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

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role that the nuclear factor (NF)-kappa B plays in regulating the biosynthesis of interleukin (IL)-1 beta, an inflammatory cytokine, has been investigated in vitro. Irreversible inhibition of the proteasome complex by carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (MG-132; 1-50 microM) had no inhibitory effect on lipopolysaccharide (LPS)-mediated IL-1 beta biosynthesis. Furthermore, selective inhibition of NF-kappa B by the action of caffeic acid phenylethyl ester (CAPE; 1-100 microM) and sulfasalazine (SSA; 0.1-10 mM), a potent and irreversible inhibitor of NF-kappa B, partially attenuated but did not abolish LPS-dependent IL-1 beta secretion. Incorporation of a selectively permeant inhibitor of NF-kappa B, SN-50 (1-20 microM), a peptide which contains the nuclear localization sequence (NLS) for the p50 NF-kappa B subunit and the amino-terminal sequence of Kaposi fibroblast growth factor to promote cell permeability, attenuated in a dose-dependent manner LPS-mediated release of IL-1 beta. It is concluded that the NF-kapp B pathway is partially implicated and its blockade attenuates but does not abrogate LPS-dependent IL-1 beta biosynthesis in alveolar epithelial cells.
...
PMID:Nuclear factor (NF)-kappa B blockade attenuates but does not abrogate LPS-mediated interleukin (IL)-1 beta biosynthesis in alveolar epithelial cells. 1205 92

Macrophage activation by particulate debris from orthopaedic implants triggers an inflammatory response that ultimately leads to periprosthetic bone resorption and implant failure. TNFalpha has been identified as a critical cytokine involved in the response to debris particles but the mechanisms involved in activation of TNFalpha synthesis are unclear. The current study demonstrates rapid induction or TNFalpha following stimulation with titanium particles in the murine macrophage cell line. ANA-1. Electrophoretic mobility shift assays demonstrated NFkappaB DNA binding activity within 15 min of exposure to titanium particles, and experiments with an NFkappaB luciferase promoter confirmed the induction of NFkappaB mediated transcription by titanium particles. Furthermore, titanium particles induced a 2-fold induction in TNFalpha promoter activity, and mutation of the kappaB2a site, one of the four NFkappaB-binding sites in the TNFalpha promoter, resulted in decreased activation. Since NFtB is a critical regulator of inflammation and is involved in activation of the TNFalpha promoter, additional experiments were performed to determine the mechanism of NFkappaB activation by particles. NFKB activation was found to be dependent upon proteasome activity, since administration of MG 132, a proteasome inhibitor, blocked NFkappaB activation. However, IkappaBalpha is only slightly decreased following Ti treatment, in contrast to marked degradation following stimulation with LPS. Recently, another proteasome-dependent pathway of NFkappaB activation has been described involving degradation of p105. a precursor of p50 that binds to p65. p105 degradation occurred following titanium stimulation. suggesting that this recently described mechanism for NFKB activation is operant in ANA-1 cells following exposure to titanium particles. These findings demonstrate that activation of the NFkappaB signaling pathway is rapidly induced by titanium particles in ANA-1 cells and is associated with p105 degradation. TNFalpha induction appears to be mediated, at least in part, through NFkappaB binding to the kappaB2a site of the TNFalpha promoter.
...
PMID:The role of p105 protein in NFkappaB activation in ANA-1 murine macrophages following stimulation with titanium particles. 1216 59

Aggresomes are pericentrosomal cytoplasmic structures into which aggregated, ubiquitinated, misfolded proteins are sequestered. Misfolded proteins accumulate in aggresomes when the capacity of the intracellular protein degradation machinery is exceeded. Previously, we demonstrated that an intact microtubule cytoskeleton is required for the aggresome formation [Johnston et al., 1998: J. Cell Biol. 143:1883-1898]. In this study, we have investigated the involvement of microtubules (MT) and MT motors in this process. Induction of aggresomes containing misfolded DeltaF508 CFTR is accompanied by a redistribution of the retrograde motor cytoplasmic dynein that colocalizes with aggresomal markers. Coexpression of the p50 (dynamitin) subunit of the dynein/dynactin complex prevents the formation of aggresomes, even in the presence of proteasome inhibitors. Using in vitro microtubule binding assays in conjunction with immunogold electron microscopy, our data demonstrate that misfolded DeltaF508 CFTR associate with microtubules. We conclude that cytoplasmic dynein/dynactin is responsible for the directed transport of misfolded protein into aggresomes. The implications of these findings with respect to the pathogenesis of neurodegenerative disease are discussed.
...
PMID:Cytoplasmic dynein/dynactin mediates the assembly of aggresomes. 1221 Nov 13

TNF family receptors can lead to the activation of NF-kappaB and this can be a prosurvival signal in some cells. Although activation of NF-kappaB by ligation of Fas (CD95/Apo-1), a member of the TNFR family, has been observed in a few studies, Fas-mediated NF-kappaB activation has not previously been shown to protect cells from apoptosis. We examined the Fas-induced NF-kappaB activation and its antiapoptotic effects in a leukemic eosinophil cell line, AML14.3D10, an AML14 subline resistant to Fas-mediated apoptosis. EMSA and supershift assays showed that agonist anti-Fas (CH11) induced nuclear translocation of NF-kappaB heterodimer p65(RelA)/p50 in these cells in both a time- and dose-dependent fashion. The influence of NF-kappaB on the induction of apoptosis was studied using pharmacological proteasome inhibitors and an inhibitor of IkappaBalpha phosphorylation to block IkappaBalpha dissociation and degradation. These inhibitors at least partially inhibited NF-kappaB activation and augmented CH11-induced cell death. Stable transfection and overexpression of IkappaBalpha in 3D10 cells inhibited CH11-induced NF-kappaB activation and completely abrogated Fas resistance. Increases in caspase-8 and caspase-3 cleavage induced by CH11 and in consequent apoptotic killing were observed in these cells. Furthermore, while Fas-stimulation of resistant control 3D10 cells led to increases in the antiapoptotic proteins cellular inhibitor of apoptosis protein-1 and X-linked inhibitor of apoptosis protein, Fas-induced apoptosis in IkappaBalpha-overexpressing cells led to the down-modulation of both of these proteins, as well as that of the Bcl-2 family protein, Bcl-x(L). These data suggest that the resistance of these leukemic eosinophils to Fas-mediated killing is due to induced NF-kappaB activation.
...
PMID:Fas resistance of leukemic eosinophils is due to activation of NF-kappa B by Fas ligation. 1224 43

The Her-2/neu oncogene, the second member of the epidermal growth factor (EGF) receptor family, encodes a transmembrane tyrosine kinase receptor. Overexpression of Her-2/neu in approximately 30% of breast cancers is associated with poor overall survival. Recently, we have found that Her-2/neu activates nuclear factor (NF)-kappaB via a phosphatidylinositol 3 kinase (PI3-K)-Akt kinase signaling pathway in mouse mammary tumor virus (MMTV)-Her-2/neu NF639 mouse breast cancer cells. Surprisingly, the IkappaB kinase (IKK) kinase complex, implicated in proteasome-mediated degradation of IkappaB-alpha and activation of NF-kappaB via the canonical pathway, was not activated in these cells. Degradation of IkappaB-alpha was mediated via calpain, which in B cells is facilitated by phosphorylation of IkappaB-alpha by the protein kinase CK2. Here, we report that the inhibition of CK2 blocks Her-2/neu-mediated activation of NF-kappaB. NF639 breast cancer cells, stably expressing CK2alpha or CK2alpha' kinase-inactive mutants, displayed decreased NF-kappaB binding and reduced ability to grow in soft agar, as well as increased sensitivity to tumor necrosis factor (TNF)-alpha killing. Similarly, CK2 kinase-inactive subunits inhibited NF-kappaB activity in Hs578T human breast cancer cells, which also display elevated CK2 activity. In NIH 3T3 fibroblasts, which express low basal NF-kappaB and CK2 activities, overexpression of CK2 by retroviral gene delivery led to increased IkappaB-alpha turnover and the induction of classical NF-kappaB (p50/RelA). Thus, CK2 plays an important role in Her-2/neu signaling, promoting IkappaB-alpha degradation and, thereby, NF-kappaB activation. Furthermore, because ectopic CK2 activity appears sufficient to induce NF-kappaB, the elevated CK2 activity observed in many primary human breast cancers likely plays a role in aberrant activation of NF-kappaB and, therefore, represents a potential therapeutic target.
...
PMID:Protein kinase CK2 promotes aberrant activation of nuclear factor-kappaB, transformed phenotype, and survival of breast cancer cells. 1243 79

The NF-kappa B transcription factor p50 and the Rel protein-specific transcription inhibitor p105 are both encoded by the nfkb1 gene. The p50 protein is incorporated within the N-terminal portion of p105 and is a unique product of proteasomal processing. Because proteasome-mediated proteolysis generally results in complete degradation of the substrate, how p50 survives the proteasomal processing remains unknown. Survival of proteasomal processing has also been observed recently for the yeast transcription factors SPT23 and MGA2, but the mechanism is also unclear. Here we show evidence that stability of the Rel homology domain (RHD) within the N-terminal portion of the NF-kappa B 1 protein is required for p50 generation. We demonstrated that proteolysis initiated at an internal location of the NF-kappa B 1 protein, which normally generates p50, degrades the N-terminal portion of the NF-kappa B 1 protein when the RHD is destabilized. Our findings highlight the critical role of the unique structure of the RHD for the survival of p50 during proteosomal processing.
...
PMID:Stability of the Rel homology domain is critical for generation of NF-kappa B p50 subunit. 1280 80

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that has been shown to induce angiogenesis, apoptosis in tumor cells, and NF-kappaB activation through binding to its receptor, fibroblast growth factor-inducible 14. We have identified TWEAK as an inducer of constitutive NF-kappaB activation by expression cloning, and we report here sequential regulation by TWEAK of two separate signaling cascades for NF-kappaB activation, the NF-kappaB essential modulator-dependent and -independent signaling pathways. Upon TWEAK stimulation, IkappaBalpha is rapidly phosphorylated, generating NF-kappaB DNA-binding complexes containing p50 and RelA in a manner dependent on the canonical IkappaB kinase complex. Unlike TNF-alpha, TWEAK stimulation results in prolonged NF-kappaB activation with a transition of the DNA-binding NF-kappaB components from RelA- to RelB-containing complexes by 8 h, and the latter remained active in binding at least until 24 h post-stimulation. This long lasting activation is accompanied by the proteasome-mediated processing of NF-kappaB2/p100, which does not depend on the NF-kappaB essential modulator but requires IkappaB kinase 1 and functional NF-kappaB-inducing kinase activity. Finally, we show that fibroblast growth factor-inducible 14 with a mutation at its TNF receptor-associated factor (TRAF)-binding site cannot activate NF-kappaB and that TWEAK fails to induce the p100 processing and IkappaBalpha phosphorylation in cells deficient for TRAF2 and TRAF5. Our results thus identify TWEAK as a novel physiological regulator of the non-canonical pathway for NF-kappaB activation.
...
PMID:TWEAK induces NF-kappaB2 p100 processing and long lasting NF-kappaB activation. 1284 22

B lymphocyte stimulator (BLyS), a TNF family protein essential for peripheral B cell development, functions primarily through attenuation of B cell apoptosis. In this study, we show that BLyS activates NF-kappaB through both classical and alternative pathways with distinct kinetics in quiescent mature B cells. It rapidly and transiently enhances the p50/p65 DNA binding activity and induces phosphorylation of IkappaBalpha characteristic of the classical NF-kappaB pathway, albeit maintaining IkappaBalpha at a constant level through ongoing protein synthesis and proteasome-mediated destruction. With delayed kinetics, BLyS promotes the processing of p100 to p52 and sustained formation of p52/RelB complexes via the alternative NF-kappaB pathway. p50 is dispensable for p100 processing. However, it is required to mediate the initial BLyS survival signals and concomitant activation of Bcl-x(L) in quiescent mature B cells ex vivo. Although also a target of BLyS activation, at least one of the A1 genes, A1-a, is dispensable for the BLyS survival function. These results suggest that BLyS mediates its survival signals in metabolically restricted quiescent B cells, at least in part, through coordinated activation of both NF-kappaB pathways and selective downstream antiapoptotic genes.
...
PMID:NF-kappa B1 p50 is required for BLyS attenuation of apoptosis but dispensable for processing of NF-kappa B2 p100 to p52 in quiescent mature B cells. 1284 43

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disorder characterized by the presence of multiple gastrointestinal polyps and an increased risk for various types of cancers. Inactivating germline mutations of the LKB1 gene, which encodes a serine/threonine kinase, are responsible for the majority of PJS cases. Here, we show that the heteromeric complex containing the molecular chaperones Hsp90 and Cdc37/p50 interacts with the kinase domain of LKB1. Treatment of cells with either geldanamycin or novobiocin, two pharmacological inhibitors of Hsp90 causes the destabilization of LKB1. Furthermore, geldanamycin treatment leads to the ubiquitination and the rapid degradation of LKB1 by the proteasome-dependent pathway. In addition, we found that a LKB1 point mutation identified in a sporadic testicular cancer, weakens the interaction of LKB1 with both Hsp90 and Cdc37/p50 and enhances its sensitivity to the destabilizing effect of geldanamycin. Collectively, our results demonstrate that the Hsp90/Cdc37 complex is a major regulator of the stability of the LKB1 tumor suppressor. Furthermore, these data draw attention to the possible adverse consequences of antitumor drugs that target Hsp90, such as antibiotics related to geldanamycin, which could disrupt LKB1 function and promote the development of polyps and carcinomatous lesions.
...
PMID:Stability of the Peutz-Jeghers syndrome kinase LKB1 requires its binding to the molecular chaperones Hsp90/Cdc37. 1466 98

Mechanisms underlying the pathophysiology of minimal change nephrotic syndrome (MCNS), the most frequent of glomerular diseases in children, remain elusive, although recent arguments suggest that T cell dysfunction may be involved in the pathogenesis of this disease. Recently, we reported that activated T cells of these patients display a down-regulation of IL-12R beta2 chain, suggesting an early commitment toward Th2 phenotype. In this study, we show that the short form of the proto-oncogene c-maf, a known activator of the IL-4 gene, is highly induced in MCNS T cells during relapse, where it translocates to the nuclear compartment and binds to the DNA responsive element. Unexpectedly, the nuclear localization of c-maf did not promote the IL-4 gene transcription in relapse. Using several approaches, we show in this study that RelA blunts IL-4 induction in T cells during the relapse in these patients. We demonstrate that the ex vivo inhibition of proteasome activity in T cells from relapse, which blocks NF-kappaB activity, strongly increases the IL-4 mRNA levels. Overexpression of c-maf in T cells induces a high level of IL-4 promoter-driven luciferase activity. In contrast, coexpression of c-maf with NF-kappaB RelA/p50, or RelA, but not p50, inhibits the c-maf-dependent IL-4 promoter activity. Finally, we demonstrated that, in T cell overexpressing RelA and c-maf, RelA expelled c-maf from its DNA binding site on IL-4 gene promoter, which results in active inhibition of IL-4 gene transcription. Altogether, these results suggest that the involvement of c-maf in Th2 commitment in MCNS operates through IL-4-independent mechanisms.
...
PMID:NF-kappa B p65 antagonizes IL-4 induction by c-maf in minimal change nephrotic syndrome. 1468 82


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---