Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proteolytic degradation of the inhibitory protein MAD3/I kappa B alpha in response to extracellular stimulation is a prerequisite step in the activation of the transcription factor NF-kappa B. Analysis of the expression of human I kappa B alpha protein in stable transfectants of mouse 70Z/3 cells shows that, as for the endogenous murine protein, exogenous I kappa B alpha is degraded in response to inducers of NF-kappa B activity, such as phorbol myristate acetate or lipopolysaccharide. In addition, pretreatment of the cells with the proteasome inhibitor N-Ac-Leu-Leu-norleucinal inhibits this ligand-induced degradation and, in agreement with previous studies, stabilizes a hyperphosphorylated form of the human I kappa B alpha protein. By expressing mutant forms of the human protein in this cell line, we have been able to delineate the sequences responsible for both the ligand-induced phosphorylation and the degradation of I kappa B alpha. Our results show that deletion of the C terminus of the I kappa B alpha molecule up to amino acid 279 abolishes constitutive but not ligand-inducible phosphorylation and inhibits ligand-inducible degradation. Further analysis reveals that the inducible phosphorylation of I kappa B alpha maps to two serines in the N terminus of the protein (residues 32 and 36) and that the mutation of either residue is sufficient to abolish ligand-induced degradation, whereas both residues must be mutated to abolish inducible phosphorylation of the protein. We propose that treatment of 70Z/3 cells with either phorbol myristate acetate or lipopolysaccharide induces a kinase activity which phosphorylates serines 32 and that these phosphorylations target the protein for rapid proteolytic degradation, possibly by the ubiquitin-26S proteasome pathway, thus allowing NF-kappa B to translocate to the nucleus and to activate gene expression.
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PMID:N- and C-terminal sequences control degradation of MAD3/I kappa B alpha in response to inducers of NF-kappa B activity. 756 83

Monoclonal non-specific suppressor factor (MNSF), a lymphokine produced by a murine hybridoma, was originally found to inhibit the generation of lipopolysaccharide (LPS)-induced Ig-secreting cells. Most recently, we demonstrated the recombinant form of the ubiquitin-like segment (rUbi-L) or MNSF beta, an isoform of MNSF, has a MNSF activity. To investigate the possible role of rUbi-L, a 8.5 kDa ubiquitin-like polypeptide, in the regulation of Ig isotype secretion, rUbi-L was added to purified B cell cultures stimulated with LPS plus IL-4. rUbi-L notable suppressed the IgE and IgG1 responses when added at culture initiation. In addition, rUbi-L had a strong effect on IgG3 production and a little effect on IgM production by LPS-stimulated B cells, whereas the level of other isotypes (IgG2a, IgG2b and IgA) was not affected. These findings demonstrate the isotype-specific suppression, but not pan-suppression, of Ubi-L. IFN-alpha and IFN-gamma, which are also known to inhibit the IgE response, showed a synergistic effect with Ubi-L, albeit the effects of IFN-alpha were smaller. The action was reversed by the addition of neutralizing antibodies of these cytokines. Therefore, Ubi-L, a ubiquitin-like protein, may have an important immunoregulatory role on the IgE response.
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PMID:Ubiquitin-like polypeptide inhibits the IgE response of lipopolysaccharide-activated B cells. 894 60

Monoclonal non-specific suppressor factor (MNSF), a lymphokine produced by a murine T-cell hybridoma, possesses pleiotrophic non-specific suppressive functions. MNSFbeta (a subunit of MNSF) is a 14.5 kDa fusion protein consisting of a protein with 36% homology with ubiquitin and ribosomal protein S30. The ubiquitin-like segment of MNSFbeta (Ubi-L) is an 8 kDa polypeptide with MNSF-like activity. Since the amino acids critical for the ubiquitination process are conserved in Ubi-L, we examined whether Ubi-L may conjugate with intracellular proteins in a manner similar to the ubiquitin system. Rabbit polyclonal antibodies specific for Ubi-L detected the induction of Ubi-L conjugations, including 33.5 kDa and 70 kDa molecules in concanavalin A (Con A)-stimulated T-cells, but not in lipopolysaccharide-stimulated B-cells and macrophages. High-molecular-mass conjugates were consistently present in pan-T-cells. However, free Ubi-L could not be observed in all the cells tested. Con A-activated CD8+ T-cells, but not CD4+ T-cells, induced the 70 kDa Ubi-L adduct, which was recognized by an anti-MNSF monoclonal antibody. Treatment of CD8+ T-cells with interferon (IFN) gamma also caused the expression of the 70 kDa Ubi-L adduct, whereas the responses to IFNalpha and IFNbeta were nil. Antigen- and Con A- stimulated D.10 G4.1, a murine T helper clone type 2, induced the 33.5 kDa, but not the 70 kDa, adduct. These results suggest a role for Ubi-L conjugation in the regulation of T-cell activation.
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PMID:Ubiquitin-like polypeptide conjugates to acceptor proteins in concanavalin A- and interferon gamma-stimulated T-cells. 948 Aug 75

K48R ubiquitin (K48R-Ub) is an analogue of native ubiquitin that does not form polyubiquitin chain conjugates. Targeted delivery of this recombinant mutant ubiquitin to human macrophages results in an intracellular increase in the ubiquitin analogue. IkappaBalpha polyubiquitination and degradation were significantly inhibited in K48R-Ub targeted macrophages upon stimulation with lipopolysaccharide. The ability to reduce IkappaBalpha degradation was also associated with a reduced production of TNF-alpha, the gene of which is under NF-kappaB control. At a concentration of 0.1 microM, dexamethasone was less effective than K48R-Ub in preventing IkappaBalpha depletion and TNF-alpha release. These data suggest that ubiquitin analogues are potent suppressors of TNF-alpha release in macrophages.
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PMID:Efficient inhibition of macrophage TNF-alpha production upon targeted delivery of K48R ubiquitin. 1008 82

Ubiquitin synergistically augmented the production of tumor necrosis factor alpha (TNF-alpha) in the presence of lipopolysaccharide (LPS) in murine macrophage cell line RAW 264.7. To investigate the mechanism of this augmentation, we analyzed the effect of ubiquitin during TNF-alpha mRNA synthesis and degradation, and TNF-alpha degradation on RAW 264.7 cells stimulated by LPS. It is found that ubiquitin augmented TNF-alpha mRNA synthesis. Ubiquitin did not affect the degradation of TNF-alpha mRNA and TNF-alpha. In the presence of LPS, extracellular accumulation of TNF-alpha by ubiquitin was twice than those by LPS, but intracellular accumulation of TNF-alpha produced by ubiquitin with LPS or by LPS had no difference. These data indicate that ubiquitin might induce TNF-alpha accumulation mainly by up-regulation of the TNF-alpha gene transcription. Although extracellular functions of ubiquitin remain largely unknown, we postulate that ubiquitin might be involved in the modulatory mechanisms of immune response.
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PMID:Synergistic effect of ubiquitin on lipopolysaccharide-induced TNF-alpha production in murine macrophage cell line RAW 264.7 cells. 1023 52

The ubiquitin/proteasome pathway mediates the degradation of many short-lived proteins that are critically involved in the regulation of cell proliferation and cell death, including the tumor suppressor protein p53. Accumulation of p53 and induction of apoptosis in RAW 264.7 macrophages in response to nitric oxide are well established. However, the molecular mechanisms involved in nitric oxide-induced p53 accumulation are unknown. Here we show that, similar to nitric oxide, treatment of macrophages with specific proteasome inhibitors, including clastolactacystin-beta-lactone, induces p53 accumulation and apoptosis, suggesting that nitric oxide may affect the activity of the proteasome. In support of this hypothesis, both exposure of cells to S-nitrosoglutathione and stimulation of endogenous nitric oxide production by lipopolysaccharide/interferon-gamma treatment result in inhibition of proteasome activity as measured in vitro by the degradation of the proteasome-specific substrate succinyl-Leu-Leu-Val-Tyr-4-methylcoumarin-7-amide. Moreover, chemically diverse nitric oxide donors interfere with proteasome-mediated degradation of polyubiquitinated p53 in vitro. These data imply that nitric oxide-induced apoptosis and accumulation of p53 are, at least in part, mediated by inhibition of the proteasome.
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PMID:Activation of the cell death program by nitric oxide involves inhibition of the proteasome. 1039 92

Ascorbate-enhanced nitric oxide (NO) production in lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-activated macrophage J774.1 cells through the inducible nitric oxide synthase (iNOS) pathway. The iNOS gene was synergistically induced by LPS and IFN-gamma. The inductive mechanism of ascorbate on the iNOS gene was studied by examining the degradation of I kappa B alpha by Western blotting, activation of the nuclear factor kappa B (NF-kappa B) by gel shift assays, and protein levels of interferon regulatory factor 1 (IRF-1) in LPS- and IFN-gamma-activated cells. Ascorbate had no effect on the onset of either I kappa B alpha degradation or the nuclear translocation of NF-kappa B, but it delayed the recovery of I kappa B alpha. The prolonged degradation of I kappa B alpha caused by ascorbate in LPS- and IFN-gamma-activated cells paralleled elevated NF-kappa B binding to DNA, which led to an increase in the iNOS protein level. Ascorbate alone did not induce I kappa B alpha degradation or NF-kappa B activation. Furthermore, ascorbate exerted no effect on the expression of I kappa B alpha and ubiquitin genes in the activated cells. Ascorbate could modulate NF-kappa B DNA binding activity in response to combined LPS and IFN-gamma activation, which increases NO production in activated macrophages.
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PMID:Molecular role of ascorbate in enhancement of NO production in activated macrophage-like cell line, J774.1. 1057 33

It has been demonstrated from studies using NF-kappaB inhibitors that NF-kappaB may be involved in the iNOS induction stimulated by cytokines and/or lipopolysaccharide (LPS) in various cell types and tissues. However, the actions of the inhibitors are less selective and highly cytotoxic. We constructed stable clones of C6 cells transfected with two types of IkappaBalpha mutant genes (IkappaBalpha(SS --> AA); Ser-32/36 to Ala-32/36, IkappaBalpha(KK --> RR); Lys-21/22 to Arg-21/22). IkappaBalpha(SS --> AA) strongly inhibited (1) LPS-, IL-1beta-, and TNF-alpha-induced nuclear translocation and DNA binding of NF-kappaB to the kappaB site; and (2) iNOS induction stimulated by LPS or IL-1beta plus IFN-gamma. These results indicate that NF-kappaB plays a critical role in cytokines and/or LPS-induced iNOS induction. Surprisingly, similar to the endogenous IkappaBalpha, IkappaBalpha(KK --> RR) was degraded by various stimuli, and proteasome inhibitors blocked this event. These results suggest that another Lys residue(s), other than Lys-21/22, may be required for the ligand-induced IkappaBalpha degradation by the ubiquitin-proteasome pathway.
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PMID:Involvement of nuclear factor-kappaB (NF-kappaB) signaling in the expression of inducible nitric oxide synthase (iNOS) gene in rat C6 glioma cells. 1096 56

Activation of NF-kappaB and production of NF-kappaB-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (CI-1) blocks activation of NF-kappaB by preventing proteolysis of the inhibitory protein IkappaB-alpha by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-kappaB activation in vivo after intraperitoneal (i.p.) treatment with bacterial lipopolysaccharide (LPS), and that NF-kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. We treated rats with a single i.p. injection of CI-1 (10 mg/kg) two hours prior to i.p. LPS (7 mg/kg). Treatment with Cl-1 prevented degradation of IkappaB-alpha and activation of NF-kappaB in the liver in response to LPS; however, Cl-1 treatment had no detected effect on NF-kappaB activation in lung tissue. CI-1 treatment prior to LPS resulted in 40% lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/- 112 pg/ml vs. 859 +/-144 pg/ml, P < 0.05). In addition, CI-1 treatment substantially inhibited LPS-induced neutrophilic alveolitis (2.7+ /- 1.2 x 10(5) vs. 43.7 +/- 12.2 x 10(5) lung lavage neutrophils, P < 0.01). These data indicate that NF-kappaB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver-lung interaction contributes to the inflammatory response of the lung.
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PMID:Suppression of lung inflammation in rats by prevention of NF-kappaB activation in the liver. 1129 63

The development of new pharmacological approaches for preventing muscle wasting in cancer is an important goal because cachectic patients display a reduced response to chemotherapy and radiotherapy. Xanthine derivatives such as pentoxifylline inhibit tumour necrosis factor-alpha (TNF) production, which has been implicated in the signalling of muscle wasting. However, the effect of pentoxifylline has been inconclusive in clinical trials. We report here the first direct evidence that daily injections of torbafylline (also known as HWA 448), another xanthine derivative, had no effect by itself on muscle proteolysis in control healthy rats. In cancer rats, the drug blocked the lipopolysaccharide-induced hyperproduction of TNF and prevented muscle wasting. In these animals HWA 448 suppressed the enhanced proteasome-dependent proteolysis, which is sensitive to the proteasome inhibitor MG132, and the accumulation of high-molecular-mass ubiquitin (Ub) conjugates in the myofibrillar fraction. The drug also normalized the enhanced muscle expression of Ub, which prevails in the atrophying muscles from cancer rats. In contrast, HWA 448 did not reduce the increased expression of either the 14 kDa Ub conjugating enzyme E2 or the ATPase and non-ATPase subunits of the 19 S regulatory complex of the 26 S proteasome, including the non-ATPase subunit S5a, which recognizes polyUb degradation signals. Finally, the drug also prevented muscle wasting in septic rats (which exhibit increased TNF production), and was much more potent than pentoxifylline or other xanthine derivatives. Taken together, the data indicate that HWA 448 is a powerful inhibitor of muscle wasting that blocks enhanced Ub-proteasome-dependent proteolysis in situations where TNF production rises, including cancer and sepsis.
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PMID:Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin-proteasome-dependent proteolysis in cancer and septic rats. 1177 90


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