The IκB kinase complex: master regulator of NF-κB signaling

Solt, Laura A.; May, Michael J.

doi:10.1007/s12026-008-8025-1

Cited by 242 publications

(218 citation statements)

References 94 publications

(237 reference statements)

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“…It is well known that NF-κB is a crucial transcription factor that is involved in the regulation of inflammation. NF-κB regulates a vast number of genes, including those encoding cytokines (IL-1β, IL-6, IL-8, TNF-α, MCP-1, and interferon-β) [25] . The transplantation of MSCs could inhibit the activity of NF-κB and modulate the cytokine production in the peri-infarct myocardium [26] .…”

Section: Discussionmentioning

confidence: 99%

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

et al. 2014

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Aim: Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) have been shown to ameliorate cerebral ischemia in animal models. In this study we investigated the effects of hUCB-MSCs on inflammatory responses and neuronal apoptosis during the early stage of focal cerebral ischemia in rabbits. Methods: Focal cerebral ischemia was induced in male New Zealand rabbits by occlusion of MCA for 2 h. The blood samples were collected at different time points prior and during MCAO-reperfusion. The animals were euthanized 3 d after MCAO, and the protein levels of IL-1β, IL-6, IL-10, and TNF-α in the serum and peri-ischemic brain tissues were detected using Western blot and ELISA, respectively. Inflammatory cell infiltration, neuronal apoptosis and neuronal density were measured morphologically. hUCB-MSCs (5×10 6 ) were iv injected a few minutes after MCAO. Results: The serum levels of IL-1β, IL-6, and TNF-α were rapidly increased, and peaked at 2 h after the start of MCAO. hUCB-MSC transplantation markedly and progressively suppressed the ischemia-induced increases of serum IL-1β, IL-6, and TNF-α levels within 6 h MCAO-reperfusion. Focal cerebral ischemia decreased the serum level of IL-10, which was prevented by hUCB-MSC transplantation. The expression of IL-1β, IL-6, IL-10, and TNF-α in the peri-ischemic brain tissues showed similar changes as in the serum. hUCB-MSC transplantation markedly suppressed the infiltration of inflammatory cells, and increased the neuronal density around the ischemic region. Furthermore, hUCB-MSC transplantation significantly decreased the percentage of apoptosis around the ischemic region. Conclusion: hUCB-MSCs transplantation suppresses inflammatory responses and neuronal apoptosis during the early stage focal cerebral ischemia in rabbits.

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Section: Discussionmentioning

confidence: 99%

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

et al. 2014

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“…Both IKK␣ and IKK␤ have been shown to phosphorylate IB proteins, targeting them for ubiquitination and subsequent degradation by the chymotrypsin-like proteasome activity (39,45,46). This results in the exposure of a nuclear localization sequence on the p50/p65 heterodimer and leads to nuclear import and subsequent transcription of NF-B-responsive genes.…”

Section: Discussionmentioning

confidence: 99%

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Warfel

D’Agnillo

2009

Journal of Biological Chemistry

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Anthrax lethal toxin (LT) was previously shown to enhance transcriptional activity of NF-B in tumor necrosis factor-␣-activated primary human endothelial cells. Here we show that this LT-mediated increase in NF-B activation is associated with the enhanced degradation of the inhibitory proteins IB␣ and IB␤ but not IB⑀. Moreover, this was accompanied by enhanced activation of the IB kinase complex (IKK), which is responsible for targeting IB proteins for degradation. Importantly, LT enhancement of IB␣ degradation was completely blocked by a selective IKK␤ inhibitor, whereas IB␤ degradation was attenuated, suggesting a mechanistic link. Consistent with the above data, LT-cotreated cells show elevated phosphorylation of two IKK substrates, IB␣ and p65, both of which were blocked by incubation with the IKK␤ inhibitor. Consistent with NF-B activation, LT increased transcription of the NF-B regulated gene CD40. Conversely, LT inhibited transcription of another NF-B-regulated gene, CCL2. This inhibition was linked to the LT-mediated suppression of another CCL2-regulating transcription factor, AP-1 (activator protein-1). These data suggest that LT-mediated enhancement of NF-B is IKKdependent, but importantly, the net effect of LT on the transcription of proinflammatory genes is driven by the cumulative effect of LT on the particular set of transcription factors that regulate a given promoter. Together, these findings provide new mechanistic insight on how LT may disrupt the host response to anthrax.

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“…(50) IKKa is involved in both canonical and noncanonical pathways. (46,51,52) Our data indicate that the canonical pathways, involving both IKKa and IKKb, are important for the activation of NF-kB in trastuzumabresistant BT-474-R cells. Silencing and overexpression of both IKK kinases will determine the role of this kinase individually in the development of resistance in the BT-474-R cell line.…”

Section: Mechanism Of Nf-jb Activation In Trastuzumab-resistant Cellsmentioning

confidence: 69%

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

Kanzaki

Mukhopadhya

Cui

et al. 2016

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy

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A major clinical problem in the treatment of breast cancer is mortality due to metastasis. Understanding the molecular mechanisms associated with metastasis should aid in designing new therapeutic approaches for breast cancer. Trastuzumab is the main therapeutic option for HER2+ breast cancer patients; however, the molecular basis for trastuzumab resistance (TZR) and subsequent metastasis is not known. Earlier, we found expression of basal-like molecular markers in TZR tissues from patients with invasive breast cancer. (1) The basal-like phenotype is a particularly aggressive form of breast cancer. This observation suggests that TZR might contribute to an aggressive phenotype. To understand if resistance to TZR can lead to basal-like phenotype, we generated a trastuzumab-resistant human breast cancer cell line (BT-474-R) that maintained human epidermal growth factor receptor 2 (HER2) overexpression and HER2 mediated signaling. Analysis showed that nuclear factor-kappa B (NF-kB) was constitutively activated in the BT-474-R cells, a feature similar to the basal-like tumor phenotype. Pharmacologic inhibition of NF-kB improved sensitivity of BT-474-R cells to trastuzumab. Interestingly, activation of HER2 independent NF-kB is not shown in luminal B breast cancer cells. Our study suggests that by activating the NF-kB pathway, luminal B cells may acquire a HER2+ basal-like phenotype in which NF-kB is constitutively activated; this notion is consistent with the recently proposed ''progression through grade'' or ''evolution of resistance'' hypothesis. Furthermore, we identified IKK-a/IKK-b and nuclear accumulation of RelA/p65 as the major determinants in the resistant cells. Thus our study additionally suggests that the nuclear accumulation of p65 may be a useful marker for identifying metastasis-initiating tumor cells and targeting RelA/p65 may limit metastasis of breast and other cancers associated with NF-kB activation.

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The IκB kinase complex: master regulator of NF-κB signaling

Cited by 242 publications

References 94 publications

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

Human umbilical cord blood mesenchymal stem cell transplantation suppresses inflammatory responses and neuronal apoptosis during early stage of focal cerebral ischemia in rabbits

Anthrax Lethal Toxin Enhances IκB Kinase Activation and Differentially Regulates Pro-inflammatory Genes in Human Endothelium

Trastuzumab-Resistant Luminal B Breast Cancer Cells Show Basal-Like Cell Growth Features Through NF-κB-Activation

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