by deactivating IκB kinase (IKK) complex. In response to TNF stimulation, hCINAP dynamically associates with IKKα and IKKβ and inhibits IKK phosphorylation. Notably, hCINAP directly interacts with the catalytic subunits of protein phosphatase 1 (PP1) and mediates the formation of IKK-hCINAP-PP1 complex, serving as an adaptor protein that recruits PP1 to dephosphorylate IKK. Furthermore, decreased levels of hCINAP are observed in several inflammatory diseases with NF-κB hyperactivity. Our study suggests a novel mechanism underlying deactivation of IKK and provides new insight into the negative regulation of NF-κB signaling. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.
    Full-text · Article · Jun 2015 · Journal of Molecular Cell Biology
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    • "It is also associated with the regulation of intracellular level of OFRs [21]. NF-kB is a crucial transcription factor for regulating the genes responsible for the inflammatory and immune reactions in both cytoprotective and cell death pathways [22]. The expression of both immunomodulatory genes and genes involved in apoptotic processes are regulated by NFk B. It is also considered as a principal mediator of the systemic inflammation in the case of IR injury. "
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    ABSTRACT: Background Spironolactone (Sp), a mineralocorticoid receptor antagonist, protects against the ischemia reperfusion (IR) injury of retina, kidney, heart, and brain. We aimed to investigate the effects of Sp on intestinal IR injury. Methods Male Wistar rats were randomly divided into: (1) a sham control group; (2) an IR control group, subjected to 30 min ischemia and 3 h reperfusion; (3) a group treated with Sp (20 mg/kg) for 3 d before the IR; and (4) a sham-operated control group treated with Sp (20 mg/kg). After the reperfusion, blood and intestinal tissue samples were collected to evaluate histopathologic state, neutrophil infiltration (by measuring myeloperoxidase activity), levels of the cytokines (tumor necrosis factor α, interleukin 1α [IL-1α], interferon γ, monocyte chemotactic protein-1, granulocyte macrophage-colony stimulating factor, and IL-4), malondialdehyde (MDA) and reduced glutathione contents, and immunohistochemical expressions of nuclear factor κB, inducible nitric oxide synthase (iNOS), and caspase-3. Results MDA content, myeloperoxidase activity, and plasma levels of tumor necrosis factor α, IL-1α, and monocyte chemotactic protein-1 were all elevated in IR, indicating the oxidative stress and local and systemic inflammatory response. Sp administration markedly reduced the MDA content and the cytokine levels. The pretreatment alleviated intestinal injury, neutrophil infiltration, and the expressions of caspase-3, iNOS, and NFκB. Conclusions The results implicate that Sp may have a strong protective effect against the intestinal IR injury. The effect can be mediated via suppression of both systemic inflammatory response and apoptosis through amelioration of oxidative stress and generation of proinflammatory cytokines, iNOS, caspase-3, and nuclear factor κB. Therefore, mineralocorticoid receptor antagonism might be of potential therapeutic benefit in cases of intestinal IR damage.
    Full-text · Article · May 2014 · Journal of Surgical Research
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    • "It is also associated with the regulation of intracellular level of OFRs [21]. NF-kB is a crucial transcription factor for regulating the genes responsible for the inflammatory and immune reactions in both cytoprotective and cell death pathways [22]. The expression of both immunomodulatory genes and genes involved in apoptotic processes are regulated by NFk B. It is also considered as a principal mediator of the systemic inflammation in the case of IR injury. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Spironolactone (Sp), a mineralocorticoid receptor antagonist, protects against the ischemia reperfusion (IR) injury of retina, kidney, heart, and brain. We aimed to investigate the effects of Sp on intestinal IR injury. Methods: Male Wistar rats were randomly divided into: (1) a sham control group; (2) an IR control group, subjected to 30 min ischemia and 3 h reperfusion; (3) a group treated with Sp (20 mg/kg) for 3 d before the IR; and (4) a sham-operated control group treated with Sp (20 mg/kg). After the reperfusion, blood and intestinal tissue samples were collected to evaluate histopathologic state, neutrophil infiltration (by measuring myeloperoxidase activity), levels of the cytokines (tumor necrosis factor α, interleukin 1α [IL-1α], interferon γ, monocyte chemotactic protein-1, granulocyte macrophage-colony stimulating factor, and IL-4), malondialdehyde (MDA) and reduced glutathione contents, and immunohistochemical expressions of nuclear factor κB, inducible nitric oxide synthase (iNOS), and caspase-3. Results: MDA content, myeloperoxidase activity, and plasma levels of tumor necrosis factor α, IL-1α, and monocyte chemotactic protein-1 were all elevated in IR, indicating the oxidative stress and local and systemic inflammatory response. Sp administration markedly reduced the MDA content and the cytokine levels. The pretreatment alleviated intestinal injury, neutrophil infiltration, and the expressions of caspase-3, iNOS, and NFκB. Conclusions: The results implicate that Sp may have a strong protective effect against the intestinal IR injury. The effect can be mediated via suppression of both systemic inflammatory response and apoptosis through amelioration of oxidative stress and generation of proinflammatory cytokines, iNOS, caspase-3, and nuclear factor κB. Therefore, mineralocorticoid receptor antagonism might be of potential therapeutic benefit in cases of intestinal IR damage.
    Full-text · Article · May 2014 · Journal of Surgical Research
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