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)

Adaptation to hypoxia is a topic of considerable clinical relevance, as it influences the pathophysiology of anaemia, polycythaemia, tissue ischaemia and cancer. A growing number of physiologically relevant genes are regulated in response to changes in intracellular oxygen tension. These include genes encoding erythropoietin, vascular endothelial growth factor and tyrosine hydroxylase. Studies on the regulation of the erythropoietin gene have provided insights into the common mechanism of oxygen sensing and signal transduction, leading to activation of the hypoxia-inducible transcription factor 1 (HIF-1). Activation of HIF-1 by hypoxia depends on rescue of its alpha-subunit from oxygen-dependent degradation in the proteasome, allowing it to form a heterodimer with HIF-1 beta. This then translocates to the nucleus. There, HIF-1 assembles with a highly conserved orphan nuclear receptor, HNF-4, and a critical transcriptional adaptor, p300. This complex binds to a 3' enhancer on the erythropoietin gene, enabling transcription of erythropoietin. HIF-1 also activates other genes, the cis-acting elements of which contain cognate hypoxia response elements. There is growing evidence that the oxygen sensor is a flavohaem protein and that the signal transduction pathway involves changes in the level of intracellular reactive oxygen intermediates. We have recently cloned a novel fusion protein called cytochrome b5/b5 reductase, which is a cyanide-insensitive NADPH oxidase and, therefore, a candidate to be the oxygen sensor. This flavohaem protein is widely expressed in cell lines and tissues, with localization in the perinuclear space. In the presence of oxygen and iron, it may induce oxidative modifications that target HIF-1 alpha for ubiquitination and degradation.
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PMID:Detecting and responding to hypoxia. 1181 5

Hypoxia-inducible factor-1alpha (HIF-1alpha), a member of the transcription family characterized by a basic helix-loop-helix (bHLH) domain and a PAS domain, regulates the transcription of hypoxia-inducible genes involved in erythropoiesis, vascular remodelling and glucose/energy metabolism. It contains bHLH/PAS domains in the N-terminal half, and a nuclear localization signal (NLS) and two transactivation domains (TADs) in the C-terminal half. It also has an oxygen-dependent degradation (ODD) domain, which is required to degrade HIF-1alpha protein by the ubiquitin-proteasome pathway. In this study, we identified a new alternatively spliced variant of human HIF-1alpha mRNA, which lacked both exons 11 and 12, producing a frame shift and giving a shorter form of HIF-1alpha. In the corresponding protein, a part of the ODD domain, both TADs and the C-terminal NLS motif were missing. Expression of endogenous HIF-1alpha variant protein was identified using immunoprecipitation and immunoblotting methods. The expressed HIF-1alpha variant exhibited neither the activity of transactivation nor hypoxia-induced nuclear translocation. In contrast with HIF-1alpha, the variant was strikingly stable in normoxic conditions and not up-regulated to such an extent by hypoxia, cobalt ions or desferrioxamine. It was also demonstrated that the HIF-1alpha variant competed with endogenous HIF-1alpha and suppressed HIF-1 activity, resulting in the down-regulation of mRNA expression of hypoxia-inducible genes. The association of the variant and arylhydrocarbon receptor nuclear translocator in the cytoplasm may be related to the inhibition of HIF-1 activity. It is assumed that this isoform preserves the balance between aerobic and anaerobic metabolism by counteracting the overaction of HIF-1alpha.
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PMID:A dominant-negative isoform lacking exons 11 and 12 of the human hypoxia-inducible factor-1alpha gene. 1182 41

Various low-temperature-inducible genes such as fatty acid desaturase genes are essential for all living organisms to acclimate to low temperature. However, a low-temperature signal transduction pathway has not been identified in eukaryotes. In yeast Saccharomyces cerevisiae, the Delta9 fatty acid desaturase gene OLE1 is activated by ubiquitin/proteasome-dependent processing of two homologous endoplasmic reticulum membrane proteins, Spt23p and Mga2p. We found that OLE1 transcription was transiently activated with resultant increases in the degree of unsaturation of total fatty acids when culture temperature was downshifted from 30 degrees C to 10 degrees C. This activation was greatly depressed in Deltamga2 cells. Although Mga2p is essential for hypoxic activation of OLE1 transcription, and its hypoxic functions are repressed by unsaturated fatty acids (UFAs), low-temperature activation of the OLE1 gene was not repressed by UFAs. These observations suggest that low-temperature and hypoxic signal transduction pathways share some components, and Mga2p is the first identified eukaryotic sensor for low temperature and oxygen.
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PMID:Mga2p is a putative sensor for low temperature and oxygen to induce OLE1 transcription in Saccharomyces cerevisiae. 1185 48

Ionizing radiation shares with proinflammatory cytokines a pathway that involves reactive oxygen species and activation of the redox-sensitive nuclear transcription factor NF-kappa B, which leads to expression of inflammatory and cell survival programs. NF-kappa B activation normally requires phosphorylation of its inhibitor I kappa B and the inhibitor's subsequent degradation by the proteasome. Nonlinear dose-response curves have been reported for both radiation-induced cytokines and NF-kappa B and I kappa B expression with maximum exposures of less than 2 Gy and greater than 4 Gy, respectively. Radiation-inhibited proteasomes function over a wide dose range, suggesting that the proteasome is a redox-sensitive target for radiation that may function along with transcription to cause nonlinear dose-response relationships for early expression of many molecules, including NF-kappa B and cytokines. These pathways are relevant to low-dose radiation effects, adaptive responses, and carcinogenesis.
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PMID:NF-kappa B, cytokines, proteasomes, and low-dose radiation exposure. 1187 21

A significant body of evidence supports a key role for free radicals in causing cumulative damage to cellular macromolecules, thereby contributing to senescence/aging, and a number of age-related disorders. Proteins are recognized as major targets for oxidative damage (in addition to DNA and lipids) and the accumulation of oxidized proteins has been reported for many experimental aging models, as measured by several markers for protein oxidation. In young and healthy individuals, moderately oxidized soluble cell proteins are selectively and rapidly degraded by the proteasome. However, severely oxidized, cross-linked proteins are poor substrates for degradation and actually inhibit the proteasome. Considerable evidence now indicates that proteasome activity declines during aging, as the protease is progressively inhibited by binding to ever increasing levels of oxidized and cross-linked protein aggregates. Cellular aging probably involves both an increase in the generation of reactive oxygen species and a progressive decline in proteasome activity, resulting in the progressive accumulation of oxidatively damaged protein aggregates that eventually contribute to cellular dysfunction and senescence.
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PMID:Protein turnover by the proteasome in aging and disease. 1203 93

The major environmental influence for epidermal cells is sun exposure and the harmful effect of UV radiation on skin is related to the generation of reactive oxygen species that are altering cellular components including proteins. It is now well established that the proteasome is responsible for the degradation of oxidized proteins. Therefore, the effects of UV-irradiation on proteasome have been investigated in human keratinocyte cultures. Human keratinocytes were irradiated with 10 J/cm(2) of UVA and 0.05 J/cm(2) of UVB and proteasome peptidase activities were measured in cell lysates using fluorogenic peptides. All three peptidase activities were decreased as early as 1 h and up to 24 h after irradiation of the cells. Increased levels of oxidized and ubiquitinated proteins as well as proteins modified by the lipid peroxidation product 4-hydroxy-2-nonenal were also observed in irradiated cells. However, immunopurified 20S proteasome exhibited no difference in both peptidase specific activities and 2D gel pattern of subunits in irradiated cells, ruling out the possibility that the 20S proteasome could be a target for the UV-induced damage. Finally, extracts from irradiated keratinocytes were able to inhibit degradation by the proteasome, demonstrating the presence of endogeneous inhibitors, including 4-hydroxy-2-nonenal modified proteins, generated upon UV-irradiation.
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PMID:Impairment of proteasome function upon UVA- and UVB-irradiation of human keratinocytes. 1203

Oxidative stress in mammalian cells is an inevitable consequence of their aerobic metabolism. The production of reactive oxygen and nitric oxide species causes oxidative modifications of proteins often combined with a loss of their biological function. Like most partially denatured proteins, moderately oxidized proteins are more sensitive to proteolytic attack by proteases. The diverse cellular proteolytic systems are an important secondary defense against oxidative stress by degrading oxidized and damaged proteins, thereby preventing their intracellular accumulation. In mammalian cells, a range of proteases exists which are distributed throughout the cell. In this review we summarize the function of the cytosolic (proteasome and calpains), the lysosomal, the mitochondrial and the nuclear proteolytic pathways in response to oxidative stress. Particular emphasis is given to the proteasomal system, since this pathway appears to be the most important proteolytic system involved in the removal of oxidatively modified or damaged proteins.
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PMID:Proteolytic response to oxidative stress in mammalian cells. 1203 44

HIF-1 alpha is a normally labile proangiogenic transcription factor that is stabilized and activated in hypoxia. Although the von Hippel Lindau (VHL) gene product, the ubiquitin ligase responsible for regulating HIF-1 alpha protein levels, efficiently targets HIF-1 alpha for rapid proteasome-dependent degradation under normoxia, HIF-1 alpha is resistant to the destabilizing effects of VHL under hypoxia. HIF-1 alpha also associates with the molecular chaperone Hsp90. To examine the role of Hsp90 in HIF-1 alpha function, we used renal carcinoma cell (RCC) lines that lack functional VHL and express stable HIF-1 alpha protein under normoxia. Geldanamycin (GA), an Hsp90 antagonist, promoted efficient ubiquitination and proteasome-mediated degradation of HIF-1 alpha in RCC in both normoxia and hypoxia. Furthermore, HIF-1 alpha point mutations that block VHL association did not protect HIF-1 alpha from GA-induced destabilization. Hsp90 antagonists also inhibited HIF-1 alpha transcriptional activity and dramatically reduced both hypoxia-induced accumulation of VEGF mRNA and hypoxia-dependent angiogenic activity. These findings demonstrate that disruption of Hsp90 function 1) promotes HIF-1 alpha degradation via a novel, oxygen-independent E3 ubiquitin ligase and 2) diminishes HIF-1 alpha transcriptional activity. Existence of an Hsp90-dependent pathway for elimination of HIF-1 alpha predicts that Hsp90 antagonists may be hypoxic cell sensitizers and possess antiangiogenic activity in vivo, thus extending the utility of these drugs as therapeutic anticancer agents.
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PMID:Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. 1205 35

It is proposed that a primary mechanism leading to neuronal cell death in common neurodegenerative diseases is interference with proteasome function. This can involve genetic defects, direct inactivation of the proteasome (e.g., by reactive oxygen species), or overloading with proteins. The latter can be caused by excessive production of normal proteins or by the formation of poorly degradable proteins as a result of genetic mutations, faulty posttranslational modification, or protein modification by reactive oxygen or nitrogen species. Blockage of the proteasome leads to increased oxidative and nitrative stress, the latter apparently due to upregulation of nitric oxide synthase. Thus, agents that increase proteasome function may be generally neuroprotective, as may be NOS inhibitors. Proteasome inhibitors should be used with caution as therapeutic agents.
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PMID:Hypothesis: proteasomal dysfunction: a primary event in neurogeneration that leads to nitrative and oxidative stress and subsequent cell death. 1207 74

During cold exposure, animals upregulate their metabolism and food intake, potentially exposing them to elevated reactive oxygen species (ROS) production and oxidative damage. We investigated whether acute cold (7 +/- 3 degrees C) exposure (1, 10, or 100 h duration) affected protein oxidation and proteasome activity, when compared to warm controls (22 +/- 3 degrees C), in a small mammal model, the short-tailed field vole Microtus agrestis. Protein carbonyls and the chymotrypsin-like proteasome activity were measured in plasma, heart, liver, kidney, small intestine (duodenum), skeletal muscle (gastrocnemius), and brown adipose tissue (BAT). Trypsin-like and peptidyl-glutamyl-like proteasome activities were determined in BAT, liver, and skeletal muscle. Resting metabolic rate increased significantly with duration of cold exposure. In skeletal muscle (SM) and liver, protein carbonyl levels also increased with duration of cold exposure, but this pattern was not repeated in BAT where protein carbonyls were not significantly elevated. Chymotrpsin-like proteasome activity did not differ significantly in any tissue. However, trypsin-like activity in SM and peptidyl-glutamyl-like activity in both skeletal muscle and liver, were reduced during the early phase of cold exposure (1-10 h), correlated with the increased carbonyl levels in these tissues. In contrast there was no reduction in proteasome activity in BAT during the early phase of cold exposure and peptidyl-glutamyl-like activity was significantly increased, correlated with the lack of accumulation of protein carbonyls in this tissue. The upregulation of proteasome activity in BAT may protect this tissue from accumulated oxidative damage to proteins. This protection may be a very important factor in sustaining uncoupled respiration, which underpins nonshivering thermogenesis at cold temperatures.
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PMID:The consequences of acute cold exposure on protein oxidation and proteasome activity in short-tailed field voles, microtus agrestis. 1210 21


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