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)

To evaluate the acute effect of human erythropoietin (r-HuEPO) on basal and stimulated prolactin (PRL) secretion, 18 normal subjects (12 females, 6 males) were studied. The PRL response to thyrotropin-releasing hormone (TRH; 200 micrograms intravenously, n = 7), metoclopramide (MCP, 20 mg intravenously, n = 5) and fenfluramine (FF, 60 mg os, n = 6) was tested in presence of saline or r-HuEPO (30 U/kg intravenously). The drug neither modified basal PRL levels nor affected the normal PRL release to TRH, MCP and FF. Our results indicate that, in normal subjects, the acute administration of therapeutic doses of r-HuEPO does not interfere with PRL secretion both after a direct pituitary stimulus and after stimuli involving dopaminergic and serotoninergic pathways.
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PMID:Effects of erythropoietin administration on prolactin secretion in normal subjects. 830 3

The hypoxia-inducible factor 1 transcriptional activator complex (HIF-1) is involved in the activation of the erythropoietin and several other hypoxia-responsive genes. The HIF-1 complex is composed of two protein subunits: HIF-1beta/ARNT (aryl hydrocarbon receptor nuclear translocator), which is constitutively expressed, and HIF-1alpha, which is not present in normal cells but induced under hypoxic conditions. The HIF-1alpha subunit is continuously synthesized and degraded under normoxic conditions, while it accumulates rapidly following exposure to low oxygen tensions. The involvement of the ubiquitin-proteasome system in the proteolytic destruction of HIF-1 in normoxia was studied by the use of specific inhibitors of the proteasome system. Lactacystin and MG-132 were found to protect the degradation of the HIF-1 complex in cells transferred from hypoxia to normoxia. The same inhibitors were able to induce HIF-1 complex formation when added to normoxic cells. Final confirmation of the involvement of the ubiquitin-proteasome system in the regulated degradation of HIF-1alpha was obtained by the use of ts20TGR cells, which contain a temperature-sensitive mutant of E1, the ubiquitin-activating enzyme. Exposure of ts20 cells, under normoxic conditions, to the non-permissive temperature induced a rapid and progressive accumulation of HIF-1. The effect of proteasome inhibitors on the normoxic induction of HIF-1 binding activity was mimicked by the thiol reducing agent N-(2-mercaptopropionyl)-glycine and by the oxygen radical scavenger 2-acetamidoacrylic acid. Furthermore, N-(2-mercaptopropionyl)-glycine induced gene expression as measured by the stimulation of a HIF-1-luciferase expression vector and by the induction of erythropoietin mRNA in normoxic Hep 3B cells. These last findings strongly suggest that the hypoxia induced changes in HIF-1alpha stability and subsequent gene activation are mediated by redox-induced changes.
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PMID:Hypoxia-inducible factor 1alpha (HIF-1alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox-induced changes. 927 21

Hypoxia induces a group of physiologically important genes such as erythropoietin and vascular endothelial growth factor. These genes are transcriptionally up-regulated by hypoxia-inducible factor 1 (HIF-1), a global regulator that belongs to the basic helix-loop-helix PAS family. Although HIF-1 is a heterodimer composed of alpha and beta subunits, its activity is primarily determined by hypoxia-induced stabilization of HIF-1alpha, which is otherwise rapidly degraded in oxygenated cells. We report the identification of an oxygen-dependent degradation (ODD) domain within HIF-1alpha that controls its degradation by the ubiquitin-proteasome pathway. The ODD domain consists of approximately 200 amino acid residues, located in the central region of HIF-1alpha. Because portions of the domain independently confer degradation of HIF-1alpha, deletion of this entire region is required to give rise to a stable HIF-1alpha, capable of heterodimerization, DNA-binding, and transactivation in the absence of hypoxic signaling. Conversely, the ODD domain alone confers oxygen-dependent instability when fused to a stable protein, Gal4. Hence, the ODD domain plays a pivotal role for regulating HIF-1 activity and thereby may provide a means of controlling gene expression by changes in oxygen tension.
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PMID:Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. 965 27

The hypoxia-inducible factor 1 complex (HIF-1) is involved in the transcriptional activation of several genes, like erythropoietin and vascular endothelial growth factor, that are responsive to the lack of oxygen. The HIF-1 complex is composed of two b-HLH proteins: HIF-1beta that is constitutively expressed, and HIF-1alpha, that is present only in hypoxic cells. The HIF-1alpha subunit is continuously synthesized and degraded by the ubiquitin-proteasome under oxic conditions. Hypoxia, transition metals, iron chelators, and several antioxidants stabilize the HIF-1alpha protein, allowing the formation of the transcriptionally active HIF-1 complex. The mechanisms of oxygen sensing and the pathways leading to HIF-1alpha stabilization are unclear. Because the involvement of a heme protein oxygen sensor has been postulated, we tested the heme sensor hypothesis by using a luciferase-expressing cell line (B-1), that is highly responsive to hypoxia. Exposure of B-1 cells to carbon monoxide and heme synthesis inhibitors failed to show any effect on the hypoxia responsiveness of these cells, suggesting that heme proteins are not involved in hypoxia sensing. Measurement of iron in recombinantly expressed HIF-1alpha protein revealed that this protein binds iron in vivo. Iron binding was localized to a 129-amino acid peptide between sequences 529 and 658 of the HIF-1alpha protein. Although the exact structure of the iron center has not been yet defined, a 2:1 metal/protein molar ratio suggests a di-iron center, probably similar to the one found in hemerythrin. This finding is compatible with a model where redox reaction may occur directly in the iron center of the HIF-1alpha subunit, affecting its survival in oxic conditions.
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PMID:Hypoxia-inducible factor 1alpha (HIF-1alpha) is a non-heme iron protein. Implications for oxygen sensing. 1037 3

Cis is an Src homology 2 domain-containing protein, which binds to the erythropoietin receptor and decreases erythropoietin-stimulated cell proliferation. We show that Cis associates with the second tyrosine residue of the intracellular domain of the erythropoietin receptor (Tyr401). Two forms of Cis with molecular masses of 32 and 37 kDa were detected, and we demonstrate that the 37-kDa protein resulted from post-translational modifications of the 32-kDa form. Anti-ubiquitin antibodies recognized the 37-kDa form of Cis and the proteasome inhibitors N-acetyl-leucyl-leucyl-norleucinal and lactacystin inhibited its degradation, showing that the 37-kDa form of Cis is a ubiquitinated protein, which seems to be rapidly degraded by the proteasome. In erythropoietin-stimulated UT-7 cells, the activation of the erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) was transient and returned to basal levels after 30-60 min of erythropoietin stimulation. In contrast, these proteins remained strongly phosphorylated, and STAT5 remained activated for at least 120 min in the presence of proteasome inhibitors. These experiments demonstrate that the proteasomes are involved in the down-regulation of the erythropoietin receptor activation signals. Because the proteasome inhibitors induced the accumulation of both the ubiquitinated form of Cis and the Cis-erythropoietin receptor complexes, our results suggest that the ubiquitinated form of Cis could be involved in the proteasome-mediated inactivation of the erythropoietin receptor.
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PMID:Proteasomes regulate erythropoietin receptor and signal transducer and activator of transcription 5 (STAT5) activation. Possible involvement of the ubiquitinated Cis protein. 977 39

The binding of erythropoietin (Epo) to its receptor leads to the transient phosphorylation of the Epo receptor (EpoR) and the activation of intracellular signaling pathways. Inactivation mechanisms are simultaneously turned on, and Epo-induced signaling pathways return to nearly basal levels after 30-60 min of stimulation. We show that proteasomes control these inactivation mechanisms. In cells treated with the proteasome inhibitors N-Ac-Leu-Leu-norleucinal (LLnL) or lactacystin, EpoR tyrosine phosphorylation and activation of intracellular signaling pathways (Jak2, STAT5, phosphatidylinositol 3-kinase) were sustained for at least 2 h. We show that this effect was due to the continuous replenishment of the cell surface pool of EpoRs in cells treated with proteasome inhibitors. Proteasome inhibitors did not modify the internalization and degradation of Epo.EpoR complexes, but they allowed the continuous replacement of the internalized receptors by newly synthesized receptors. Proteasome inhibitors did not modify the synthesis of EpoRs, but they allowed their transport to the cell surface. N-Ac-Leu-Leu-norleucinal, but not lactacystin, also inhibited the degradation of internalized Epo.EpoR complexes, most probably through cathepsin inhibition. The internalized EpoRs were not tyrosine-phosphorylated, and they did not activate intracellular signaling pathways. Our results show that the proteasome controls the down-regulation of EpoRs in Epo-stimulated cells by inhibiting the cell surface replacement of internalized EpoRs.
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PMID:Proteasomes regulate the duration of erythropoietin receptor activation by controlling down-regulation of cell surface receptors. 1084 44

Cadmium is a substantial industrial and environmental pollutant which seriously impairs erythropoiesis. Cd has been demonstrated to aggravate anemia by suppressing erythropoietin gene expression in anemic patients. As hypoxic induction of erythropoietin mRNA depends on a transcription factor, hypoxia-inducible factor 1 (HIF-1), we hypothesized that Cd suppresses the hypoxic activation of HIF-1. In hypoxic Hep3B cells, all mRNAs of various genes, which are known to be upregulated by HIF-1 activation under hypoxia, were suppressed by Cd in a dose-dependent manner. Cd inhibited the hypoxia-induced activity of luciferase in 293 cells which was transfected with a reporter plasmid carrying a hypoxia response element. By electrophoretic mobility gel shift assay, Cd inhibited the DNA-binding activity of HIF-1 in hypoxic Hep3B cells. Cd reduced the amount of HIF-1alpha protein in hypoxia, whereas it didn't affect HIF-1 alpha mRNA levels. Moreover, Cd inhibited HIF-1alpha accumulation induced by cobalt and desferrioxamine. Antioxidants and a proteasome inhibitor prevented the HIF-1alpha degradation caused by Cd. The possibility that oxidative stress mediates this action of Cd was examined. Cd didn't affect protein oxidation and reduced glutathione levels in hypoxic cells. These results indicate that Cd triggers a redox/proteasome-dependent degradation of HIF-1alpha protein, reducing HIF-1 activity and in turn suppressing the hypoxic induction of hypoxia-inducible genes.
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PMID:Cadmium blocks hypoxia-inducible factor (HIF)-1-mediated response to hypoxia by stimulating the proteasome-dependent degradation of HIF-1alpha. 1086 24

While positive effectors of cytokine signaling pathways are relatively well defined, negative regulation can be just as important but is poorly understood. The recently discovered suppressor of cytokine signaling (SOCS) family of proteins has been implicated in the negative regulation of several cytokine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (AK/STAT) pathways of transcriptional activation. Biochemical studies revealed that inhibition can occur via a variety of mechanisms. SOCS proteins bind to tyrosine-phosphorylated residues of target proteins via their SH2 domains, then inhibit JAK activity through their N-terminal domains, and are thought to induce degredation of bound molecules through a conserved SOCS-box motif that interacts with the proteasome. SOCS protein expression is induced by a wide variety of cytokines with each member displaying varying kinetics of induction. Gene modification studies in mice have demonstrated that SOCS-1 has a clear role in the negative regulation of interferon-gamma signaling, while other SOCS family members have also been shown to be involved in the regulation of T cell, growth hormone, and erythropoietin signaling systems.
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PMID:The suppressors of cytokine signaling (SOCS) proteins: important feedback inhibitors of cytokine action. 1102 28

This review discusses the evolution of novel diagnostic and treatment strategies for multiple myeloma based upon increased understanding of basic disease pathogenesis. Although myeloma has remained an incurable illness to date, these new developments will derive treatments to improve outcome and achieve eventual cure. In Section I, Dr. Kyle reviews the results of current therapy for multiple myeloma, including high dose therapy and stem cell transplantation which have proven to achieve improved response rates, event-free, and overall survival. Supportive therapy, such as erythropoietin to treat disease-related anemia, and methods of prophylaxis against infection, which both lessen toxicities of treatment and improve quality of life for patients, are also addressed. In Section II, Dr. Dalton with Drs. Landowski, Shain, Jove and Hazlehurst discusses mechanisms of drug resistance in myeloma, with emphasis on novel treatment approaches to prevent development of drug resistance and to overcome drug resistance. Laboratory studies delineating mechanisms whereby myeloma cells resist drug-induced apoptosis provide the framework for related treatment protocols for patients with refractory disease. In Section III, Dr. Berenson reviews the management of complications in bone, which occur in the majority of patients with myeloma and are the major cause of decreased quality of life. New insights into the mediators of bone resorption and new bone formation in the marrow milieu have already derived effective bisphosphonate therapy. These drugs not only reduce bone complications and related pain, thereby improving quality of life, but also may have intrinsic anti-tumor activity by virtue of inducing tumor cell adherence to marrow, reducing interleukin-6 secretion, inducing tumor cell apoptosis, or inhibiting angiogenesis. In the last section, Dr. Anderson explores the potential for future therapies which offer great promise to improve patient outcomes. First, drugs which alter the marrow microenvironment include thalidomide and its derivative immunomodulatory drugs, which act directly on tumor cells to induce apoptosis or G1 growth arrest, alter tumor cell adhesion to marrow stroma, inhibit angiogenesis, and trigger a cellular anti-tumor response. The proteasome inhibitors both act directly on tumor cells and also inhibit the transcription factor NFkappaB-dependent upregulation of IL-6 secretion triggered by tumor cell adhesion. Second, delineation of both growth and apoptotic pathways has derived novel treatment strategies. Third, the preclinical basis and early clinical trial results using vaccination and adoptive immunotherapy to harness autoimmune and alloimmune anti-myeloma responses are presented. This review sets the stage for an evolving new biologically based treatment paradigm in myeloma targeting both the tumor and its microenvironment to improve outcome and achieve eventual cure.
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PMID:Multiple Myeloma: New Insights and Therapeutic Approaches. 1170 40

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


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