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)

Parkinson's disease is characterized by the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin. Involvement of neuromelanin in the pathogenesis may be either cytotoxic or protective. Recently we found that neuromelanin reduces the activity of 26S proteasome. In this paper, the detailed mechanisms behind the reduced activity were studied using neuromelanin isolated from the human brain. Neuromelanin increased the oxidative stress, but synthetic melanin did not. Superoxide dismutase and deferoxamine completely suppressed the increase, indicating that superoxide produced by an iron-mediated reaction plays a central role. Iron was shown to reduce in situ 26S proteasome activity in SH-SY5Y cells and the reduction was protected by antioxidants. These results suggest that iron released from neuromelanin increases oxidative stress in mitochondria, and then causes mitochondrial dysfunction and reduces proteasome function. The role of neuromelanin is discussed in relation to the selective vulnerability of dopamine neurons in Parkinson's disease.
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PMID:Neuromelanin induces oxidative stress in mitochondria through release of iron: mechanism behind the inhibition of 26S proteasome. 1636 26

Nitric oxide (*NO) was shown to stimulate the proteasomal function and the ubiquitin-proteasome pathway and to ameliorate endothelial apoptotic signaling induced by oxidants. Understanding the regulatory mechanisms by which *NO stimulates proteasomes and affords cytoprotection in endothelial cells has therapeutic implications, as many vascular diseases are characterized by a deficiency in *NO. Here we report that *NO/cGMP/cAMP-induced immunoproteasome subunit expression is responsible for the increased proteasomal activities. Cells pretreated with protein kinase G and protein kinase A inhibitors markedly attenuated *NO-dependent proteasome activation. Results show that the *NO/cGMP/cAMP signaling mechanism enhanced the phosphorylation of the transcription factor cAMP-response element-binding protein, elevated the cAMP-response element-promoter activity and induced the expression of immunoproteasomal subunits (LMP2 and LMP7). *NO-dependent proteasomal activity was abrogated in cells transfected with antisense LMP2 and LMP7 oligonucleotides. Lower levels of LMP2 and LMP7 were detected in aorta of iNOS(-/-) mice compared to wild-type controls, suggesting that endogenous production of *NO is important in the basal regulation of immunoproteasome. The *NO/cGMP/cAMP signaling pathway mitigates transferrin-iron-mediated oxidative stress and apoptosis through induction of immunoproteasomes. These results provide new insights on the regulatory mechanisms by which the *NO-mediated immunoproteasome signaling pathway affords cytoprotection in endothelial cells.
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PMID:Upregulation of immunoproteasomes by nitric oxide: potential antioxidative mechanism in endothelial cells. 1654 Mar 99

We set out to determine whether cellular hypoxia, via mitochondrial reactive oxygen species, promotes Na,K-ATPase degradation via the ubiquitin-conjugating system. Cells exposed to 1.5% O2 had a decrease in Na,K-ATPase activity and oxygen consumption. The total cell pool of alpha1 Na,K-ATPase protein decreased on exposure to 1.5% O2 for 30 hours, whereas the plasma membrane Na,K-ATPase was 50% degraded after 2 hours of hypoxia, which was prevented by lysosome and proteasome inhibitors. When Chinese hamster ovary cells that exhibit a temperature-sensitive defect in E1 ubiquitin conjugation enzyme were incubated at 40 degrees C and 1.5% O2, the degradation of the alpha1 Na,K-ATPase was prevented. Exogenous reactive oxygen species increased the plasma membrane Na,K-ATPase degradation, whereas, in mitochondrial DNA deficient rho(0) cells and in cells transfected with small interfering RNA against Rieske iron sulfur protein, the hypoxia-mediated Na,K-ATPase degradation was prevented. The catalase/superoxide dismutase (SOD) mimetic (EUK-134) and glutathione peroxidase overexpression prevented the hypoxia-mediated Na,K-ATPase degradation and overexpression of SOD1, but not SOD2, partially inhibited the Na+ pump degradation. Accordingly, we provide evidence that during hypoxia, mitochondrial reactive oxygen species are necessary to degrade the plasma membrane Na,K-ATPase via the ubiquitin-conjugating system.
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PMID:Hypoxia-mediated degradation of Na,K-ATPase via mitochondrial reactive oxygen species and the ubiquitin-conjugating system. 1661 3

Aceruloplasminemia is a neurodegenerative disease characterized by parenchymal iron accumulation owing to mutations in the ceruloplasmin gene. Ceruloplasmin is expressed in the central nervous system in which most of the ceruloplasmin is located on the surface of astrocytes in a glycosylphosphatidylinositol (GPI)-anchored form. We herein describe the biochemical features of wild-type and mutant GPI-anchored ceruloplasmin. An overexpression of wild-type GPI-anchored ceruloplasmin in Chinese hamster ovary cells led to the formation of aggresome-like inclusions, especially in the presence of proteasome inhibitors. As expected from the properties of aggresomes, the inclusions were colocalized with gamma-tubulin and a disruption of microtubules using nocodazole blocked the formation of such inclusions. Aceruloplasminemia-linked mutant proteins failed to form such inclusions even after treatment with proteasomal inhibitors. An immunofluorescent analysis indicated that the mutant proteins were thus retained in the endoplasmic reticulum (ER), whereas the transfected cells showed a decreased viability. The expression of glucose-regulated protein 78 that is one of the ER stress sensor proteins, and the activity of glucose-regulated protein 78 promoter was upregulated in the cells transfected with the mutants. These findings indicated that when the overexpressed cytoplasmic wild-type ceruloplasmin was not subjected to degradation by the proteasome-ubiquitin system, then the wild-type protein was transported along the microtubules, thus forming inclusions at the microtubule organizing center, whereas the mutant ceruloplasmin failed to form any such inclusions, because the mutant protein might not have been translocated across the ER into the cytoplasm. Therefore, the mutant protein was considered to have accumulated in the ER thus leading to the ER stress, which resulted in cell death.
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PMID:Biochemical features of ceruloplasmin gene mutations linked to aceruloplasminemia. 1677 87

Ferritins play an essential role in iron homeostasis by sequestering iron in a bioavailable and non-toxic form. In plants, ferritin mRNAs are highly and quickly accumulated in response to iron overload. Such accumulation leads to a subsequent ferritin protein synthesis and iron storage, thus avoiding oxidative stress to take place. By combining pharmacological and imaging approaches in an Arabidopsis cell culture system, we have identified several elements in the signal transduction pathway leading to the increase of AtFer1 transcript level after iron treatment. Nitric oxide quickly accumulates in the plastids after iron treatment. This compound acts downstream of iron and upstream of a PP2A-type phosphatase to promote an increase of AtFer1 mRNA level. The AtFer1 gene transcription has been previously shown to be repressed under low iron conditions with the involvement of the cis-acting element iron-dependent regulatory sequence identified within the AtFer1 promoter sequence. We show here that the repressor is unlikely a transcription factor directly bound to the iron-dependent regulatory sequence; such a repressor is ubiquitinated upon iron treatment and subsequently degraded through a 26 S proteasome-dependent pathway.
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PMID:An iron-induced nitric oxide burst precedes ubiquitin-dependent protein degradation for Arabidopsis AtFer1 ferritin gene expression. 1678 6

Indoleamine 2,3-dioxygenase (IDO) is a heme-containing enzyme, which catalyzes the initial and rate-determining step of L-tryptophan (L-Trp) metabolism via the kynurenine pathway in nonhepatic tissues. Similar to inducible nitric oxide synthase (iNOS), IDO is induced by interferon-gamma and lipopolysaccharide in the inflammatory response. In vivo studies indicate that the nitric oxide (NO) produced by iNOS inhibits IDO activity by directly interacting with it and by promoting its degradation through the proteasome pathway. In this work, the molecular mechanisms underlying the interactions between NO and human recombinant IDO (hIDO) were systematically studied with optical absorption and resonance Raman spectroscopies. Resonance Raman data show that the heme prosthetic group in the NO-bound hIDO is situated in a unique protein environment and adopts an out-of-plane deformed geometry that is sensitive to L-Trp binding. Under mildly acidic conditions, the proximal heme iron-His bond is prone to rupture, resulting in a five-coordinate (5C) NO-bound species. The bond breakage reaction induces significant conformational changes in the protein matrix, which may account for the NO-induced inactivation of hIDO and its enhanced proteasome-linked degradation in vivo. Moreover, it was found that the NO-induced bond breakage reaction occurs more rapidly in the ferrous protein than in the ferric protein and is fully inhibited by L-Trp binding. The spectroscopic data presented here not only provide the first glimpse of the possible regulatory mechanism of hIDO by NO in the cell at the molecular level, but they also suggest that the NO-dependent regulation can be modulated by cellular factors, such as the NO abundance, pH, redox environment, and L-Trp availability.
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PMID:Interactions between nitric oxide and indoleamine 2,3-dioxygenase. 1683 26

Heme oxygenase-1 (HO-1) protects endothelial cells (EC) from undergoing apoptosis. This effect is mimicked by CO, generated via the catabolism of heme by HO-1. The antiapoptotic effect of CO in EC was abrogated when activation of the p38alpha and p38beta MAPKs was inhibited by the pyridinyl imidazole SB202190. Using small interfering RNA, p38beta was found to be cytoprotective in EC, whereas p38alpha was not. When overexpressed in EC, HO-1 targeted specifically the p38alpha but not the p38beta MAPK isoform for degradation by the 26S proteasome, an effect reversed by the 26S proteasome inhibitors MG-132 or lactacystin. Inhibition of p38alpha expression was also observed when HO-1 was induced physiologically by iron protoporphyrin IX (hemin). Inhibition of p38alpha no longer occurred when HO activity was inhibited by tin protoporphyrin IX, suggesting that p38alpha degradation was mediated by an end product of heme catabolism. Exogenous CO inhibited p38alpha expression in EC, suggesting that CO is the end product that mediates this effect. The antiapoptotic effect of HO-1 was impaired when p38alpha expression was restored ectopically or when its degradation by the 26S proteasome was inhibited by MG-132. Furthermore, the antiapoptotic effect of HO-1 was lost when p38beta expression was targeted by a specific p38beta small interfering RNA. In conclusion, the antiapoptotic effect of HO-1 in EC is dependent on the degradation of p38alpha by the 26S proteasome and on the expression of p38beta.
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PMID:The antiapoptotic effect of heme oxygenase-1 in endothelial cells involves the degradation of p38 alpha MAPK isoform. 1684 2

Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1beta and an oxygen-regulated subunit HIF-1alpha (or its paralogs HIF-2alpha and HIF-3alpha). The stability and activity of the alpha subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1alpha trigger its association with pVHL E3 ligase complex, leading to HIF-1alpha degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1alpha subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.
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PMID:Hypoxia-inducible factor-1 (HIF-1). 1688 34

A central means by which mammalian cells respond to low oxygen tension is through the activation of the transcription factor HIF-1 (hypoxia-inducible factor-1). Under normoxic conditions, HIF-1alpha (the alpha subunit of HIF-1) is targeted for rapid degradation by the ubiquitin-proteasome pathway. Under hypoxic conditions, this degradation is inhibited, thereby leading to the stabilization and activation of HIF-1alpha. Here, we report the identification of IOP1 (iron-only hydrogenase-like protein 1), a protein homologous with enzymes present in anaerobic organisms that contain a distinctive iron-sulfur cluster. IOP1 is present in a broad range of cell types. Knockdown of IOP1 using siRNA (small interfering RNA) in mammalian cells increases protein levels of HIF-1alpha under both normoxic and hypoxic conditions, and augments hypoxia-induced HRE (hypoxia response element) reporter gene and endogenous HIF-1alpha target gene expressions. We find that IOP1 knockdown up-regulates HIF-1alpha mRNA levels, thereby providing a mechanism by which knockdown induces the observed effects. The results collectively provide evidence that IOP1 is a component of the protein network that regulates HIF-1alpha in mammalian cells.
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PMID:IOP1, a novel hydrogenase-like protein that modulates hypoxia-inducible factor-1alpha activity. 1695 24

In Parkinson's disease (PD), the selective depletion of dopamine neurons in the substantia nigra, particular those containing neuromelanin (NM), is the characteristic pathological feature. The role of NM in the cell death of dopamine neurons has been considered either to be neurotoxic or neuroprotective, but the precise mechanism has never been elucidated. In human brain, NM is synthesized by polymerization of dopamine and relating quinones, to which bind heavy metals including iron. The effects of NM prepared from human brain were examined using human dopaminergic SH-SY5Y cells. It was found that NM inhibits 26S proteasome activity through generation of reactive oxygen and nitrogen species from mitochondria. The mitochondrial dysfunction was also induced by oxidative stress mediated by iron released from NM. NM accumulated in dopamine neurons in ageing may determine the selective vulnerability of dopamine neurons in PD.
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PMID:The effect of neuromelanin on the proteasome activity in human dopaminergic SH-SY5Y cells. 1701 19


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