Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.10 (IKK)
4,900 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTEN is a lipid phosphatase responsible for down-regulating the phosphoinositide 3-kinase product phosphatidylinositol 3,4,5-triphosphate. Phosphatidylinositol 3,4,5-triphosphate is involved in the activation of the anti-apoptotic effector target, Akt. Although the Akt pathway has been implicated in regulating NF-kappaB activity, it is controversial as to whether Akt activates NF-kappaB predominantly through mechanisms that regulate nuclear translocation or transactivation potential. In this report, we utilized PTEN as a natural biological inhibitor of Akt activity to study the effects on tumor necrosis factor (TNF)-induced activation of NF-kappaB. We found that the reintroduction of PTEN into prostate cells inhibited TNF-stimulated NF-kappaB transcriptional activity. PTEN failed to block TNF-induced IKK activation, IkappaBalpha degradation, p105 processing, p65 (RelA) nuclear translocation, and DNA binding of NF-kappaB. However, PTEN inhibited NF-kappaB-dependent transcription by blocking the ability of TNF to stimulate the transactivation domain of the p65 subunit. PTEN also inhibited the transactivation potential of the cyclic AMP-response element-binding protein, but this was not observed for c-Jun. The transactivation potential of p65 following TNF stimulation could be rescued from PTEN-dependent repression by re-introducing expression constructs encoding activated forms of phosphoinositide 3-kinase, Akt, or Akt and IKK. The ability of PTEN to inhibit the TNF-induced transactivation function of p65 is important, because expression of PTEN blocked TNF-stimulated NF-kappaB-dependent gene expression, thus sensitizing cells to TNF-induced apoptosis. Maintenance of the PTEN tumor suppressor protein is therefore required to modulate Akt activity and to concomitantly control the transcriptional activity of the anti-apoptotic transcription factor NF-kappaB.
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PMID:PTEN blocks tumor necrosis factor-induced NF-kappa B-dependent transcription by inhibiting the transactivation potential of the p65 subunit. 1179 12

Rel/NF-kappaB transcription factors are implicated in the control of cell proliferation, apoptosis and transformation. The key to NF-kappaB regulation is the inhibitory IkappaB proteins. During response to diverse stimuli, IkappaBs are rapidly phosphorylated by IkappaB kinases (IKKs), ubiquitinated and undergo degradation. We have investigated the expression and function of NF-kappaB, IkappaB inhibitors and IKKs in normal prostate epithelial cells and prostate carcinoma (PC) cell lines LNCaP, MDA PCa 2b, DU145, PC3, and JCA1. We found that NF-kappaB was constitutively activated in human androgen-independent PC cell lines DU145, PC3, JCA1 as well as androgen-independent CL2 cells derived from LNCaP. In spite of a strong difference in constitutive kappaB binding, Western blot analysis did not reveal any significant variance in the expression of p50, p65, IkappaBs, IKKalpha, and IKKbeta between primary prostate cells, androgen-dependent and androgen-independent PC cells. However, we found that in androgen-independent PC cells IkappaBalpha was heavily phosphorylated and displayed a faster turnover. Using an in vitro kinase assay we demonstrated constitutive activation of IKK in androgen-independent PC cell lines. Blockage of NF-kappaB activity in PC cells by dominant-negative IkappaBalpha resulted in increased constitutive and TNF-alpha-induced apoptosis. Our data suggest that increased IKK activation leads to the constitutive activation of NF-kappaB 'survival signaling' pathway in androgen-independent PC cells. This may be important for the support of their androgen-independent status and growth advantage.
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PMID:The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. 1180 32

Nuclear factor-kappaB activation depends on phosphorylation and degradation of its inhibitor protein, IkappaB. The phosphorylation of IkappaBalpha on Ser(32) and Ser(36) is initiated by an IkappaB kinase (IKK) complex that includes a catalytic heterodimer composed of IkappaB kinase 1 (IKK-1) and IkappaB kinase 2 (IKK-2) as well as a regulatory adaptor subunit, NF-kappaB essential modulator. Recently, two related IkappaB kinases, TBK-1 and IKK-i, have been described. TBK-1 and IKK-i show sequence and structural homology to IKK-1 and IKK-2. TBK-1 and IKK-i phosphorylate Ser(36) of IkappaBalpha. We describe the kinetic mechanisms in terms of substrate and product inhibition of the recombinant human (rh) proteins, rhTBK-1, rhIKK-I, and rhIKK-1/rhIKK-2 heterodimers. The results indicate that although each of these enzymes exhibits a random sequential kinetic mechanism, the effect of the binding of one substrate on the affinity of the other substrate is significantly different. ATP has no effect on the binding of an IkappaBalpha peptide for the rhIKK-1/rhIKK-2 heterodimer (alpha = 0.99), whereas the binding of ATP decreased the affinity of the IkappaBalpha peptide for both rhTBK-1 (alpha = 10.16) and rhIKK-i (alpha = 62.28). Furthermore, the dissociation constants of ATP for rhTBK-1 and rhIKK-i are between the expected values for kinases, whereas the dissociation constants of the IkappaBalpha peptide for each IKK isoforms is unique with rhTBK-1 being the highest (K(IkappaBalpha) = 69.87 microm), followed by rhIKK-i (K(IkappaBalpha) = 5.47 microm) and rhIKK-1/rhIKK-2 heterodimers (K(IkappaBalpha) = 0.12 microm). Thus this family of IkappaB kinases has very unique kinetic properties.
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PMID:Kinetic mechanisms of IkappaB-related kinases (IKK) inducible IKK and TBK-1 differ from IKK-1/IKK-2 heterodimer. 1181 18

The human herpesvirus 8 (HHV8, also called Kaposi's sarcoma-associated herpesvirus) has been linked to Kaposi's sarcoma and primary effusion lymphoma (PEL) in immunocompromised individuals. We demonstrate that PEL cell lines have a constitutively active NF-kappaB pathway, which is associated with persistent phosphorylation of IkappaBalpha. To elucidate the mechanism of NF-kappaB activation in PEL cell lines, we have investigated the role of viral FLICE inhibitory protein (vFLIP) in this process. We report that stable expression of HHV8 vFLIP in a variety of cell lines is associated with persistent NF-kappaB activation caused by constitutive phosphorylation of IkappaBalpha. HHV8 vFLIP gets recruited to a approximately 700-kDa IkappaB kinase (IKK) complex and physically associates with IKKalpha, IKKbeta, NEMO/IKKgamma, and RIP. HHV8 vFLIP is incapable of activating NF-kappaB in cells deficient in NEMO/IKKgamma, thereby suggesting an essential role of an intact IKK complex in this process. Our results suggest that HHV8 vFLIP might contribute to the persistent NF-kappaB activation observed in PEL cells by associating with and stimulating the activity of the cellular IKK complex.
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PMID:The human herpes virus 8-encoded viral FLICE inhibitory protein physically associates with and persistently activates the Ikappa B kinase complex. 1183 May 87

Recent studies suggest that sodium arsenite downregulates NF-kappaB activity by inhibiting phosphorylation and subsequent degradation of IkappaBalpha. Many effects of sodium arsenite are secondary to induction of heat shock proteins. The role of the heat shock response in arsenite-induced inhibition of NF-kappaB, however, is not known. We examined the involvement of the heat shock response in arsenite-induced inhibition of NF-kappaB activity in IL-1beta-stimulated Caco-2 cells, a human colorectal adenocarcinoma cell line with enterocytic properties. Treatment of the cells with IL-1beta resulted in increased IkappaB kinase activity, reduced levels of IkappaBalpha and increased NF-kappaB DNA binding activity. Sodium arsenite blocked all of these responses to IL-1beta without inducing changes in heat shock factor activity or heat shock protein levels. Results from additional experiments showed that the protective effect of sodium arsenite on IkappaBalpha was not influenced by the oxygen radical scavenger catalase or by inhibitors of the MAP-kinase signaling pathway. The present results suggest that sodium arsenite stabilizes IkappaBalpha and prevents NF-kappaB activation in IL-1beta-stimulated Caco-2 cells independent of the heat shock response. In addition, stabilization of IkappaBalpha by sodium arsenite does not require oxygen radical formation or activation of the MAP kinase signaling pathway.
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PMID:Arsenite stabilizes IkappaBalpha and prevents NF-kappaB activation in IL-1 beta-stimulated Caco-2 cells independent of the heat shock response. 1183 94

NF-kappaB is sequestered in the cytoplasm by the inhibitory IkappaB proteins. Stimulation of cells by agonists leads to the rapid phosphorylation of IkappaBs leading to their degradation that results in NF-kappaB activation. IKK-1 and IKK-2 are two direct IkappaB kinases. Two recently identified novel IKKs are IKK-i and TBK-1. We have cloned, expressed, and purified to homogeneity recombinant human (rh)IKK-i and rhTBK-1 and compared their enzymatic properties with those of rhIKK-2. We show that rhIKK-i and rhTBK-1 are enzymatically similar to each other. We demonstrate by phosphopeptide mapping and site-specific mutagenesis that rhIKK-i and rhTBK-1 are phosphorylated on serine 172 in the mitogen-activated protein kinase kinase activation loop and that this phosphorylation is necessary for kinase activity. Also, rhIKK-i and rhTBK-1 have differential peptide substrate specificities compared with rhIKK-2, the mitogen-activated protein kinase kinase activation loop of IKK-2 being a more favorable substrate than the IkappaBalpha peptide. Finally, using analogs of ATP, we demonstrate unique differences in the ATP-binding sites of rhIKK-i, rhTBK-1, and rhIKK-2. Thus, although these IKKs are structurally similar, their enzymatic properties may provide insights into their unique functions.
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PMID:IKK-i and TBK-1 are enzymatically distinct from the homologous enzyme IKK-2: comparative analysis of recombinant human IKK-i, TBK-1, and IKK-2. 1183 43

The heat shock response is known to inhibit NF-kappaB activation and NF-kappaB-dependent gene expression. Herein we determined if cells lacking heat shock factor-1 (HSF-1), the major transcription factor regulating heat shock protein gene expression, have an altered ability to modulate NF-kappaB activation. Embryonic fibroblasts from HSF-1-null mutant mice (HSF-1-/- cells) had a drastically reduced ability to express heat shock protein-70 in response to heat shock, compared to embryonic fibroblasts from wild-type mice (HSF+/+ cells). There was no difference, however, in the ability of heat shock to inhibit TNFalpha-mediated NF-kappaB activation, IkappaBalpha degradation, IkappaB kinase activation, and macrophage chemotactic protein-1 expression in the HSF-1-/- cells compared to the HSF-1+/+ cells. These data demonstrate that heat shock inhibits activation of the NF-kappaB/IkappaBalpha pathway and NF-kappaB-dependent gene expression in the absence of an intact heat shock response.
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PMID:Heat shock inhibits activation of NF-kappaB in the absence of heat shock factor-1. 1185 10

Nuclear factor kappa B (NF-kappaB)/Rel proteins are dimeric, sequence-specific transcription factors involved in the activation of an exceptionally large number of genes in response to inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. In unstimulated cells, NF-kappaB is sequestered in an inactive form in the cytoplasm bound to inhibitory IkappaB proteins. Stimulation leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IkappaB, which frees NF-kappaB to translocate to the nucleus and activate the transcription of its target genes. The multisubunit IkappaB kinase (IKK) responsible for the inducible phosphorylation of IkappaB appears to be the initial point of convergence for most stimuli that activate NF-kappaB. IKK contains two catalytic subunits, IKKalpha and IKKbeta, both of which phosphorylate IkappaB at sites phosphorylated in vivo. Gene knockout studies indicate that IKKbeta is primarily responsible for the activation of NF-kappaB in response to proinflammatory stimuli, whereas IKKalpha is essential for keratinocyte differentiation. The activity of IKK is regulated by phosphorylation. IKK contains a regulatory subunit, IKKgamma, which is critical for activation of IKK and is postulated to serve as a recognition site for upstream activators. When phosphorylated, the IKK recognition site on IkappaBalpha serves as a specific recognition site for the kappa-TrCP-like component of a Skp1-Cullin-F-box-type E3 ubiquitin-protein ligase. A variety of other signaling events, including phosphorylation of NF-kappaB, phosphorylation of IKK, new synthesis of IkappaBs, and the processing of NF-kappaB precursors provide mechanisms of modulating the amount and duration of NF-kappaB activity.
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PMID:The NF-kappa B activation pathway: a paradigm in information transfer from membrane to nucleus. 1186 84

We have shown that thalidomide (Thal) and its immunomodulatory derivatives (IMiDs), proteasome inhibitor PS-341, and As(2)O(3) act directly on multiple myeloma (MM) cells and in the bone marrow (BM) milieu to overcome drug resistance. Although Thal/IMiDs, PS-341, and As(2)O(3) inhibit nuclear factor (NF)-kappaB activation, they also have multiple and varied other actions. In this study, we therefore specifically address the role of NF-kappaB blockade in mediating anti-MM activity. To characterize the effect of specific NF-kappaB blockade on MM cell growth and survival in vitro, we used an IkappaB kinase (IKK) inhibitor (PS-1145). Our studies demonstrate that PS-1145 and PS-341 block TNFalpha-induced NF-kappaB activation in a dose- and time-dependent fashion in MM cells through inhibition of IkappaBalpha phosphorylation and degradation of IkappaBalpha, respectively. Dexamethasone (Dex), which up-regulates IkappaBalpha protein, enhances blockade of NF-kappaB activation by PS-1145. Moreover, PS-1145 blocks the protective effect of IL-6 against Dex-induced apotosis. TNFalpha-induced intracellular adhesion molecule (ICAM)-1 expression on both RPMI8226 and MM.1S cells is also inhibited by PS-1145. Moreover, PS-1145 inhibits both IL-6 secretion from BMSCs triggered by MM cell adhesion and proliferation of MM cells adherent to BMSCs. However, in contrast to PS-341, PS-1145 only partially (20-50%) inhibits MM cell proliferation, suggesting that NF-kappaB blockade cannot account for all of the anti-MM activity of PS-341. Importantly, however, TNFalpha induces MM cell toxicity in the presence of PS-1145. These studies demonstrate that specific targeting of NF-kappaB can overcome the growth and survival advantage conferred both by tumor cell binding to BMSCs and cytokine secretion in the BM milieu. Furthermore, they provide the framework for clinical evaluation of novel MM therapies based upon targeting NF-kappaB.
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PMID:NF-kappa B as a therapeutic target in multiple myeloma. 1187 48

The heat shock response (HSR) and the nuclear factor (NF)-kappaB signaling pathway are two fundamental cellular responses. Various laboratories have documented in vitro and in vivo interactions between the HSR and NF-kappaB activation when they are activated sequentially. For example, induction of the HSR before a proinflammatory signal inhibits NF-kappaB activation and NF-kappaB-dependent proinflammatory gene expression. The central point of control appears to be at the level of IkappaBalpha phosphorylation as demonstrated by HSR-mediated inhibition of IkappaB kinase activation and HSR-mediated induction of intracellular phosphatase activity. In addition, induction of the HSR can independently increase de novo expression of the IkappaBalpha gene, thereby providing another potential mechanism through which the HSR can modulate cellular proinflammatory signaling. Another level of interaction is illustrated by the observation that various pharmacologic inhibitors of the NF-kappaB pathway are capable of simultaneously inducing the HSR. In direct contrast, induction of the HSR after a proinflammatory signal can lead to programmed cell death. Further understanding of how these two fundamental cellular responses interact at the molecular level holds the potential to elucidate some of the molecular interactions that occur during disease states common to critical care medicine.
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PMID:Interactions between the heat shock response and the nuclear factor-kappaB signaling pathway. 1189 9


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