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

The adenyl cyclase deficient cr-1 mutant of Neurospora crassa grew poorly in bovine serum albumin as an alternative and only source of either sulfur, nitrogen or carbon. The low growth of the cr-1 mutant in protein was correlated with limited secretion of extracellular alkaline protease. The defect was specific for the cr-1 mutant and was suppressed by exogenous cyclic AMP. Cyclic AMP relieved protease deficiency under carbon, nitrogen or sulfur limiting conditions to unequal extents. Protease stimulation was greatest under carbon-limited conditions, but the resulting growth was least. Most of the cyclic AMP-mediated increase of alkaline protease was extracellular.
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PMID:Alkaline protease deficiency in the cr-1 (crisp) mutant of Neurospora crassa. 302 33

Among bacterial toxins, the adenylate cyclase toxin of Bordetella pertussis (CyaA) has a unique mechanism of entry that consists in the direct translocation of its catalytic domain across the plasma membrane of target cell, a mechanism supposed to be independent of any endocytic pathway. Here, we report that the CyaA toxin is delivered to the cytosolic pathway for MHC class I-restricted Ag presentation. Using peritoneal macrophages as APC, we show that the OVA 257-264 CD8+ epitope genetically inserted into a detoxified CyaA (CyaA-OVA E5) is presented to CD8+ T cells by a mechanism requiring 1) proteasome processing, 2) TAP, and 3) neosynthesis of MHC class I. We demonstrate that the presentation of CyaA-OVA E5, like the translocation of CyaA into eukaryotic cells, is dependent on extracellular Ca2+ and independent of vacuolar acidification. Moreover, inhibitors of the phagocytic and macropinocytic endocytic pathways do not affect the CyaA-OVA E5 presentation. The absence of specific cellular receptors for CyaA correlates with the ability of various APC to present the recombinant CyaA toxin, including dendritic cells, macrophages, splenocytes, and lymphoid tumoral lines. Taken together, our results show that the CyaA presentation pathway is not cell type specific and is unrelated to a defined type of endocytic mechanism. Thus, it represents a new and unconventional delivery of an exogenous Ag into the conventional cytosolic pathway.
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PMID:Direct delivery of the Bordetella pertussis adenylate cyclase toxin to the MHC class I antigen presentation pathway. 997 58

The transcription factor Sp1 is important for the expression of many cellular genes. Previously, it was shown that reduced O-glycosylation of Sp1 is associated with increased proteasome susceptibility. Sp1 undergoes proteasome-dependent degradation in cells stressed with glucose deprivation and adenylate cyclase activation, and this process is blocked in cells treated with glucosamine. In this study, using a reconstituted in vitro system, we identified the principal structural determinant in Sp1 that targets Sp1 for proteasome-dependent degradation. We found by using deletion analysis that the N-terminal 54 amino acids of Sp1 is required for Sp1 degradation. This element can act as an independent processing signal by directing degradation of an unrelated protein. Recognition of this Sp1 element by the proteasome-dependent system is saturable, and ubiquitination of this element is not required for recognition. Time course experiments revealed that Sp1 degradation is a two-step process. First, a discrete endoproteolytic cleavage occurs downstream of the target region immediately C-terminal to Leu56. The Sp1 sequence C-terminal to the cleavage site is subsequently degraded, whereas the N-terminal peptide remains intact. The identification of this Sp1 degradation-targeting signal will facilitate the identification of the critical proteins involved in the control of Sp1 proteasome-dependent degradation and the role of OGlcNAc in this process.
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PMID:An N-terminal region of Sp1 targets its proteasome-dependent degradation in vitro. 1032 28

The transcription factor Sp1 was previously shown to undergo proteasome-dependent degradation when cells were glucose-starved and stimulated with the adenylate cyclase inducer, forskolin. However, the control of the Sp1 degradation process is largely unknown. Using in vitro and in vivo interaction studies, we show in the present study that Sp1 interacts with human Sug1 [hSug1, also known as p45 or thyroid-hormone-receptor interacting protein ('TRIP1')], an ATPase subunit of the 26 S proteasome and a putative transcriptional modulator. This interaction with Sp1 occurs through the C-terminus of hSug1, the region that contains the conserved ATPase domain in this protein. Both in vitro studies, in reconstituted degradation assays, and in vivo experiments, in which hSug1 is overexpressed in normal rat kidney cells, show that full-length hSug1 is able to stimulate the proteasome-dependent degradation of Sp1. However, hSug1 truncations that lack either the N- or C-terminal domain of hSug1 act as dominant negatives, inhibiting Sp1 degradation in vitro. Also, an ATPase mutant of hSug1, while still able to bind Sp1, acts as a dominant negative, blocking Sp1 degradation both in vitro and in vivo. These results demonstrate that hSug1 is involved in the degradation of Sp1 and that ATP hydrolysis by hSug1 is necessary for this process. Our findings indicate that hSug1 is an exchangeable proteasomal component that plays a critical regulatory role in the proteasome-dependent degradation of Sp1. However, hSug1 is not the factor limiting Sp1 degradation in the cells treated with glucosamine. This and other considerations suggest that hSug1 co-operation with other molecules is necessary to target Sp1 for proteasome degradation.
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PMID:Human Sug1/p45 is involved in the proteasome-dependent degradation of Sp1. 1081 20

Patients with cancer cachexia experience a profound wasting of adipose tissue and lean body mass. Anorexia, although often present, is insufficient to account for tissue wasting because 1) cachexia involves massive depletion of skeletal muscle that does not occur during anorexia, 2) nutritional supplementation cannot replenish the loss of lean body mass, 3) cachexia can occur without anorexia, and 4) food intake might be normal for the lower weight of the cancer patient. Anorexia can arise from 1) decreased taste and smell of food, 2) early satiety, 3) dysfunctional hypothalamic membrane adenylate cyclase, 4) increased brain tryptophan, and 5) cytokine production. Appetite stimulants such as cyproheptadine, medroxyprogesterone acetate, and megestrol acetate do not significantly improve lean body mass. Tumor products might be more important in the development of cachexia. Cachectic patients excrete in their urine a lipid-mobilizing factor that directly stimulates lipolysis in a cyclic AMP-dependent manner and increases energy expenditure. Loss of skeletal muscle in cachexia is caused by upregulation of the ubiquitin-proteasome catabolic pathway. Cachexia-inducing tumors elaborate a sulfated glycoprotein, which directly initiates protein catabolism in skeletal muscle. The action of this proteolysis-inducing factor is attenuated by the polyunsaturated fatty acid eicosapentaenoic acid, which is also effective in preventing loss of skeletal muscle in cancer patients. Antagonists of tumor catabolic factors will provide important new agents in the treatment of cancer cachexia.
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PMID:Cancer anorexia and cachexia. 1137 46

Treatment of murine myoblasts, myotubes and tumour cells with a tumour-produced lipid mobilizing factor (LMF), caused a concentration-dependent stimulation of protein synthesis, within a 24 h period. There was no effect on cell number or [(3)H] thymidine incorporation, but a similar concentration-dependent stimulation of 2-deoxyglucose uptake. LMF produced an increase in intracellular cyclic AMP levels, which was linearly (r(2)= 0.973) related to the increase in protein synthesis. The effect of LMF was attenuated by the adenylate cyclase inhibitor MDL(12330A), and was additive with the stimulation produced by forskolin. Both propranolol (10 microM) and the specific beta(3)-adrenergic receptor antagonist SR 59230A (10(-5)M), significantly reduced the stimulation of protein synthesis induced by LMF. Protein synthesis was also increased by 69% (P = 0.006) in soleus muscles of mice administered LMF, while there was a 26% decrease in protein degradation (P = 0.03). While LMF had no effect on the lysosomal enzymes, cathepsins B and L, there was a decrease in proteasome activity, as determined both by the 'chymotrypsin-like' enzyme activity, as well as expression of proteasome alpha-type subunits, determined by Western blotting. These results show that in addition to its lipid-mobilizing activity LMF also increases protein accumulation in skeletal muscle both by an increase in protein synthesis and a decrease in protein catabolism.
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PMID:Effect of a tumour-produced lipid-mobilizing factor on protein synthesis and degradation. 1140 19

Inhibition of proteasome activity is associated with a reduction in proliferation and apoptosis in cancer cells, depending upon the extent of inhibition. We have reported that a minimal inhibition of proteasome activity prevented adenosine 3'5'-cyclic monophosphate (cAMP)-induced differentiation and caused apoptosis in murine neuroblastoma (NB) cells in culture. In order to establish whether an elevated cAMP level increases the sensitivity of proteasome to its inhibitors, MG-132 and lactacystin (proteasome inhibitors) were added concomitantly with a stimulator of adenylate cyclase (prostaglandin A1) and an inhibitor of cyclic nucleotide phosphodiesterase (RO20-1724). Results showed that concentrations of MG-132 that did not reduce or that minimally inhibited proteasome activity also did not affect the proliferation of undifferentiated NB cells. However, these concentrations of MG-132 in the presence of an elevated cAMP level markedly inhibited proteasome activity and caused extensive cell death. Similar results were obtained with lactacystin. In normal murine fibroblasts, cAMP-induced reduction in proliferation was not affected by any concentration of MG-132 used in this study. These results suggest that proteasome exhibits increased sensitivity to its inhibitors following an elevation of cAMP level in NB cells, but not in normal fibroblasts, and that this may account for the enhanced cell death in NB cells. Thus, the strategy of using low doses of a proteasome inhibitor in combination with a cAMP-stimulating agent may be useful in pre-clinical and clinical studies on NB tumor because of the selectivity of the effect on cancer cells.
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PMID:Sensitivity of proteasome to its inhibitors increases during cAMP-induced differentiation of neuroblastoma cells in culture and causes decreased viability. 1474 34

The adenylate cyclase (AC)/cyclic AMP (cAMP)/cAMP-dependent protein kinase pathway controls many biological phenomena. The ubiquitin/proteasome system, controlling the levels of many proteins, modulates important cellular processes such as cell cycle and cell growth. Here we describe a novel mechanism for AC regulation by proteasome pathway. Pharmacological inhibition of proteasome function in human osteosarcoma U2OS cells results in up-regulation of AC activity, increase of levels of alpha subunit of heterotrimeric stimulatory GTP-binding proteins (alphas) and, remarkably, also in preventing of beta-adrenergic receptor-mediated down-regulation of alphas protein levels. Accumulation of alphas protein is also accompanied by the appearance of polyubiquitinated alphas species. Our results: (1) identify alphas protein as a novel proteasome substrate in mammalian cells; (2) indicate that proteasome might play a physiological role in controlling AC/cAMP mediated pathways by modulating the levels of Galphas protein; (3) suggest a role for the proteasome also in controlling alphas-mediated signaling pathways other than those affecting AC complex.
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PMID:Adenylate cyclase regulation via proteasome-mediated modulation of Galphas levels. 1533 22

The adenylate cyclase (CyaA) produced by Bordetella pertussis is able to deliver CD8+ and CD4+ T-cell epitopes genetically grafted within the catalytic domain of the molecule into antigen presenting cells in vivo. We develop now a new approach in which peptides containing CD8+ epitopes are chemically linked to CyaA. We show that CTL responses were induced in mice immunized with CyaA bearing these CD8+ epitopes. Moreover, we demonstrate that the OVA257-264 CD8+ epitope chemically grafted to CyaA is presented to CD8+ T cells by a mechanism requiring (1) proteasome processing, (2) TAP and (3) neosynthesis of MHC class I molecules. Thus, this novel strategy represents a very versatile system as a single CyaA carrier protein could be easily and rapidly coupled to any desired synthetic peptide.
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PMID:Bordetella pertussis adenylate cyclase delivers chemically coupled CD8+ T-cell epitopes to dendritic cells and elicits CTL in vivo. 1554 80

Monocyte chemotactic protein-1 (MCP-1) binds its G-protein-coupled seven transmembrane (TM) receptor, CCR2B, and causes infiltration of monocytes/macrophages into areas of injury, infection or inflammation. To identify functionally important amino acid residues in CCR2B, we made specific mutations of nine residues selected on the basis of conservation in chemokine receptors and located TM1 (Tyr(49)), TM2 (Leu(95)), TM3 (Thr(117) and Tyr(120)), and TM7 (Ala(286), Thr(290), Glu(291), and His(297)) and in the extracellular loop 3 (Glu(278)). MCP-1 binding was drastically affected only by mutations in TM7. Reversing the charge at Glu(291) (E291K) and at His(297) (H297D) prevented MCP binding although substitution with Ala at either site had little effect, suggesting that Glu(291) and His(297) probably stabilize TM7 by their ionic interaction. E291A elicited normal Ca(2+) influx. H297A, Y49F in TM1 and L95A in TM2 that showed normal MCP-1 binding did not elicit Ca(2+) influx and elicited no adenylate cyclase inhibition at any MCP-1 concentration. MCP-1 treatment of HEK293 cells caused lamellipodia formation only when they expressed CCR2B. The mutants that showed no Ca(2+) influx and adenylate cyclase inhibition by MCP-1 treatment showed lamellipodia formation and chemotaxis. Our results show that induction of lamellipodia formation, but not Ca(2+) influx and adenylate cyclase inhibition, is necessary for chemotaxis.
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PMID:Site-directed mutagenesis of CCR2 identified amino acid residues in transmembrane helices 1, 2, and 7 important for MCP-1 binding and biological functions. 1562 46


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