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)

Dopamine (DA) is the most abundant catecholamines in human plasma and exists mostly in the sulfo-conjugated form (DA sulfate), a biologically inactive metabolite. The paucity of unconjugated DA (PDA) in plasma throws doubt on its physiological significance. However, PDA, when measured with a highly sensitive radioenzymatic method, showed quite different features from norepinephrine and epinephrine in some types of clinical hypertension, lower in essential hypertension and higher in primary aldosteronism and pheochromocytoma. There was a weak but significant correlation between the values of PDA and DA sulfate measured in the same specimens, but DA sulfate was more susceptible to impaired renal function. Upright posture, high salt diets and an intravenous injection of metoclopramide (MCP, 10 mg), a DA receptor antagonist, induced a slight but significant increase in PDA in normal and hypertensive subjects. An intravenous dexamethasone (2 mg) caused a gradual increase in PDA over 150 min after medication, which was completely blocked by concomitant administration of alpha-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. The responses of PDA to both high salt diets and MCP were blunted in salt-sensitive patients with uncomplicated essential hypertension. The results suggest that DA is not only a precursor of norepinephrine biosynthesis but also plays an inherent role as an active neurotransmitter in the peripheral sympathoadrenal system, and that PDA is a sensitive marker of peripheral dopaminergic activity, which may operate to modulate the cardiovascular and endocrine functions and participate in the pathogenesis of some types of hypertension.
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PMID:Plasma free dopamine: physiological variability and pathophysiological significance. 852 77

We investigated the ability of bryostatin 1 to block nerve growth factor (NGF)-induced differentiation of pheochromocytoma PC12 cells and to effect expression of protein kinase C (PKC) isoforms. Compared with phorbol myristate acetate (PMA), a likewise potent activator of PKC, high doses of bryostatin (> 200 nM) failed to down-regulate delta-PKC, as with zeta-PKC, whereas, alpha-PKC was completely down-regulated. Two forms of delta-PKC were expressed in PC12 cells, a phosphorylated 78.000 M(r) species and a de-phosphorylated 76.000 M(r) form. High-dose bryostatin treatment resulted in a 4.5-fold increase in phosphorylated delta-PKC and a 2.5-fold increase in phosphotyrosine. Inhibition of tyrosine kinase activity, with either herbimycin or genistein, prior to addition of bryostatin abrogated protection from down-regulation and led to simultaneous increases in ubiquitinated 110.000 M(r)-delta-PKC. Similarly, pre-treatment of cells with N-acetyl-L-leucinyl-L-leucinyl-L-norleucinal, an inhibitor of the proteasome pathway, prior to low-dose treatment with bryostatin resulted in a dose-dependent accumulation of delta-PKC and inhibition of down-regulation. Protection of delta-PKC from down-regulation by high-dose bryostatin requires a counter-balance between protein tyrosine kinase and phosphatase systems. High doses of bryostatin blocked NGF-induced neurite outgrowth without altering Y-490 TrK A phosphorylation or an alteration in pp44/42 mitogen-activated protein kinase. Our findings suggest that the phosphorylation state of delta-PKC may regulate its ability to participate in signal coupling and modulation of cell growth and differentiation pathways. Moreover, these data reveal the existence of a signalling pathway independent of MAP kinase that affects NGF differentiation in a negative fashion.
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PMID:Delta-protein kinase C phosphorylation parallels inhibition of nerve growth factor-induced differentiation independent of changes in Trk A and MAP kinase signalling in PC12 cells. 961 84

Pheochromocytoma accounts for approximately 25% of incidentally discovered adrenal masses. Certain diagnostic procedures (e.g., adrenal arteriography, needle biopsy of an adrenal mass), anesthesia and abdominal surgery may cause a sudden release of catecholamines from a pheochromocytoma and induce paroxysmal attacks of hypertension. In addition, pheochromocytoma is well known to cause unsuspected operating room deaths. Therefore, we must carefully separate this functioning neoplasm from other types of adrenal masses. In this study, we compared the results of noninvasive tests including (1) assay of urinary catecholamines and their metabolites, (2) a provocative pharmacologic test using metoclopramide (MCP test), and (3) 131I-metaiodobenzylguanidine (MIBG) scintigraphy to screen for pheochromocytoma in 10 consecutive patients with an incidentally discovered adrenal mass (6 pheochromocytomas and 4 non-functioning adrenocortical adenomas). We measured the 24-hour urinary excretion of catecholamines, metanephrines and vanillyl mandelic acid in all 10 patients; 5 were positive, 4 were negative and 1 was false-negative (sensitivity = 83%, specificity = 100%). The MCP test was performed in 7 patients; 3 were positive, 3 were negative and 1 was false-negative (sensitivity = 75%, specificity = 100%). MIBG scintigraphy was performed in 7 patients; 4 were positive, 1 was negative and 2 were false-negative (sensitivity = 67%, specificity = 100%). According to these results, all patients with an incidentally discovered adrenal mass should undergo a determination of the 24-hour urinary excretion of catecholamines and their metabolites, including metanephrines. If this urine assay is negative, other noninvasive tests including the MCP test and MIBG scintigraphy should be considered in selected patients with radiographic characteristics of pheochromocytoma.
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PMID:[Noninvasive screening for pheochromocytoma in patients with an incidentally discovered adrenal mass: usefulness of provocative test with metoclopramide and 131I-metaiodobenzylguanidine scintigraphy]. 1058 57

The unicellular motile cyanobacterium Synechocystis sp. PCC 6803 exhibits phototactic motility that depends on the type IV-like thick pilus structure. By gene disruption analysis, we showed that a gene cluster of slr1041, slr1042, slr1043 and slr1044, whose predicted products are homologous to PatA, CheY, CheW and MCP, respectively, was more or less required for pilus assembly, motility and natural transformation competency with extraneous DNA. By sequence homology, the missing cheA-like gene in this cluster was identified as novel split genes, slr0073 and slr0322, at separate loci on the genome. This was confirmed by non-motile phenotype of their disruptants. Unique hyperpiliation was observed in the slr1042 and slr0073 disruptants, suggestive of their specific interaction with pilT1. The genes, thus identified as pil genes in this study, were designated pilG (slr1041), pilH (slr1042), pilI (slr1043), pilJ (slr1044), pilL-N (slr0073) and pilL-C (slr0322).
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PMID:pilG Gene cluster and split pilL genes involved in pilus biogenesis, motility and genetic transformation in the cyanobacterium Synechocystis sp. PCC 6803. 1204 98

The extract of Anemarrhenae Rhizoma (rhizomes of Anemarrhena asphodeloides BUNGE) showed neurotrophic activity toward rat pheochromocytoma (PC-12) cells. Bioassay-guided purification afforded four compounds, 2,6,4'-trihydroxy-4-methoxybenzophenone (1), 7-hydroxy-3-(4-hydroxybenzyl)chroman (2), broussonin B (3), and cis-hinokiresinol (4). Compounds 1-3 induced neurite outgrowth in PC-12 cells at concentration of 50 microg/ml, while 4 was less active. In addition, compounds 2-4 showed moderate inhibitory activities against a chymotrypsin-like activity of the proteasome.
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PMID:7-hydroxy-3-(4-hydroxybenzyl)chroman and broussonin b: neurotrophic compounds, isolated from Anemarrhena asphodeloides BUNGE, function as proteasome inhibitors. 1614 65

Inhibition of the proteasome by lactacystin, a specific blocker of the catalytic beta-subunits, results in transient neurite outgrowth by neuronal cell lines. Vice versa, as demonstrated in this study, treatment of pheochromocytoma (PC12) cells with nerve growth factor (NGF) or other differentiating agents reduces proteasomal activity. This is accompanied by an increase in mRNA and protein levels of the catalytically active subunits beta1, beta2 and beta5, but not of their inducible counterparts, indicating changes in subunit composition of the proteasome during neuronal differentiation. In contrast to neuronal cell lines, however, pre-treatment of primary neurons with proteasome inhibitors completely prevents axon formation, and lower concentrations of lactacystin (0.5-5 microm) significantly reduce axonal elongation and branching in vitro. Furthermore, established axonal networks degenerate rapidly and long-term survival of peripheral neurons is impaired in the presence of proteasome inhibitors. Axonal pathology is reminiscent of the morphological changes observed in neurodegenerative disorders and supports a crucial role of the constitutive catalytic subunits in axon initiation, maintenance and regeneration.
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PMID:Constitutively expressed catalytic proteasomal subunits are up-regulated during neuronal differentiation and required for axon initiation, elongation and maintenance. 1653 86

Protoporphyrin IX (PpIX) synthesis by malignant cells is successfully exploited for photodynamic therapy (PDT) following administration of 5-aminolevulinic acid (ALA) and light irradiation. The influence of two environmental heavy metal poisons, lead and gallium, on PpIX-synthesis and ALA-PDT was studied in two neu-ronal cell lines, SH-SY5Y neuroblastoma and PC12 pheochromocytoma. The heavy metal intoxication affected two of the heme-synthesis enzymes, ALA-dehydratase (ALAD) and porphobilinogen deaminase (PBGD). The present results show that lead poisoning significantly decreased the PBGD cellular level and inhibited its enzymatic activity, whereas the effects of gallium were less prominent. Although, the protein levels were reduced, the mRNA levels of PBGD remained unchanged during metal intoxication. These findings show additional inhibitory activity of lead on top of its classical effect on ALAD. Proteasome activity was enhanced during lead treatment, as measured by the AMC fluorigenic proteasome assay. The reduction in PBGD levels was not a consequence of PBGD mRNA reduced synthesis, which remained unchanged as shown by RT-PCR analysis. As a result of the lead poisoning, marked alterations in the cell cycle were observed, including a decreased G1 phase and an increased number of S phase cells. The efficacy of ALA-PDT was reduced in correlation with decreased activities of the enzymes during lead intoxication. We may conclude that lead poisoning adversely affects the outcome of ALA photodynamic therapy of cancer.
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PMID:Regulation of porphyrin synthesis and photodynamic therapy in heavy metal intoxication. 1656 14

Lig-8, a lignophenol derivative from bamboo lignin, potently suppresses oxidative stress-induced apoptosis. Here, we first examined in vitro whether lig-8 protects against neuronal damage induced by oxygen-glucose deprivation (OGD) followed by reoxygenation, tunicamycin [endoplasmic reticulum (ER)-stress inducer], or PSI (proteasome inhibitor). In pheochromocytoma (PC12) cell cultures, lig-8 (1 to 30 microM) concentration-dependently inhibited OGD- and tunicamycin (2 microg/ml)-induced cell deaths (significant at >/=3 microM and >/=1 microM, respectively). In human neuroblastoma (SH-SY5Y) cell culture, the PSI-induced apoptotic cell death and fusion protein accumulation (revealing reduced proteasome activity) was inhibited by lig-8 (30 microM). On the other hand, lig-8 at 30 microM alone did not affect any proteasome activity under resting conditions. In vivo, lig-8 (0.1 nmol/eye) reduced intravitreal N-methyl-D-aspartate (NMDA, 20 nmol)-induced retinal damage (decreases in retinal ganglion cells and inner plexiform layer thickness). Hence, lig-8 protects, partly by inhibiting excessive ER-stress, against neuronal damage in vitro and in vivo.
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PMID:Lig-8, a bioactive lignophenol derivative from bamboo lignin, protects against neuronal damage in vitro and in vivo. 1703 Oct 70

Parkinson's disease is a common neurodegenerative disease in the elderly. Its causes and mechanisms are not clearly understood. To explore the specific role of autophagy and the ubiquitin-proteasome pathway in apoptosis, a specific proteasome inhibitor and macroautophagy inhibitor and stimulator were selected to investigate pheochromocytoma (PC12) cell lines transfected with human mutant (A30P) and wild-type (WT) alpha-synuclein. The apoptosis ratio was assessed by flow cytometry. LC3, heat shock protein 70 (hsp70) and caspase-3 expression in cell culture were determined by Western blot. The hallmarks of apoptosis and autophagy were assessed with transmission electron microscopy. Compared to the control group or the rapamycin (autophagy stimulator) group, the apoptosis ratio in A30P and WT cells was significantly higher after treatment with inhibitors of the proteasome and macroautophagy. The results of Western blots for caspase-3 expression were similar to those of flow cytometry; hsp70 protein was significantly higher in the proteasome inhibitor group than in control, but in the autophagy inhibitor and stimulator groups, hsp70 was similar to control. These findings show that inhibition of the proteasome and autophagy promotes apoptosis, and the macroautophagy stimulator rapamycin reduces the apoptosis ratio. And inhibiting or stimulating autophagy has less impact on hsp70 than the proteasome pathway.
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PMID:Role of autophagy and proteasome degradation pathways in apoptosis of PC12 cells overexpressing human alpha-synuclein. 1942 84

Ubiquitination is a key event for protein degradation by the proteasome system, membrane protein internalization, and protein trafficking among cellular compartments. Few data are available on the role of the ubiquitin-proteasome system (UPS) in the trafficking of neuronal nicotinic acetylcholine receptors (nAChRs). Experiments conducted in neuron-like differentiated rat pheochromocytoma cells (PC12 cells) show that the alpha3, beta2, and beta4 nAChR subunits are ubiquitinated and that their ubiquitination is necessary for degradation. A 24-h treatment with the proteasome inhibitor PS-341 increased the total levels of alpha3 and the two beta subunits in both whole cell lysates and fractions enriched for the ER/Golgi compartment. nAChR subunit upregulation was also detected in plasma membrane-enriched fractions. Inhibition of the lysosomal degradation machinery by E-64 had a significantly smaller effect on nAChR turnover. The present data, together with previous results showing that the alpha7 nAChR subunit is a target of the UPS, point to a prominent role of the proteasome in nAChR trafficking.
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PMID:The ubiquitin-proteasome system regulates the stability of neuronal nicotinic acetylcholine receptors. 1969 7


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