PubMed 14587863

NFKB PDTC Preclinical treatment (44) PS-341 Preclinical treatment (45,46)

PubMed 15140220

Furthermore, TWEAK induced rapid phosphorylation of IkappaB-alpha in human keratinocytes.

PubMed 15489375

TNF-alpha induced both phosphorylation and degradation of IKappaB-alpha in A549 cells within several minutes

PubMed 15477018

Figures 2C and D show that exposure to hyperoxia induced a degradation of I?B?, supporting the EMSA data for hyperoxia-induced NF-?B activation.

PubMed 16547522

Reconstitution of NEMO-deficient Jurkat cells with wild-type, but not NEMOL329P, restored TNF-alpha-induced IkappaB degradation. Similar results were obtained for TNF-alpha-induced IkappaB degradation (Fig. 3c, d) and NF-kappaB binding (Fig. 3e) in NEMO-deficient mouse embryonic fibroblast (MEF) subclones reconstituted with wildtype NEMO or NEMOL329P.

PubMed 11777919

Expression of SphKG82D dramatically blocked the degradation of IKBa (Fig. 5a) and inhibited the NF-KB DNA binding activity in a dose-dependent manner (Fig. 5, b and c).

PubMed 12771144

OPN also induces NFkappaB activation through phosphorylation and degradation of IkappaBalpha by inducing the IKK activity.

PubMed 16924232

TNF induced NF-kappaB activation as measured by DNA binding but deletion of PKR abolished this activation.This inhibition was associated with suppression of inhibitory subunit of NF-kappaB (IkappaB)alpha kinase (IKK) activation, IkappaBalpha phosphorylation and degradation, p65 phosphorylation and nuclear translocation, and NF-kappaB-dependent reporter gene transcription.

PubMed 10973957

Moreover, IGF-I-mediated dephosphorylation of IkappaBalpha protects this molecule from tumor necrosis factor alpha (TNFalpha)-stimulated degradation; therefore, IGF-I also inhibits the nuclear translocation of NFkappaB (p65) induced by TNFalpha exposure.

PubMed 14561188

Inducers of NF-kB, which include inflammatory cytokines, reactive oxygen species, and viral products, activate a dimeric IkB kinase (IKK) complex, which phophorylates IkBa leading to subsequent ubiquitination and degradation of IkBa and release of NF-kB proteins [33,34].

PubMed 11976320

In human embryonic kidney 293 cells, IL-1beta induces IkappaB kinase beta (IKKbeta) activation, IkappaBalpha degradation, NF-kappaB transactivation, and weak Akt activation.

PubMed 19956541

Cytoplasmic and total cell protein extracts were analyzed by Western blotting for total IkBa and IkBa phosphorylated at serine residues 32 and 36. LPS exposure induced the rapid (within 15 min) phosphorylation and degradation of IkBa in both THP-1 cells (p,0.0001 for both processes; Figure 8, A and B) and elutriated primary human monocytes (p =0.003 and p,0.0001, respectively, ANOVA post hoc contrast of LPS vs. control for each; Figure 8, C and D).

PubMed 8622692

These studies provide new evidence that the protein kinase CKII physically associates with I kappa B alpha in vivo, induces multisite (serine/threonine) phosphorylation, and is required for the basal and HIV-induced degradation of I kappa B alpha in vitro.

PubMed 16980310

The lipopolysaccharide-induced degradation of IL-1R-associated kinase 1, IkappaBalpha, and IkappaBbeta was inhibited by elafin

PubMed 9418855

ctivation of NF-kappaB by TNF and IL-1 is initiated by the phosphorylation of the inhibitory subunit, IkappaB, which targets IkappaB for degradation and leads to the release of active NF-kappaB.

PubMed 12486103

reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, IkappaBalpha.

PubMed 15916985

The mechanism of adiponectin action in endothelial cells has been further investigated. TNF-A activates nuclear transcription factor NF-KB in these cells by stimulating protein kinase NIK (NF-kB inducing kinase), which phosphorylates the NF-kB inhibitor, IkB, initiating its degradation and thus leading to NF-KB activation. NF-KB stimulates the expression of cytokines and adhesion molecules involved in the inflammatory process.

PubMed 10779355

Two related kinases, IkappaB kinase alpha (IKKalpha) and IKKbeta, phosphorylate the IkappaB proteins, leading to their degradation and the subsequent activation of gene expression by NF-kappaB

PubMed 12044776

phosphorylation and ubiquitination-dependent degradation of IkappaBalpha, the cytoplasmic inhibitor of NFkappaB, via the inducible IkappaB kinase (IKK) complex, liberates NFkappaB to translocate into the nucleus and to transcriptionally activate its target genes, including the IL2 gene

PubMed 15653325

Activation of NF-kappaB mainly occurs via IkappaB kinase (IKK)-mediated phosphorylation of inhibitory molecules, including IkappaBalpha

PubMed 10788439

SUMO-1 modification was found to antagonize IkappaBalpha ubiquitination and protect it from degradation

PubMed 16951373

The degradation of IKappaB-alpha at 20 min after stimulation by LPS was completely abolished in the presence of paxilline

PubMed 20200353

we found that IL-33R signaling induced a time-dependent activation of Erk1/2, protein kinase B (PKB), JNK1/2, NF-kB, and p38, and degradation of IkB (supplemental Figure 1B).

PubMed 20351055

The incubation of ECs for 1 h in the presence of TNF-a alone induced significant degradation of IkB-a.

PubMed 17615396

Figure 1. Pathways to MUC5AC expression in COPD

PubMed 11983155

The actual recognition of N-terminally phosphorylated IKappaBs is carried out by aWD repeat- and F box-containing protein called beta-TrCP (Ben-Neriah, 2002). Upon ubiquiti-nation, the IKappaB proteins are rapidly degraded by the proteasome,

PubMed 14580335

# from full text # Here we show that UVC radiation leads to activation of a signaling pathway, distinct from the IKK pathway, which induces I?B? degradation in a manner dependent on phosphorylation of a cluster of C-terminal sites. The kinase that phosphorylates these sites is CK2.

PubMed 19409098

Stimulation of the MDMs with CSM for 30 min induced the phosphorylation of IRAK which was abolished by adding NAC (Fig. 6A). Moreover, CSM and LPS (as a control) degradated I?B-? and preincubation of MDMs with NAC suppressed the degradation of I?B-? induced by CSM (Fig. 6D).

PubMed 9244310

CHUK specifically phosphorylates IkappaB-alpha on both serine 32 and serine 36, modifications that are required for targeted degradation of IkappaB-alpha via the ubiquitin-proteasome pathway

PubMed 19768635

fro full text Results - Plumbagin inhibited TPA-induced DNA-binding activities of NF-kB, c-Fos, and c-Jun/IkBa degradation and phosphorylation in A549 cells

PubMed 12048203

Immunoblotting analyses revealed that constitutively active AKT2 significantly promoted IkBalpha degradation (Fig. 4D).

PubMed 11850407

It also associates specifically with phosphorylated IkappaBalpha and beta-catenin destruction motifs, probably functioning in multiple transcriptional programs by activating the NF-kappaB pathway and inhibiting the beta-catenin pathway.

PubMed 11306700

The microtubule disassembly also induced IkappaB degradation.

PubMed 14514686

ursodeoxycholic acid UDCA inhibited TGF-beta1-induced degradation of nuclear factor kappaB (NF-kappaB) and its inhibitor IkappaB (p < 0.05).

PubMed 16271147

Activation-induced induction of transcription factor NFkappaB in T lymphocytes is regulated by its inhibitor IkappaBalpha. NFkappaB activation has been demonstrated to occur either by phosphorylation on serine residues 32 and 36 of the inhibitor, IkappaBalpha, followed by ubiquitination and degradation of the inhibitor by the 26S proteasome, or by a proteasome-independent mechanism involving tyrosine phosphorylation, but not degradation.

PubMed 16865089

In turn, IKK2 phosphorylates inhibitor of NF-kappaB (I-kappaBalpha), leading to its ubiquitination and subsequent degradation by the proteasome. This frees up the p65 and p50 subunits of NF-kappaB, which translocate to the nucleus. Intranuclear NF-kappaB then binds to kappaB recognition sites in the 5'-promoter (upstream) region of inflammatory genes, resulting in increased gene transcription, messenger RNA, and synthesis of inflammatory proteins.

PubMed 15125834

Here we show that beta-arrestin2 directly interacts with IkappaBalpha (inhibitor of NF-kappaB, the key molecule in innate and adaptive immunity) and thus prevents the phosphorylation and degradation of IkappaBalpha. Consequently, beta-arrestin2 effectively modulates activation of NF-kappa

PubMed 17307160

Treatment of A549 cells with TGF-beta1-induced IkappaB kinase alpha/beta (IKKalpha/beta) phosphorylation, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 Ser536 phosphorylation, and kappaB-luciferase activity. The TGF-beta1-mediated increases in IKKalpha/beta phosphorylation, p65 Ser536 phosphorylation, and kappaB-luciferase activity were inhibited by LY 294002, an Akt inhibitor

PubMed 15330761

PKC (protein kinase C) enzymes which phosphorylate IkappaBalpha, leading to its degradation

PubMed 9388244

Activation of NF-kappaB by TNF-alpha occurred within 15 min and coincided with rapid degradation of IkappaBalpha. Co-treatment with NO donors did not prevent IkappaBalpha phosphorylation or degradation. However, after 2 h of TNF-alpha stimulation, NO donors inhibited NF-kappaB activation and augmented IkappaBalpha resynthesis and nuclear translocation by 2.5- and 3-fold, respectively. This correlated with a 75% reduction in TNF-alpha-induced VCAM-1 expression. In a time-dependent manner, NO donors alone caused the nuclear translocation of IkappaBalpha

PubMed 15024018

CD86 stimulation also increased the level of IkappaB-alpha phosphorylation but in a protein kinase C-independent manner

PubMed 12170775

PAR-4 was found to directly inhibit the phosphorylation and degradation of I kappa B alpha, which led to the loss of NF kappa B activity causing repression of endogenous and radiation-induced Bcl-2 protein.

PubMed 11152622

MIP-1alpha treatment stimulated the degradation of IkappaBalpha, a cytoplasmic inhibitor of NF-kappaB

PubMed 14602581

Pretreatment with EGF protected monolayers by increasing native PKC-beta1 activity, decreasing IkappaBalpha phosphorylation/degradation, suppressing NF-kappaB activation (p50/p65 subunit nuclear translocation/activity), enhancing stable actin (increased F-actin-to-G-actin ratio), increasing stability of actin cytoskeleton, and reducing barrier hyperpermeability.

PubMed 11909978

from the paper:

PubMed 12897149

HSP27 does not affect I-kappaBalpha phosphorylation but enhances the degradation of phosphorylated I-kappaBalpha by the proteasome. The interaction of HSP27 with the 26S proteasome is required to activate the proteasome and the degradation of phosphorylated I-kappaBalpha. A protein complex that includes HSP27, phosphorylated I-kappaBalpha, and the 26S proteasome is formed

PubMed 12297126

the I-kappaB kinase (IKK) is present and may phosphorylate I-kappaB during platelet activation. Coupled with intracellular calcium flux, this leads to I-kappaB dissociation from the NF-kappaB/I-kappaB complex and proteolysis.

PubMed 11850814

BetaTrCP and HOS are closely related F-box proteins, which play key roles in ubiquitination and degradation of beta-catenin and IkappaB through associating with those phosphorylated substrates and recruiting SCF E3 ubiquitin ligase

PubMed 9990853

Moreover, immunopurified beta-TrCP ubiquitinates phosphorylated IkappaBalpha at specific lysines in the presence of Ub-activating (E1) and -conjugating (Ubch5) enzymes.

PubMed 12893815

The IRAK4:IRAK1:TRAF6 complex then interacts at the membrane with another preformed complex consisting of TAK1, TAB1 and TAB2. This interaction induces phosphorylation of TAB2 and TAK1. TAK1 is subsuequently activated in the cytoplasm, leading to the activation of IKK. Activation leads to phosphorylation and degradation of IKB and consequent release of NFKB. Activation of TAK1 also results in the activation of MAP kinases and JNK.

PubMed 12244195

neutrophil stimulation with pro-inflammatory signals results in degradation of IkappaBalpha that occurs in both cytoplasm and nucleus.

PubMed 10398585

Phosphorylation of IkappaBalpha at serine 32 (S32) and serine 36 (S36) is necessary for this stimuli-induced degradation. IKKalpha/beta kinases and p90(rsk1)are involved in stimuli-induced targeting of one or both of these IkappaBalpha sites.

PubMed 10946303

As shown in Fig. 10C, TNF-a rapidly induced complete degradation of I-kB-a

PubMed 17322026

Since activation of NF-B in A549 cells is dependent on IKK2, which phosphorylates serines 32 and 36 of IB as a prelude to IB degradation and activation of NF-B (Catley et al., 2005

PubMed 19842832

CSM-induced activation of TLR-4 has been shown to induce IRAK1 phosphorylation and TRAF6 degradation. An increase in IkB phosphorylation and degradation is also observed which ultimately leads to the translocation of NF-kB (p65) into the nucleus. The ability of cigarette smoke condensate (CSC) to activate NF-kB has also been demonstrated in another study using U937 cells. CSC has been shown to induce the activation of IKK (-a and -b) at 15 minutes post treatment, which resulted in increased phosphorylation of I?-B? at serine 32, resulting in Ik-Ba degradation and subsequent activation of NF-kB [53].

PubMed 15162444

In human neutrophils, TNF-alpha (200 U/ml) induced rapid I kappa B-alpha degradation

PubMed 9727009

The Bcl-2-mediated loss of IkappaBalpha could be prevented by the proteasome inhibitor lactacystin, consistent with the notion that the targeted degradation of IkappaBalpha consequent to overexpression of Bcl-2 utilizes the ubiquitin-proteasome pathway. This was further tested in human 293 cells in which the N-terminal region of IkappaBalpha was identified to be an important regulatory site for Bcl-2. Deletion of this region or a serine to alanine substitution mutant at amino acids 32 and 36, which are defective for both phosphorylation and degradation, were more resistant than wild type IkappaBalpha to the inhibitory effects of Bcl-2.

PubMed 19074142

We found that IL-1 caused rapid phosphorylation of ERK1/2, JNK, p38, MKK3/6, Akt, IKK, c-Jun, ATF-2, ATF-1, CREB, p65, and IKBa, induced the degradation of IKBa and IKBe, and activated the synthesis of c-fos (Fig. 4)

PubMed 10748083

Consistent with this, these reagents also eliminate the ability of the Skp1-CUL1-HOS-ROC1 E3 ligase complex to support the ubiquitination of IkappaBalpha.

PubMed 18955562

IL-33 rapidly activated ERK1/2, JNK, p38, and NF-kB signaling cascades, as evidenced by phosphorylation of MAP kinases and phosphorylation and degradation of the NF-kB inhibitor IkB-a.

PubMed 10373514

Ubiquitin-tagged Ikappa Balpha is degraded by the proteasome releasing NF-kappa B for migration to the nucleus. As a first approach to check the role of NF-kappa B in PKR-induced apoptosis, the NF-kappa B induction pathway was blocked by using the specific proteasome inhibitors, lactacystin and PSI.

PubMed 10764587

overexpressing PKC-zeta results in lower steady-state protein levels of free IkappaBalpha, which is dependent on S293.

PubMed 12167702

In contrast to the serine 32/34 phosphorylation that triggers ubiquitination and degradation of IkappaBalpha, c-Abl-mediated phosphorylation at tyrosine 305 is associated with an increase of the IkappaBalpha protein stability. We also demonstrate that c-Abl targets the nuclear subpopulation of IkappaBalpha for phosphorylation and induces it to accumulate in the nucleus

PubMed 15477018

Similar to wild-type A549 cells, treatment with TNF-? for 30 min induced I?B? degradation in vector control cells (Fig. 4B). On the other hand, TNF-?-induced I?B? degradation was blunted in DN I?B mutant cells (Fig. 4B), further supporting that these DN I?B mutant cells are less efficient in response to a NF-?B activator compared to the vector control cells.

PubMed 12559172

agents that inhibit NF?B activation are desired, and are currently being pursued,based on strategies that seek to maintain levels of endogenous NF?B-inhibiting I?B-family proteins, by either suppressing the IkB kinases (IKKs) responsible for phosphorylation of IkBalpha (which induces its polyubiquitination) or blocking the proteolytic activity of the 26s proteasome responsible for degrading IkB following ubiquitination (Figure 2A).

PubMed 10699758

Simultaneous overexpression of selenophosphate synthetase and phospholipid-hydroperoxide GSH peroxidase (PHGPx) [250] blocks activation of NF-kB by IL-1. Overexpression of SOD [84] or GSH peroxidase [81, 211] abolished NF-kB activation by preventing degradation of IkB after stimulation with TNF-a. The precise mechanism(s) through which oxidants and reductants influence activation of NF-kB is presently unknown; however, there is evidence that antioxidant enzyme (AOE372), a redox-sensitive thioredoxin peroxidase, regulates IkB phosphorylation [246]. Phosphatases The phosphatases are an important component of most signal transduction pathways, because failure to reverse kinase actions can disrupt normal cellular functions. For example, transfection of human fibroblasts with constitutively active ras (hRasV12) inhibits cell growth and ultimately results in a senescentlike phenotype [441]. Similarly, constitutive ERK activation has an inhibitory effect on cell cycle progression [442,443]. Both the serine/threonine phosphatases and the PTPs are known to be redox-sensitive [82,144,153,156,271,281, 444-449]. The mechanism of redox effects on activity is probably best understood for the PTPs. Without exception, the PTPs contain a highly conserved region of 11 amino acid residues in their catalytic domain; specifi- cally, (Ile/Val)-His-Cys-X-Ala-Gly-X-X-Arg-(Ser/Thr)- Gly, where X is a nonconserved amino acid [17]. Either oxidation or mutation of the cysteine renders these molecules inactive [17,281]. H2O2 is a potent inhibitor of PTPs. As in the case of other oxidants, H2O2 probably oxidizes the thiolate anion at the catalytic site [280]. Because formation of a phosphorylcysteine intermediate seems to be critical to PTP activity [450-452], blocking it through oxidation of the cysteine inactivates the molecules. In many cases, treatment of cells with H2O2 stimulates increases in protein phosphorylation by inhibiting phosphatase-catalyzed removal of phosphate groups. Furthermore, mitogens that increase cellular ox- idant production may stimulate phosphorylation indirectly by decreasing phosphatase activity. Additional mechanisms are involved in stimulation of pathways activated by growth factors that increase oxidant production, however, because there are known instances in which the oxidants they produce have no effect on protein phosphorylation. For example, TGF-b1 stimulates phosphorylation of numerous proteins and has been shown to cause a large increase in H2O2 production; however, its effects on protein phosphorylation are not blocked by catalase [453]. Furthermore, H2O2 is effective in promoting phosphorylation of phospholipase D, the PDGF receptor, and PKC-a even after pretreatment of Swiss 3T3 fibroblasts with orthovanadate to inhibit phosphatases [454]. Thus, although diminished phosphatase activity may partially account for increased phosphorylation in some cases, it cannot totally account for oxidation effects on phosphorylation in every case. SPECIFICITY In general, there is good agreement between studies on redox effects on any given gene; albeit, not all oxidizing or reducing treatments exert equivalent effects. This is clearly demonstrated in studies of pag , which encodes a protein associated with cellular proliferation. Pag protein inhibits the tyrosine kinase activity of the Abelson (abl ) protein by binding to its SH3-binding domain [455]. BSO, menadione, sodium arsenate, and diethyl maleate all stimulate pag expression, but H2O2 does not [269]. Conversely, H2O2 stimulates c-fos expression (Table 1), although 4-hydroynonenal (a product of v-6-polyunsaturated fatty acid peroxidation) not only fails to induce c-fos expression but is actually inhibitory to c-fos induction by EGF and PDGF [185]. Similarly, some oxidants such as diamide decrease hypoxia-induced signals [201], although others such as H2O2 increase them [124]. As might be expected, the effects of any stimu...

PubMed 8824277

5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation

PubMed 18463678

We investigated its role in NF-?B activation and ROS production induced by TNF-? by using rapamycin (sirolimus), a well-characterized immunosuppressant and potent inhibitor of the signaling cascade. As described above, the phosphorylation and subsequent degradation of I?B play a critical role in regulating NF-?B translocation to the nucleus and subsequent transcriptional regulation. In Figure 6, we asked if rapamycin has any effect on TNF-?-induced degradation of I?B?; clearly, it did. I?B? is largely stabilized by the pretreatment.

PubMed 18831712

We demonstrated recently that BCL11B controls expression from the IL (interleukin)-2 promoter through direct binding to the US1 (upstream site 1). In the present study, we provide evidence that BCL11B also participates in the activation of IL-2 gene expression by enhancing NF-kappaB (nuclear factor kappaB) activity in the context of TCR (T-cell receptor)/CD28-triggered T-cell activation. The enhanced IkappaB degradation in cells with increased levels of BCL11B was specific for T-cells activated through the TCR, but not for cells activated through TNFalpha (tumour necrosis factor alpha) or UV light, and was caused by increased activity of IkappaB kinase, as indicated by its increase in phosphorylation.

PubMed 15724247

SAA induced IkappaB-alpha degradation, RelA serine 536 (S536) phosphorylation, NF-kappaB transcriptional activity

PubMed 20577214

To exclude off-target effects, SphK1 expression was also downregulated with siRNAs targeted to two other regions of the SphK1 sequence and both inhibited TNF-alpha-induced phosphorylation of IkBalpha and IKKalpha/beta (Supplementary Fig. 2a). Similar results were obtained in several other cell types (Supplementary Fig. 2b), suggesting that SphK1 has a general role in the canonical NF-kappaB pathway. To conclusively demonstrate the involvement of SphK1, we also used pharmacological and genetic approaches. The specific SphK1 inhibitor, SK1-I, which decreases intracellular S1P levels 6, reduced TNF-alpha-induced I?B? degradation and phosphorylation of IKKalpha/beta (Fig. 1b)

PubMed 15371334

Upon phosphorylation by IKKs, I{kappa}B proteins are recognized and ubiquitinated by members of the Skp1-Culin-Roc1/Rbx1/Hrt-1-F-box (SCF or SCRF) family of ubiquitin ligases (for review, see Ben-Neriah 2002Go) and subsequently degraded (Modified from full text).

PubMed 18411230

The activation of TLR2 by Pam3CSK4 induced the degradation of the NF-kB inhibitor IkBa in human monocyte-derived macrophages. NF-kB activation was blocked by S1P at low micromolar concentrations. Statistically significant inhibition of TLR2-dependent NF-kB activation was observed with 1 mM S1P, which argues in favour of a receptor-dependent and physiologically relevant effect (Figure 4A).


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