Molecular Basis of NF-κB Signaling

Napetschnig, Johanna; Wu, Hao

doi:10.1146/annurev-biophys-083012-130338

Cited by 778 publications

(639 citation statements)

References 133 publications

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“…These are the mediators released by reactive astrocytes modulating immune cell invasion after injury (Burda and Sofroniew, 2014). Specifically NF‐κB signaling has been implicated in gene expression events that impact on cell survival, differentiation, and proliferation (Napetschnig and Wu, 2013; Oeckinghaus et al, 2011). Interestingly, cyclin D1 (Ccnd1), a known NF‐κB target (Guttridge et al, 1999; Hinz et al, 1999), is also significantly upregulated in reactive astrocytes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Sirko

Irmler

Gascón

et al. 2015

Glia

109

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Astrocytes react to brain injury in a heterogeneous manner with only a subset resuming proliferation and acquiring stem cell properties in vitro. In order to identify novel regulators of this subset, we performed genomewide expression analysis of reactive astrocytes isolated 5 days after stab wound injury from the gray matter of adult mouse cerebral cortex. The expression pattern was compared with astrocytes from intact cortex and adult neural stem cells (NSCs) isolated from the subependymal zone (SEZ). These comparisons revealed a set of genes expressed at higher levels in both endogenous NSCs and reactive astrocytes, including two lectins—Galectins 1 and 3. These results and the pattern of Galectin expression in the lesioned brain led us to examine the functional significance of these lectins in brains of mice lacking Galectins 1 and 3. Following stab wound injury, astrocyte reactivity including glial fibrillary acidic protein expression, proliferation and neurosphere‐forming capacity were found significantly reduced in mutant animals. This phenotype could be recapitulated in vitro and was fully rescued by addition of Galectin 3, but not of Galectin 1. Thus, Galectins 1 and 3 play key roles in regulating the proliferative and NSC potential of a subset of reactive astrocytes. GLIA 2015;63:2340–2361

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Section: Discussionmentioning

confidence: 99%

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Sirko

Irmler

Gascón

et al. 2015

Glia

109

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“…The activated (phosphorylated) IκK subunits, IκKβ and IκKα, in turn phosphorylate IκBα, marking pSer 32,36 -IκBα for proteasomal degradation. 1,10 In addition, activated IκKβ phosphorylates p65, promoting translocation of the transcription factor to the nucleus where it drives gene expression, including the induction of Bcl-xL. 11,12 Consistent with this model, pharmacologic inhibition of NF-κB signaling in primary thymocytes and cancer cell lines blocks Bcl-xL induction and increases cell death in response to treatment with apoptosis-inducing antibodies or exposure to DNA damage.…”

mentioning

confidence: 86%

“…1 NF-κB is critically involved in the inhibition of apoptosis by transcribing genes encoding caspase inhibitors as well as multi-domain anti-apoptotic Bcl-2 family members such as Bcl-xL. 2 Bcl-xL antagonizes multiple steps of the apoptotic program at the endoplasmic reticulum (ER)-mitochondria interface.…”

mentioning

confidence: 99%

“…8,9 The prototypical NF-κB transcription factor, p65/p50, is tightly regulated by the inhibitory protein IκBα, which sequesters this heterodimer in the cytoplasm by masking the p65 nuclear localization signal (NLS). 1,10 Release of NF-κB from IκBα requires activation of the IκK complex. The activated (phosphorylated) IκK subunits, IκKβ and IκKα, in turn phosphorylate IκBα, marking pSer 32,36 -IκBα for proteasomal degradation.…”

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confidence: 99%

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PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

et al. 2016

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Nuclear factor kappa B (NF-κB) promotes cell survival in response to genotoxic stress by inducing the expression of anti-apoptotic proteins including Bcl-xL, which protects mitochondria from stress-induced mitochondrial outer membrane permeabilization (MOMP). Here we show that the multifunctional sorting protein Pacs-2 (phosphofurin acidic cluster sorting protein-2) is required for Bcl-xL induction following DNA damage in primary mouse thymocytes. Consequently, in response to DNA damage, Pacs-2 − / − thymocytes exhibit a blunted induction of Bcl-xL, increased MOMP and accelerated apoptosis. Biochemical studies show that cytoplasmic PACS-2 promotes this DNA damage-induced anti-apoptotic pathway by interacting with ataxia telangiectasia mutated (ATM) to drive NF-κB activation and induction of Bcl-xL. However, Pacs-2 was not required for tumor necrosis factor-α-induced NF-κB activation, suggesting a role for PACS-2 selectively in NF-κB activation in response to DNA damage. These findings identify PACS-2 as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.

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“…Reporter cells were incubated with each treatment at 37 °C in 5% CO 2 for 8 h. The transcriptional level of the luciferase gene that is downstream of the NF-κB responsive element is a sensitive surrogate indicator of NF-κB activation state (Lemon and Tjian. 2000;Napetschnig and Wu. 2013), therefore NF-κB activation was quantified by luciferase mRNA level via q-PCR.…”

Section: In Vitro Evaluation Of Nf-κb Activation and The Effect Of VImentioning

confidence: 99%

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

Liu

Wang

et al. 2014

Experimental Eye Research

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Chronic inflammation is a key pathogenic process in age-related macular degeneration (AMD). Amyloid-beta (Aβ) is a constituent of AMD drusen and promotes the activation of NLRP3 inflammasome which facilitates the production of cytokines. We investigated the role of transcription factor NF-κB in the activation of inflammasome in the RPE and the effect of vinpocetine, a dietary supplement with inhibitory effect on NF-κB. ARPE19/NF-κB-luciferase reporter cells treated with Aβ demonstrated enhanced NF-κB activation that was significantly suppressed by vinpocetine. Intraperitoneal injection of vinpocetine (15 mg/kg) inhibited NF-κB nuclear translocation and reduced the expression and activation of NLRP3, caspase-1, IL-1β, IL-18, and TNF-α in the RPE of adult rats that received intraocular Aβ, as measured by retinal immunohistochemistry and Western blot. Cytokine level in the vitreous was assayed using multiplex suspension arrays and revealed significantly lower concentration of MIP-3α, IL-6, IL-1α, IL-1β, IL-18, and TNF-α in vinpocetine treated animals. These results suggest that the NF-κB pathway is activated by Aβ in the RPE and signals the priming of NLRP3 inflammasome and the expression of pro-inflammatory cytokines including the inflammasome substrates IL-1β and IL-18. NF-κB inhibition may be an effective approach to stem the chronic inflammatory milieu that underlies the development of AMD. Vinpocetine is a potentially useful anti-inflammatory agent that is well-tolerated in long term use.

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Molecular Basis of NF-κB Signaling

Cited by 778 publications

References 133 publications

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage

Vinpocetine inhibits amyloid-beta induced activation of NF-κB, NLRP3 inflammasome and cytokine production in retinal pigment epithelial cells

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