Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.10 (IKK)
 4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferators (PPs) are a class of non-genotoxic chemicals that cause rodent liver enlargement and hepatocarcinogenesis. In primary rat hepatocyte cultures, PPs suppress spontaneous apoptosis and that induced by a number of pro-apoptotic stimuli such as transforming growth factor-beta(1). Tumour necrosis factor alpha (TNF-alpha) and the transcription factor NFkappaB have been implicated in the mode of action of PPs. TNF-alpha signalling to NFkappaB is thought to be responsible for many of the effects elicited by this cytokine. NFkappaB regulates gene expression in immunity, stress responses and the inhibition of apoptosis. Activation of NFkappaB requires the successive action of NFkappaB-inducing kinase and the phosphorylation of NFkappaB inhibitory proteins (IkappaB) by an IkappaB kinase (IKK) complex. The IKK2 subunit of IkappaB kinase is thought to be essential for NFkappaB activation and prevention of apoptosis. To determine whether IKK2 plays a role in the suppression of apoptosis by PPs, we expressed a dominant negative form of IKK2 (IKK2dn) in primary rat hepatocyte cultures. Infection with an adenovirus construct expressing IKK2dn caused apoptosis in control primary rat hepatocytes in the absence of exogenous TNF-alpha. Moreover, IKK2dn-induced apoptosis could not be rescued by addition of TNF-alpha or the peroxisome proliferator nafenopin. These results demonstrate a requirement for intracellular signalling pathways mediated by IKK2 in the suppression of apoptosis by the PP class of hepatocarcinogens.
Carcinogenesis 2000 Sep
PMID:A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin. 1096 9

Epidemiological studies demonstrate that environmental and occupational exposure of chromium(VI) [Cr(VI)] or Cr(VI)-containing particles can cause a number of human diseases, including inflammation and cancer. The biological mechanisms responsible for the initiation and progression of diseases resulting from exposure to Cr(VI) are not fully understood. The present studies evaluated the ability of Cr(IV) to induce activation of NF-kappaB and AP-1, two important transcription factors governing the expression of many early response genes involved in inflammation and carcinogenesis. The activation of NF-kappaB and AP-1 by Cr(IV) was dose dependent. Aspirin, a well-established antioxidant, substantially inhibited Cr(VI)-induced activation of both NF-kappaB and AP-1. SB202190, a specific inhibitor for p38, attenuated AP-1 activation induced by Cr(IV), whereas PD98059, a specific inhibitor for Erk, exhibited no effect on Cr(IV)-induced AP-1 activation. Blockage of NF-kappaB signaling pathway by a transient transfection of a dominant negative expressing vector for IkappaB kinase beta resulted in inhibition of Cr(IV)-induced NF-kappaB, but not AP-1 activation. These data suggest that the activation of AP-1 or NF-kappaB by Cr(IV) is through the involvement of MAP kinase or IKK pathway, respectively.
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PMID:Participation of MAP kinase p38 and IkappaB kinase in chromium (VI)-induced NF-kappaB and AP-1 activation. 1098 89

Nitric oxide (NO) plays an important role in inflammation and in the multiple stages of carcinogenesis. In this study, we investigated the inhibitory effects of curcumin and its metabolites, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin, on the induction of NO synthase (NOS) in RAW 264.7 cells activated with lipopolysaccharide (LPS). Western blotting and northern blotting analyses demonstrated that curcumin strongly reduced 130-kDa protein and 4.5-kb mRNA levels of iNOS in LPS-activated macrophages compared with its metabolites, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin. Moreover, electrophoretic mobility shift assay (EMSA) experiments indicated that curcumin blocked the LPS-induced binding of nuclear factor-kappaB (NFkappaB), a transcription factor necessary for iNOS induction to its (32)P-labeled double-stranded oligonucleotide probe. The inhibition of NFkappaB activation occurred through the prevention of inhibitor kappaB (IkappaB) degradation. Transient transfection experiments also showed that curcumin inhibited NFkappaB-dependent transcriptional activity. Curcumin blocked the disappearance of inhibitory kappaBalpha (IkappaBalpha) and p65 from the cytosolic fraction, and inhibited the phosphorylation of IkappaBalpha. Furthermore, we showed that curcumin could inhibit the IkappaB kinase 1 (IKK1) and IkappaB kinase 2 (IKK2) activities induced by LPS, but tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin were less active. These results suggest that curcumin may exert its anti-inflammatory and anti-carcinogenic properties by suppressing the activation of NFkappaB through inhibition of IKK activity.
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PMID:Comparative studies on the suppression of nitric oxide synthase by curcumin and its hydrogenated metabolites through down-regulation of IkappaB kinase and NFkappaB activation in macrophages. 1107 49

Specific point mutations of the RET proto-oncogene have been demonstrated to be responsible for multiple endocrine neoplasia (MEN) types 2A and 2B, for familial medullary thyroid carcinoma (MTC) syndromes, as well as for sporadic MTC. Here we show that nuclear factor (NF)-kappaB is activated in RET-associated C-cell carcinoma specimens. TT cells, a human MTC cell line expressing MEN 2A type RET, display transcriptionally active RelA(p65) in the nucleus. NF-kappaB activity in these cells is attributable to constitutive IkappaB kinase (IKK) activity and high turn over of IkappaBalpha. RET harboring the mutations C634R (MEN 2A) or M918T (MEN 2B), in contrast to wild-type RET, activates a NF-kappaB-dependent reporter construct upon transient transfection in HeLa cells. We show that the prototype RET mutation C634R enhances phosphorylation of IkappaBalpha by IKKbeta but not by IKKalpha. RET-induced NF-kappaB and IKKbeta activity requires Ras function but does neither involve the classical mitogen-activated protein kinase kinase/extracellular signal-regulated kinase nor the phosphoinositide 3-kinase/Akt pathways. In contrast, RET-induced NF-kappaB activity is dependent on Raf and MEKK1. Inhibition of constitutive NF-kappaB activity results in cell death of TT cells and blocks focus formation induced by oncogenic forms of RET in NIH 3T3 cells. These results suggest that RET-mediated carcinogenesis critically depends on IKK activity and subsequent NF-kappaB activation.
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PMID:Nuclear factor-kappaB is constitutively active in C-cell carcinoma and required for RET-induced transformation. 1138 85

Carnosol is a naturally occurring phytopolyphenol found in rosemary. Carnosol functions as antioxidant and anticarcinogen. In the present study, we compared the antioxidant activity of carnosol and other compounds extracted from rosemary. Carnosol showed potent antioxidative activity in alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) free radicals scavenge and DNA protection from Fenton reaction. High concentrations of nitric oxide (NO) are produced by inducible NO synthase (iNOS) in inflammation and multiple stages of carcinogenesis. Treatment of mouse macrophage RAW 264.7 cell line with carnosol markly reduced lipopolysaccharide (LPS)-stimulated NO production in a concentration-related manner with an IC50 of 9.4 microM; but other tested compounds had slight effects. Western blot, reverse transcription-polymerase chain reaction, and northern blot analyses demonstrated that carnosol decreased LPS-induced iNOS mRNA and protein expression. Carnosol treatment showed reduction of nuclear factor-kappaB (NF-kappaB) subunits translocation and NF-kappaB DNA binding activity in activated macrophages. Carnosol also showed inhibition of iNOS and NF-kappaB promoter activity in transient transfection assay. These activities were referred to down-regulation of inhibitor kappaB (IkappaB) kinase (IKK) activity by carnosol (5 microM), thus inhibited LPS-induced phosphorylation as well as degradation of IkappaBalpha. Carnosol also inhibited LPS-induced p38 and p44/42 mitogen-activated protein kinase (MAPK) activation at a higher concentration (20 microM). These results suggest that carnosol suppresses the NO production and iNOS gene expression by inhibiting NF-kappaB activation, and provide possible mechanisms for its anti-inflammatory and chemopreventive action.
Carcinogenesis 2002 Jun
PMID:Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. 1208 20

Cigarette smoke (CS) contains several carcinogens known to initiate and promote tumorigenesis and metastasis. Because various genes that mediate carcinogenesis and tumorigenesis are regulated by nuclear factor-kappaB (NF-kappaB), we postulated that the effects of CS must be mediated through activation of this transcription factor. Therefore, in the present report we investigated whether cigarette smoke condensate (CSC) activates NF-kappaB, and whether the pathway employed for activation is similar to that of TNF, one of the potent activators of NF-kappaB. Our results show that the treatment of human histiocytic lymphoma U-937 cells with CSC activated NF-kappaB in a dose- and time-dependent manner. The kinetics of NF-kappaB activation by CSC was comparable with that of TNF. CSC-induced NF-kappaB activation was not cell type-specific, as it also activated NF-kappaB in T cells (Jurkat), lung cells (H1299), and head and neck squamous cell lines (1483 and 14B). Activation of NF-kappaB by CSC correlated with time-dependent degradation of IkappaB(alpha), an inhibitor of NF-kappaB. Further studies revealed that CSC induced phosphorylation of the serine residue at position 32 in IkappaB(alpha). In vitro immunocomplex kinase assays showed that CSC activated IkappaB(alpha) kinase (IKK). The suppression of CSC-activated NF-kappaB-dependent reporter gene expression by dominant negative form of IkappaB(alpha), TRAF2, NIK and IKK suggests a similarity to the TNF-induced pathway for NF-kappaB. CSC also induced the expression of cyclooxygenase-2, an NF-kappaB regulated gene product. Overall, our results indicate that through phosphorylation and degradation of IkappaB(alpha), CSC can activate NF-kappaB in a wide a variety of cells, and this may play a role in CS-induced carcinogenesis.
Carcinogenesis 2002 Sep
PMID:Cigarette smoke condensate activates nuclear transcription factor-kappaB through phosphorylation and degradation of IkappaB(alpha): correlation with induction of cyclooxygenase-2. 1218 95

Transcription factors of the nuclear factor-kappaB (NF-kappaB)/Rel family play a crucial role in gene regulation during a variety of different cellular processes. This review focuses on the increasing knowledge of the role of NF-kappaB in skin physiology and pathology. Several studies demonstrate that NF-kappaB, or components of the system such as IkappaB kinase (IKK)-alpha, seem to be involved in epidermal development and differentiation. Furthermore, a dysregulation of NF-kappaB is suggested to play an important role in skin pathology, including proliferative disorders, e.g. psoriasis, inflammatory processes such as incontinentia pigmenti (IP), sunburn, Lyme disease, allergic contact dermatitis and autoimmune diseases, as well as also in skin carcinogenesis. However, although the knowledge concerning the role of NF-kappaB in the homeostasis of the skin is steadily increasing, many more questions need to be answered.
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PMID:Involvement of NF-kappaB signalling in skin physiology and disease. 1240 14

Selective cyclooxygenase-2 (COX-2) inhibitors are promising anti-inflammatory drugs with potential antitumor activities. The nuclear factor-kappa B (NF-kappaB) family of proteins is important transcriptional regulators of genes involved in immunity, inflammation, and carcinogenesis. In the present study, we investigated whether and by which molecular mechanism the selective COX-2 inhibitors inhibit NF-kappaB activation in gastric cancer. The effects of SC236 and its derivative, but devoid of COX-2 enzyme inhibition activity on NF-kappaB signaling, were evaluated using electromobility shift, transfection, and reporter gene assay. The translocation of RelA/p65 was investigated using Western blotting and immunocytochemistry. We showed that SC236 suppressed NF-kappaB-mediated gene transcription and binding activity in gastric cancer. This effect occurred through a mechanism independent of cyclooxygenase activity and prostaglandin synthesis. Furthermore, unlike aspirin, SC236 affected neither the phosphorylation, degradation, nor expression of IkappaB-alpha, suggesting that the effects of SC236 are independent of IKK activity and IkappaB-alpha gene transcription. Instead, SC236 worked directly through suppressing nuclear translocation of RelA/p65. It is possible that SC236 directly targets proteins that facilitate the nuclear translocation of NF-kappaB. Our study suggests an important molecular mechanism by which COX-2 inhibitors reduce inflammation and suppress carcinogenesis in gastrointestinal tract.
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PMID:Suppression of RelA/p65 nuclear translocation independent of IkappaB-alpha degradation by cyclooxygenase-2 inhibitor in gastric cancer. 1260 45

Nuclear factor kappaB (NF-kappaB) is an antiapoptotic factor involved in development, regeneration, and neoplastic progression of the liver. Previously, we have shown that stabilization of inhibitor kappaB (IkappaB)-alpha protein following treatment of hepatocytes with transforming growth factor (TGF)-beta1 promoted NF-kappaB repression, which then permitted induction of AP-1/SMAD-mediated liver cell death. Because basal IkappaB-alpha protein turnover is regulated by protein kinase CK2, here we have elucidated the regulation of CK2 kinase activity and its role in control of NF-kappaB levels following treatment with TGF-beta1. We show that both messenger RNA (mRNA) and protein levels of the CK2alpha catalytic subunit are down-regulated following TGF-beta1 stimulation in murine hepatocyte cells. The ensuing inhibition of CK2 kinase activity promotes stabilization of IkappaB protein, which is followed by the shutoff of constitutive NF-kappaB activity and induction of apoptosis. Ectopic expression of CK2alpha inhibits TGF-beta1-induced apoptosis through sustained activation of NF-kappaB. Conversely, expression of a kinase-dead mutant of CK2alpha potentiates TGF-beta1 cell killing. Importantly, we show that hepatocellular carcinomas (HCCs) derived from TGF-beta1 transgenic mice and human HCC cell lines display enhanced CK2 IkappaB kinase activity that contributes in part to an elevated NF-kappaB activity in vivo. In conclusion, inhibition of CK2 expression levels by TGF-beta1 is crucial for the induction of apoptosis of hepatocytes. Circumvention of this process by up-regulation of CK2 activity in transformed cells may contribute to the promotion of TGF-beta1-induced liver carcinogenesis.
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PMID:Inhibition of CK2 activity by TGF-beta1 promotes IkappaB-alpha protein stabilization and apoptosis of immortalized hepatocytes. 1464 65

Several effects of bile acids (BAs) on colonic epithelial cells (CECs) have been described, including induction of proliferation and apoptosis. Some of these effects are mediated through activation of the NF-kappa B transcriptional system. In this study, we investigated the molecular mechanisms underlying the BA-induced gene expression in CECs. The human CEC line HT-29 and primary human CECs were treated with dilutions of salts of deoxycholic acid (DCA) and taurodeoxycholic acid (TDCA). NF-kappa B binding activity was analyzed with EMSA, RelA translocation with immunofluorescence, and I kappa B alpha- and RelA-phosphorylation with Western blot analysis. IL-8 mRNA and protein expression were assessed by quantitative PCR and ELISA. Functional impact of NF-kappa B activation was determined by blocking the proteasome activity with MG132 or by preventing IKK activity with a dominant-negative IKK beta delivered by adenoviral dominant-negative (dn) IKK beta (Ad5dnIKK beta). DCA and TDCA induced IL-8 expression in a dose- and time-dependent manner. It is interesting that DCA but not TDCA induced I kappa B alpha-phosphorylation, RelA translocation, and NF-kappa B binding activity. Accordingly, the proteasome inhibitor MG132 blocked DCA- but not TDCA-induced IL-8 gene expression. In contrast, TDCA-induced IL-8 gene expression correlated with enhanced RelA phosphorylation, which was blocked by Ad5dnIKK beta. Our data suggest that DCA-induced signal transduction mainly utilized the I kappa B degradation and RelA nuclear translocation pathway, whereas TDCA primarily induced IL-8 gene expression through RelA phosphorylation. These differences may have implications for the understanding of the pathophysiology of inflammation and carcinogenesis in the gut.
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PMID:Differential effects of deoxycholic acid and taurodeoxycholic acid on NF-kappa B signal transduction and IL-8 gene expression in colonic epithelial cells. 1472 7


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