• Korean Journal of Pharmacognosy
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• v.35 no.3 s.138
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• pp.244-249
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• 2004

The effects of hesperetin and naringenin on $NF-{\kappa}B$ activation were investigated in normal rat kidney cells transformed by temperature sensitive Rous Sarcoma Virus (tsNRK). The flavonoids, naringenin and hesperetin, significantly reduced v-Src-induced $NF-{\kappa}B$ activation as well as phosphorylation of Akt and GSK-3 in tsNRK cells, whereas these compounds did not effect on platelet-derived growth factor (PDGF)-induced $NF-{\kappa}B$ activation in $NIH3T3{\gamma}l$ cells. In addition, the DNA binding activity of SP-I was also reduced but that of AP-1 was not affected by the compounds. Our study suggests that Src-induced $NF-{\kappa}B$ activation could occur via Akt-GSK-3 pathway without $IkB{\alpha}$ degradation and that naringenin and hesperetin could be used in the treatment of cancer through the inhibition of $NF-{\kappa}B$ activation.

• Biomolecules & Therapeutics
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• v.17 no.3
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• pp.219-240
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• 2009

Since NF-${\kappa}B$ has been identified as a transcription factor associated with immune cell activation, groups of researchers have dedicated to reveal detailed mechanisms of nuclear factor of ${\kappa}B$ (NF-${\kappa}B$) in inflammatory signaling for decades. The various molecular components of NF-${\kappa}B$ transcription factor pathway have been being evaluated as important therapeutic targets due to their roles in diverse human diseases including inflammation, cystic fibrosis, sepsis, rheumatoid arthritis, cancer, atherosclerosis, ischemic injury, myocardial infarction, osteoporosis, transplantation rejection, and neurodegeneration. With regards to new drugs directly or indirectly modulating the NF-${\kappa}B$ pathway, FDA recently approved a proteasome inhibitor bortezomib for the treatment of multiple myeloma. Many pharmaceutical companies have been trying to develop new drugs to inhibit various kinases in the NF-${\kappa}B$ signaling pathway for many therapeutic applications. However, a gene knock-out study for $IKK{\beta}$ in the NF-${\kappa}B$ pathway has given rise to controversies associated with efficacy as therapeutics. Mice lacking hepatocyte $IKK{\beta}$ accelerated cancer instead of preventing progress of cancer. However, it is clear that pharmacological inhibition of $IKK{\beta}$ appears to be beneficial to reduce HCC. This article will update issues of the NF-${\kappa}B$ pathway and inhibitors regulating this pathway.

• Molecules and Cells
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• v.28 no.1
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• pp.49-55
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• 2009

Hepatitis delta virus (HDV) infection causes fulminant hepatitis and liver cirrhosis. To elucidate the molecular mechanism of HDV pathogenesis, we examined the effects of HDV viral proteins, the small hepatitis delta antigen (SHDAg) and the large hepatitis delta antigen (LHDAg), on $NF-{\kappa}B$ signaling pathway. In this study, we demonstrated that $TNF-{\alpha}-induced$ $NF-{\kappa}B$ transcriptional activation was increased by LHDAg but not by SHDAg in both HEK293 and Huh7 cells. Furthermore, LHDAg promoted TRAF2-induced $NF-{\kappa}B$ activation. Using coimmunoprecipitation assays, we demonstrated that both SHDAg and LHDAg interacted with TRAF2 protein. We showed that isoprenylation of LHDAg was not required for the increase of $NF-{\kappa}B$ activity. We further showed that only LHDAg but not SHDAg increased the $TNF-{\alpha}-mediated$ nuclear translocation of p65. This was accomplished by activation of $I{\kappa}B_{\alpha}$ degradation by LHDAg. Finally, we demonstrated that LHDAg augmented the COX-2 expression level in Huh7 cells. These data suggest that LHDAg modulates $NF-{\kappa}B$ signaling pathway and may contribute to HDV pathogenesis.

• BMB Reports
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• v.41 no.10
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• pp.705-709
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• 2008

NF-${\kappa}B$ is a transcriptional regulator involved in many biological processes including proliferation, survival, and differentiation. Recently, we reported that expression and activity of NF-${\kappa}B$ is comparatively low in undifferentiated human embryonic stem (ES) cells, but increases during differentiation. Here, we found a lower expression of NF-${\kappa}B$ p65 protein in mouse ES cells when compared with mouse embryonic fibroblast cells. Protein levels of NF-${\kappa}B$ p65 and relB were clearly enhanced during retinoic acid-induced differentiation. Furthermore, increased DNA binding activity of NF-${\kappa}B$ in response to TNF-$\alpha$, an agonist of NF-${\kappa}B$ signaling, was seen in differentiated but not undifferentiated mouse ES cells. Taken together with our previous data in human ES cells, it is likely that NF-${\kappa}B$ expression and activity of the NF-${\kappa}B$ signaling pathway is comparatively low in undifferentiated ES cells, but increases during differentiation of ES cells in general.

• Food Science and Biotechnology
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• v.17 no.6
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• pp.1294-1298
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• 2008

Toll-like receptors (TLRs) induce innate immune responses recognizing conserved microbial structural molecules. All TLR signaling pathways culminate in the activation of nuclear factor-${\kappa}B$ (NF-${\kappa}B$). The activation of NF-${\kappa}B$ leads to the induction of inflammatory gene products such as cyclooxygenase-2 (COX-2). Guggul has been used for centuries to treat a variety of diseases. Guggulstreone, one of the active ingredients in guggul, has been used to treat many chronic diseases. However, the mechanism as to how guggulsterone mediate the health effects is largely unknown. Here, we report biochemical evidence that guggulsterone inhibits the NF-${\kappa}B$ activation and COX-2 expression induced by TLR2, TLR3, and TLR4 agonists. Guggulsterone also inhibits the NF-${\kappa}B$ activation induced by downstream signaling components of TLRs, myeloid differential factor 88 (MyD88), $I{\kappa}B$ kinase ${\beta}$ ($IKK{\beta}$), and p65. These results imply that guggulsterone can modulate the immune responses regulated by TLR signaling pathways.

• BMB Reports
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• v.38 no.3
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• pp.281-289
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• 2005

Tumor necrosis factor (TNF) signaling is mediated via two distinct receptors, TNFR2 and TNFR1, which shows partially overlapping signaling mechanisms and biological roles. In the present study, TNFR2 and TNFR1 signal transduction mechanisms involved in activation of $NF{\kappa}B$ and CMV promoter-enhancer were compared with respect to their susceptibility towards inhibitors of intracellular signaling. For this, we used SW480 cells, where we have shown that TNF-signaling can occur independently through each of the two receptors. The TNFR1 response was inhibited by D609, bromophenacyl bromide (BPB), nordihydroguararetic acid (NDGA), and by sodium salicylate, while TNFR2-mediated activation of $NF{\kappa}B$ and CMV promoter-enhancer was resistant to these compounds. The signaling mechanisms known to be affected by these inhibitors include phospholipases as well as redox- and pH-sensitive intracellular components. Our results imply that TNFR2 signaling involved in $NF{\kappa}B$ activation proceeds independently of these inhibitor-sensitive signaling components, indicating distinct signaling pathways not shared with TNFR1.

• Molecules and Cells
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• v.25 no.2
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• pp.253-257
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• 2008

Acrolein is a highly electrophilic ${\alpha},{\beta}$-unsaturated aldehyde present in a number of environmental sources, especially cigarette smoke. It reacts strongly with the thiol groups of cysteine residues by Michael addition and has been reported to inhibit nuclear $factor-{\kappa}B$ ($NF-{\kappa}B$) activation by lipopolysaccharide (LPS). The mechanism by which it inhibits $NF-{\kappa}B$ is not clear. Toll-like receptors (TLRs) play a key role in sensing microbial components and inducing innate immune responses, and LPS-induced dimerization of TLR4 is required for activation of downstream signaling pathways. Thus, dimerization of TLR4 may be one of the first events involved in activating TLR4-mediated signaling pathways. Stimulation of TLR4 by LPS activates both myeloid differential factor 88 (MyD88)- and TIR domain-containing adapter inducing $IFN{\beta}$ (TRIF)-dependent signaling pathways leading to activation of $NF-{\kappa}B$ and IFN-regulatory factor 3 (IRF3). Acrolein inhibited $NF-{\kappa}B$ and IRF3 activation by LPS, but it did not inhibit $NF-{\kappa}B$ or IRF3 activation by MyD88, inhibitor ${\kappa}B$ kinase $(IKK){\beta}$, TRIF, or TNF-receptor-associated factor family member-associated $NF-{\kappa}B$ activator (TANK)-binding kinase 1 (TBK1). Acrolein inhibited LPS-induced dimerization of TLR4, which resulted in the down-regulation of $NF-{\kappa}B$ and IRF3 activation. These results suggest that activation of TLRs and subsequent immune/inflammatory responses induced by endogenous molecules or chronic infection can be modulated by certain chemicals with a structural motif that enables Michael addition.

• Molecules and Cells
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• v.37 no.3
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• pp.189-195
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• 2014

The NF-${\kappa}B$ pathway transcriptionally controls a large set of target genes that play important roles in cell survival, inflammation, and immune responses. While many studies showed anti-tumorigenic and pro-survival role of NF-${\kappa}B$ in cancer cells, recent findings postulate that NF-${\kappa}B$ participates in a senescence-associated cytokine response, thereby suggesting a tumor restraining role of NF-${\kappa}B$. In this review, we discuss implications of the NF-${\kappa}B$ signaling pathway in cancer. Particularly, we emphasize the connection of NF-${\kappa}B$ with cellular senescence as a response to chemotherapy, and furthermore, present examples how distinct oncogenic network contexts surrounding NF-${\kappa}B$ produce fundamentally different treatment outcomes in aggressive B-cell lymphomas as an example.

• Molecules and Cells
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• v.38 no.9
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• pp.759-764
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• 2015

Tripartite motif protein 25 (TRIM25), mediates K63-linked polyubiquitination of Retinoic acid inducible gene I (RIG-I) that is crucial for downstream antiviral interferon signaling. Here, we demonstrate that TRIM25 is required for melanoma differentiation-associated gene 5 (MDA5) and MAVS mediated activation of NF-${\kappa}B$ and interferon production. TRIM25 is required for the full activation of NF-${\kappa}B$ at the downstream of MAVS, while it is not involved in IRF3 nuclear translocation. Mechanical studies showed that TRIM25 is involved in TRAF6-mediated NF-${\kappa}B$ activation. These collectively indicate that TRIM25 plays an additional role in RIG-I/MDA5 signaling other than RIG-I ubiquitination via activation of NF-${\kappa}B$.

• Journal of Microbiology
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• v.37 no.4
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• pp.256-262
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• 1999

Latent membrane protein 1 (LMP1) of the Epstein-Barr virus (EBV) is an integral membrane protein with six transmembrane domains, which is essential for EBV-induced B cell transformation. LMP1 functions as a constitutively active tumor necrosis factor receptor (TNFR) like membrane receptor, whose signaling requires recruitment of TNFR-associated factors (TRAFs) and leads to NF-${\kappa}B$ activation. NF-${\kappa}B$ activation by LMP1 is critical for B cell transformation and has been linked to many phenotypic changes associated with EBV-induced B cell transformation. Deletion analysis has identified two NF-${\kappa}B$ activation regions in the carboxy terminal cytoplasmic domains of LMP1, termed CTAR1 (residues 194-232) and CTAR2 (351-386). The membrane proximal C-terminal domain was precisely mapped to a PXQXT motif (residues 204-208) involved in TRAF binding as well as NF-${\kappa}B$ activation. In this study, we dissected the CTAR2 region, which is the major NF-${\kappa}B$ signaling effector of LMP1, to determine a minimal functional sequence. A series of LMP1 mutant constructs systematically deleted for the CTAR2 region were prepared, and NF-${\kappa}B$ activation activity of these mutants were assessed by transiently expressing them in 293 cells and Jurkat T cells. The NF-${\kappa}B$ activation domain of CTAR2 appears to reside in a stretch of 6 amino acids (residues 379-384) at the end of the carboxy terminus.