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)

Hypoxia-inducible factor-1 alpha (HIF-1alpha) is the regulatory subunit of the heterodimeric transcription factor HIF-1 that is the key regulator of cellular response to low oxygen tension. Under normoxic conditions, HIF-1alpha is continuously degraded by the ubiquitin-proteasome pathway through pVHL (von Hippel-Lindau tumor suppressor protein). Under hypoxic conditions, HIF-1alpha is stabilized and induces the transcription of HIF-1 target genes. Quercetin, a flavonoid with anti-oxidant, anti-inflammatory, and kinase modulating properties, has been found to induce HIF-1alpha accumulation and VEGF secretion in normoxia. In this study, the molecular mechanisms of quercetin-mediated HIF-1alpha accumulation were investigated. Previous studies have shown that, in addition to being induced by hypoxia, HIF-1alpha can be induced through the phosphatidylinositol 3-kinase (PI3K)/Akt and p53 signaling pathways. But our study revealed, through p53 mutant-type as well as p53 null cell lines, that neither the PI3K/Akt nor the p53 signaling pathway is required for quercetin-induced HIF-1alpha accumulation. And we observed that HIF-1alpha accumulated by quercetin is not ubiquitinated and the interaction of HIF-1alpha with pVHL is reduced, compared with HIF-1alpha accumulated by the proteasome inhibitor MG132. The use of quercetin's analogues showed that only quercetin and galangin induce HIF-1/2alpha accumulation and this effect is completely reversed by additional iron ions. This is because quercetin and galangin are able to chelate cellular iron ions that are cofactors of HIF-1/2alpha proline hydroxylase (PHD). These data suggest that quercetin inhibits the ubiquitination of HIF-1/2alpha in normoxia by hindering PHD through chelating iron ions.
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PMID:Flavonoids-induced accumulation of hypoxia-inducible factor (HIF)-1alpha/2alpha is mediated through chelation of iron. 1797 96

Reactive oxygen species serve as second messengers for signal transduction; however, molecular targets of oxidant signaling have not been defined. Here, we show that ligand-receptor-mediated signaling promotes reactive oxygen species-dependent protein carbonylation. Treatment of pulmonary artery smooth muscle cells with endothelin-1 increased protein carbonyls. Carbonylation of the majority of proteins occurred transiently, suggesting that there is also a mechanism for decarbonylation induced by endothelin-1. Decarbonylation was suppressed by inhibition of thioredoxin reductase, and cellular thioredoxin was upregulated during the decarbonylation phase. These results indicate that endothelin-1 promotes oxidant signaling as well as thioredoxin-mediated reductive signaling to regulate carbonylation and decarbonylation mechanisms. In cells treated with endothelin receptor antagonists, hydrogen peroxide scavengers, or an iron chelator, we identified, via mass spectrometry, proteins that are carbonylated in a receptor- and Fenton reaction-dependent manner, including annexin A1, which promotes apoptosis and suppresses cell growth. Carbonylation of annexin A1 by endothelin-1 was followed by proteasome-dependent degradation of this protein. We propose that carbonylation and subsequent degradation of annexin A1 may play a role in endothelin-mediated cell growth and survival, important events in pulmonary vascular remodeling. Protein carbonylation in response to ligand-receptor interactions represents a novel mechanism in redox signaling.
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PMID:Protein carbonylation as a novel mechanism in redox signaling. 1827 22

Increased iron levels and iron-mediated oxidative stress play an important role in the pathogenesis of many neurodegenerative diseases. The finding that mutations in the ferritin light polypeptide (FTL) gene cause a neurodegenerative disease known as neuroferritinopathy or hereditary ferritinopathy (HF) provided a direct connection between abnormal brain iron storage and neurodegeneration. HF is characterized by a severe movement disorder and by the presence of nuclear and cytoplasmic ferritin inclusion bodies in glia and neurons throughout the CNS and in tissues of multiple organ systems. Here we report that the expression in transgenic mice of a human FTL cDNA carrying a thymidine and cytidine insertion at position 498 (FTL498-499InsTC) leads to the formation of nuclear and cytoplasmic ferritin inclusion bodies. As in HF, ferritin inclusions are seen in glia and neurons throughout the CNS as well as in cells of other organ systems. Our studies show histological, immunohistochemical, and biochemical similarities between ferritin inclusion bodies found in transgenic mice and in individuals with HF. Expression of the transgene in mice leads to a significant decrease in motor performance and a shorter life span, formation of ferritin inclusion bodies, misregulation of iron metabolism, accumulation of ubiquitinated proteins, and incorporation of elements of the proteasome into inclusions. This new transgenic mouse represents a relevant model of HF in which to study the pathways that lead to neurodegeneration in HF, to evaluate the role of iron mismanagement in neurodegenerative disorders, and to evaluate potential therapies for HF and related neurodegenerative diseases.
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PMID:Expression of a mutant form of the ferritin light chain gene induces neurodegeneration and iron overload in transgenic mice. 1817 23

Iron regulatory protein 1 (IRP1) controls the translation or stability of several mRNAs by binding to iron responsive elements (IREs) within their untranslated regions. Its activity is regulated by an unusual iron-sulfur cluster (ICS) switch. Thus, in iron-replete cells, IRP1 assembles a cubane [4Fe-4S] cluster that prevents RNA-binding activity and renders the protein to cytosolic aconitase. We show that wild type or mutant forms of IRP1 that fail to assemble a [4Fe-4S] cluster are sensitized for iron-dependent degradation by the ubiquitin-proteasome pathway. The regulation of IRP1 abundance poses an alternative mechanism to prevent accumulation of inappropriately high IRE-binding activity when the ICS assembly pathway is impaired. To study functional aspects of IRP1, we overexpressed wild type or mutant forms of the protein in human H1299 lung cancer cells in a tetracycline-inducible fashion, and analyzed how this affects cell growth. While the induction of IRP1 did not affect cell proliferation in culture, it dramatically reduced the capacity of the cells to form solid tumor xenografts in nude mice. These data provide a first link between IRP1 and cancer.
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PMID:Insights on regulation and function of the iron regulatory protein 1 (IRP1). 1827 88

Although efforts have been made to identify circadian-controlled genes regulating cell cycle progression and cell death, little is known about the metabolic signals modulating circadian regulation of gene expression. We identify heme, an iron-containing prosthetic group, as a regulatory ligand controlling human Period-2 (hPer2) stability. Furthermore, we define a novel heme-regulatory motif within the C terminus of hPer2 (SC(841)PA) as necessary for heme binding and protein destabilization. Spectroscopy reveals that whereas the PAS domain binds to both the ferric and ferrous forms of heme, SC(841)PA binds exclusively to ferric heme, thus acting as a redox sensor. Consequently, binding prevents hPer2 from interacting with its stabilizing counterpart cryptochrome. In vivo, hPer2 downregulation is suppressed by inhibitors of heme synthesis or proteasome activity, while SA(841)PA is sufficient to stabilize hPer2 in transfected cells. Moreover, heme binding to the SC(841)PA motif directly impacts circadian gene expression, resulting in altered period length. Overall, the data support a model where heme-mediated oxidation triggers hPer2 degradation, thus controlling heterodimerization and ultimately gene transcription.
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PMID:A novel heme-regulatory motif mediates heme-dependent degradation of the circadian factor period 2. 1850 21

Progressive degeneration of dopaminergic neurons of the substantia nigra and the resulting dopamine deficiency in the striatum are neuropathological basis of the movement disorders in Parkinson's disease (PD). Neuromelanin-containing neurons are particularly susceptible to degeneration and their depigmentation is the hallmark of the advanced disease. The proposed mechanisms underlaying the pathogenesis and progression of neurodegeneration in the substantia nigra include iron-catalyzed oxidative stress, mitochondrial dysfunctions, inflammation and disturbances of protein metabolism. This review presents some new concepts concerning important but ambiguous role of neuromelanin in the above mentioned processes. It seems that the imbalance between cytoprotective and cytotoxic action of the pigment may cause neuronal death via mitochondrial oxidative stress, inhibition of ubiquitine-proteasome system and alpha-synuclein accumulation. Extraneuronal melanin may contribute to chronic inflammation by excessive secretion of cytokines and nitric oxide due to prolonged microglia activation. Recent reports suggest a possible role of the lipid component of neuromelanin in pigment-dependent cytotoxicity.
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PMID:[The role of neuromelanin in Parkinson's disease--new concepts]. 1854 Jan 83

Upon stimulation by distinct bacterial/viral products/agonists, APCs including macrophages tend to express particular TLR molecules to coordinate the signaling that ultimately target at chromatin and mediate the activity of downstream transcriptional factors in regulating characteristic sets of gene expression for innate immune response. To investigate largely unknown regulatory mechanism underlying agonist-specific TLR-mediated innate immune responses, at subcellular resolution, we first analyzed Pam3CSK4-induced proteome changes in living macrophages and identified the differentially expressed proteins in the cytosol and chromatin-associated fractions, respectively, by using AACT/SILAC-based quantitative proteomic approach. In the cytosol fraction, we found that the proteins with notable Pam3CSK4-induced expression changes were primarily involved in post-translational events, energy metabolism, protein transporting, and apoptosis. Among them, a ubiquitous and highly conserved iron-binding protein, Ferritin, was further characterized as a modulator for the expression of a TLR2-specific cytokine IL-10 in murine macrophage cells by using small-interfering RNA (siRNA). Interestingly, we simultaneously identified multiple apoptosis-related proteins showing opposite trend in their regulated expressions, which clearly indicated the existence of systems regulation in differentially modulating the signal for the cross-road balance between protecting cell from apoptosis and the apoptosis of infected cells. For those regulated proteins identified in the nuclear fraction, we integrated bioinformatics to find the interactions of certain chromatin-associated proteins, which suggested their interconnected involvements in proteasome-ubiquitin pathway, DNA replication, and post-translational activity upon Pam3CSK4 stimulation. Certain regulated proteins in our quantitative proteomic data set showed the similar trend of up-regulation in both Pam3CSK4- and LPS-stimulated macrophages (Nature 2007, 447, 972), suggesting their belonging to the recently identified class of pro-inflammatory genes. The regulatory discrepancy between both data sets for other set of genes indicated their agonist-specific nature in innate immune responses.
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PMID:Proteomic dissection of agonist-specific TLR-mediated inflammatory responses on macrophages at subcellular resolution. 1857 62

Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally regulates mammalian iron homeostasis by binding to iron-responsive elements (IREs) in mRNAs that encode proteins involved in iron metabolism (e.g. ferritin and transferrin receptor 1). During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stability, whereas during iron sufficiency IRP2 is degraded by the proteasome. Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell cycle. IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G(2)/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G(2)/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. These data show that reversible phosphorylation of IRP2 during G(2)/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle.
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PMID:Iron-independent phosphorylation of iron regulatory protein 2 regulates ferritin during the cell cycle. 1857 41

The two mammalian iron regulatory proteins, IRP1 and IRP2, are post-transcriptional regulators of cellular iron homeostasis. These cytosolic RNA-binding proteins control the synthesis of proteins involved in storage, transport, and utilization of iron. Whereas IRP1 levels remain nearly constant, IRP2 is rapidly degraded by the proteasome in iron-replete cells. In non iron-loaded H1299 human lung cancer cells, the decay of transfected hemagglutinin-tagged IRP2 was significantly antagonized by addition of not only proteasomal, but also lysosomal inhibitors. Similar results were obtained with IRP2(-Ins5), a molecular form lacking the specific IRP2 domain of 73 amino acids that is absent from IRP1. These data uncover an alternative, iron independent, mechanism of IRP2 degradation via the lysosomal pathway. Transfected IRP1 decayed slowly over several days and, in contrast to IRP2, was not further stabilized by proteasomal or lysosomal inhibitors. Experiments with an IRP1/IRP2 hybrid molecule and with IRP2 variants indicated that proteins lacking the C-terminus of IRP2 were insensitive to lysosomal inhibitors. Together with previous data obtained in the presence of iron excess, these results show that the parallel degradation pathways through lysosomes and the proteasome that are active on IRP2 under normal growth conditions are preferentially shifted to the proteasome when iron becomes plentiful.
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PMID:A role for lysosomes in the turnover of human iron regulatory protein 2. 1858 96

This article briefly reviews findings from studies on neuromelanin (NM)-bound ferric iron, which provide unique insights into the physiological functions of NM and possible pathophysiological mechanisms underlying dopaminergic neuronal cell death in Parkinson's disease (PD). NM is considered an endogenous iron-binding molecule of pigmented neurons and is believed to play a physiological role in intraneuronal iron homeostasis. In PD, where nigral iron levels are increased, saturation of high-affinity iron-binding sites on NM may overwhelm the protective capacity of this molecule, leading instead to an increase in redox-active iron, and subsequent cellular damage both in vitro and in vivo. Available data also suggest that the iron released from NM affects the ubiquitin-proteasome system in mitochondria, leading to the failure to clear proteins such as alpha-synuclein and to the development of abnormal alpha-synuclein-immunopositive Lewy bodies that contribute to dopaminergic nerve cell death in PD. NM-bound ferric iron mimics certain characteristic features of the human disease in vitro and in vivo (face validity), in conformity with the theoretical rationale for PD (construct validity) and predicts aspects of PD behaviour and neurobiology (predictive validity) that makes it a valid experimental model with which to study the mechanisms of dopaminergic neurodegeneration in PD.
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PMID:Neuromelanin-bound ferric iron as an experimental model of dopaminergic neurodegeneration in Parkinson's disease. 1858 86


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