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)

There have been numerous recent advances in the understanding of the mechanisms of alcoholic liver disease pathogenesis. Endotoxin-induced Kupffer cell activation plays a role in cytokine-mediated inflammatory changes in the liver, and this can be blocked by a diet high in saturated fat, by a diet containing lactobacillus, which does not produce endotoxin, by neomycin antibiotic sterilization of the gut, by eliminating Kupffer cells, or by removing tumour necrosis factor-alpha with antibody or by using tumour necrosis factor-alpha knockout mice. The fatty liver component is mainly the result of the nicotinamide adenine dinucleotide/reduced nicotinamide adenine dinucleotide redox shift to the reduced state by ethanol oxidation generation of reduced nicotinamide adenine dinucleotide, although this too can be blocked by a diet high in saturated fat. Hepatocytic enlargement occurs due to ethanol-induced inhibition of the ubiquitin-proteasome pathway of cytoplasmic protein degradation and the retention of oxidized proteins in hepatocytes. The liver is scarred by stellate cells that have been activated by inflammatory cytokines and growth factors produced by activated Kupffer cells, and by bile ductule metaplasia. Mallory bodies and balloon cell degeneration develop through the ethanol-induced oxidative stress-protein kinase activation pathway, inhibition of phosphatase activity and inhibition of the ubiquitin-proteasome pathway.
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PMID:Mechanisms of alcoholic liver injury. 1079 86

The 2-phenylaminopyrimidine derivative STI571 is a selective inhibitor of c-Abl, c-kit, and platelet-derived growth factor-receptor tyrosine kinases and is presently in phase II-III clinical studies. Here, this study reports on a novel pharmacologic activity of the compound, ie, enhancement of the cyto-differentiating, growth-inhibitory, and apoptogenic actions of all-trans-retinoic acid (ATRA). Whereas STI571 is not a cytodifferentiating agent by itself, the compound interacts with ATRA and enhances the myeloid maturation program set in motion by the retinoid in the PML-RARalpha(+) acute promyelocytic leukemia NB4 and the PML-RARalpha(-) myeloblastic HL60 and U937 cell lines. In addition, STI571 relieves the cyto-differentiation block observed in the ATRA-resistant cell lines, NB4.R1, NB4.306, and NB4.007. In NB4 promyelocytes, a RARalpha agonist, but not an RXR agonist, can substitute for ATRA and interact with STI571. By contrast, STI571 is unique among c-Abl-specific tyrosine kinase inhibitors in modulating the pharmacologic activity of ATRA. In NB4 cells, enhanced cyto-differentiation results in increased up-regulation of the expression of a number of genes coding for myeloid differentiation markers, including CD11b, CD11c, and some of the components of the nicotinamide adenine dinucleotide phosphate-oxidase enzymatic complex. All this is accompanied by inhibition of c-Abl tyrosine phosphorylation and retardation of the retinoid-dependent degradation of PML-RARalpha and RARalpha. Stabilization of the 2 retinoic acid receptors is likely to be the result of augmented and accelerated inhibition of the proteasome-dependent proteolytic activity observed on ATRA treatment.
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PMID:Tyrosine kinase inhibitor STI571 potentiates the pharmacologic activity of retinoic acid in acute promyelocytic leukemia cells: effects on the degradation of RARalpha and PML-RARalpha. 1134 54

Ethylene is a plant hormone that regulates many aspects of growth and development. Despite the well-known association between ethylene and stress signalling, its effects on stomatal movements are largely unexplored. Here, genetic and physiological data are provided that position ethylene into the Arabidopsis guard cell signalling network, and demonstrate a functional link between ethylene and hydrogen peroxide (H(2)O(2)). In wild-type leaves, ethylene induces stomatal closure that is dependent on H(2)O(2) production in guard cells, generated by the nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase AtrbohF. Ethylene-induced closure is inhibited by the ethylene antagonists 1-MCP and silver. The ethylene receptor mutants etr1-1 and etr1-3 are insensitive to ethylene in terms of stomatal closure and H(2)O(2) production. Stomata of the ethylene signalling ein2-1 and arr2 mutants do not close in response to either ethylene or H(2)O(2) but do generate H(2)O(2) following ethylene challenge. Thus, the data indicate that ethylene and H(2)O(2) signalling in guard cells are mediated by ETR1 via EIN2 and ARR2-dependent pathway(s), and identify AtrbohF as a key mediator of stomatal responses to ethylene.
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PMID:Ethylene-induced stomatal closure in Arabidopsis occurs via AtrbohF-mediated hydrogen peroxide synthesis. 1696 32

Nicotinamide at mM concentration is a potent inhibitor of certain key molecules involved in cell survival, such as SIRT1 and PARP-1, and affects cell survival in various conditions in vivo and in vitro. However, the effect of an acute treatment of nicotinamide on gene expression has rarely been closely examined. In our study, the treatment of 10mM nicotinamide downregulated p21WAF1 expression in various human cells including p53-negative or SIRT1-knockdown cells indicating gene regulation not mediated by p53 or SIRT1. Meanwhile, in the nicotinamide-treated cells, Sp1 activity and protein level was substantially reduced due to increased proteasome-mediated degradation. Our results indicate that nicotinamide treatment attenuates p21WAF1 expression through Sp1 downregulation, and suggest a possible involvement of nicotinamide metabolism in cellular gene expression.
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PMID:p53-, SIRT1-, and PARP-1-independent downregulation of p21WAF1 expression in nicotinamide-treated cells. 1823 Mar 37

Nicotinamide at millimolar concentrations affects cell survival in various conditions, and is being utilized therapeutically in many human diseases. However, the effect of an acute treatment of nicotinamide at such high dose on gene expression and cellular metabolism has rarely been determined previously. In this study, we found that levels of O-N-acetylglucosamin(O-GlcNAc)ylated proteins including Sp1 acutely decreased upon treatment of 10 mM nicotinamide. Concomitantly, Sp1 protein level decreased rapidly through accelerated proteasome-mediated proteolysis. Cotreatment of glucosamine or 2-deoxyglucose, which inhibits protein deGlcNAcylation, effectively blocked the decrease induced by nicotinamide. Interestingly, the decline in the levels of Sp1 and protein O- GlcNAcylation was only transient lasting for two days post treatment, and this pattern matched closely the rapid fluctuation of the cellular [NAD+]. Our results suggest a possible link between cellular nicotinamide metabolism and protein O-GlcNAcylation, and an existence of cellular [NAD+] homeostasis.
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PMID:Transient downregulation of protein O-N-acetylglucosaminylation by treatment of high-dose nicotinamide in human cells. 1844 63

Quinone reductases are ubiquitous soluble enzymes found in bacteria, fungi, plants and animals. These enzymes utilize a reduced nicotinamide such as NADH or NADPH to reduce the flavin cofactor (either FMN or FAD), which then affords two-electron reduction of cellular quinones. Although the chemical nature of the quinone substrate is still a matter of debate, the reaction appears to play a pivotal role in quinone detoxification by preventing the generation of potentially harmful semiquinones. In recent years, an additional role of quinone reductases as regulators of proteasomal degradation of transcription factors and possibly intrinsically unstructured protein has emerged. To fulfil this role, quinone reductase binds to the core particle of the proteasome and recruits certain transcription factors such as p53 and p73alpha to the complex. The latter process appears to be governed by the redox state of the flavin cofactor of the quinone reductase, thus linking the stability of transcription factors to cellular events such as oxidative stress. Here, we review the current evidence for protein complex formation between quinone reductase and the 20S proteasome in eukaryotic cells and describe the regulatory role of this complex in stabilizing transcription factors by acting as inhibitors of their proteasomal degradation.
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PMID:New roles of flavoproteins in molecular cell biology: an unexpected role for quinone reductases as regulators of proteasomal degradation. 1962 32

Axon degeneration has been proposed to be a new therapeutic target for neurodegenerative diseases, because it usually occurs earlier than neuronal cell body death with a distinct active program from apoptosis and necrosis. Overexpression of Wld(S) or Nmnats (nicotinamide mononucleotide adenylytransferase, EC2.7.7.1) has been demonstrated to delay axon degeneration initiated by various insults. NAD synthesis activity of Wld(S) and Nmnats was shown to be responsible for their axon-protective function. The mitochondrial Nmnat3 and cytoplasm-localized mutants of Wld(S) and Nmnat1 have similar or even stronger effect than Wld(S) to delay axon degeneration, which suggest that increased mitochondrial or local NAD synthesis might contribute to the protective function of Wld(S) and Nmnats. Further studies show NAD synthesis pathway and ubiquitin proteasome system play important roles in delaying axon degeneration. Wld(S) mice are resistant to a variety of neurodegenerative diseases, but the role of Nmnats in neurodegenerative diseases are largely unknown. NAD plays key roles in energy metabolism, mitochondrial functions and aging, and is suggested to be involved in neuron degenerative diseases. Future studies to identify the upstream factors inducing NAD depletion and the downstream NAD effectors responsible for the axon-protective function will provide more meaningful insights into the molecular mechanisms of axon degeneration in neurodegenerative diseases.
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PMID:Axon degeneration: Mechanisms and implications of a distinct program from cell death. 2011 62

Changes in membrane fluidity are the earliest cellular events that occur in plant cells upon exposure to cold. This subsequently triggers physiological processes, such as calcium influx and reorganization of actin cytoskeletons, and induces expression of cold-responsive genes. The plasma-membrane-anchored NAC (NAM/ATAF/CUC) transcription factor NTL6 is of particular interest. Cold triggers proteolytic activation of the dormant NTL6 protein, which in turn elicits pathogen-resistance responses by inducing a small group of cold-inducible PR (pathogenesis-related) genes in Arabidopsis. In the present study, we show that proteolytic processing of NTL6 is regulated by cold-induced remodelling of membrane fluidity. NTL6 processing was stimulated rapidly by cold. The protein stability of NTL6 was also enhanced by cold. The effects of cold on NTL6 processing and protein stability were significantly reduced in cold-acclimatized plants, supporting the regulation of NTL6 processing by membrane fluidity. Consistent with this, although NTL6 processing was stimulated by pharmacological agents that reduce membrane fluidity and thus mimic cold, it was inhibited when plants were treated with a 18:3 unsaturated fatty acid, linolenic acid. In addition, the pattern of NTL6 processing was changed in Arabidopsis mutants with altered membrane lipid compositions. Assays employing chemicals that inhibit activities of the proteasome and proteases showed that NTL6 processing occurs via the regulated intramembrane proteolysis mechanism. Interestingly, a metalloprotease inhibitor blocked the NTL6 processing. These observations indicate that a metalloprotease activity is responsible for NTL6 processing in response to cold-induced changes in membrane fluidity.
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PMID:Proteolytic processing of an Arabidopsis membrane-bound NAC transcription factor is triggered by cold-induced changes in membrane fluidity. 2015 99

Silent information regulator (SIR)2 is an nicotinamide adenine dinucleotide dependent deacetylase implicated in the regulation of life span in species as diverse as yeast, worms, and flies. Mammalian Sirt1 is the most closely related homolog of the SIR2 gene. Pharmacological activators of Sirt1 have been reported to increase the life span and improve the health of mice fed a high-fat diet and to reverse diabetes in rodents. Sirt1 links the energy availability status with cellular metabolism in peripheral organs including liver, pancreas, muscle, and white adipose tissue. Insulin and leptin signaling regulate food intake by controlling the expression of orexigenic and anorexigenic neuropeptides in the arcuate nucleus of the hypothalamus via Forkhead box O (Foxo)-1 and signal transducer and activator of transcription-3. Sirt1 has been reported to improve insulin sensitivity in vitro, but the role of hypothalamic Sirt1 in regulating feeding has not been addressed. We found that hypothalamic Sirt1 protein levels increase on feeding, and this induction is abrogated in diet-induced obese mice and db/db mice. We also demonstrate for the first time that Sirt1 protein turnover is regulated by the proteasome and ubiquitination in a hypothalamic cell line and in vivo by feeding, and this regulation is not seen in a pituitary cell line AtT20. Forced expression of wild-type Sirt1 in the mediobasal hypothalamus by adenovirus microinjection suppressed Foxo1-induced hyperphagia, a model for central insulin resistance. Moreover, Sirt1 suppressed Foxo1-dependent expression of the orexigenic neuropeptide Agouti-related peptide in vitro. We propose that on feeding, Sirt1 protein is stabilized in the hypothalamus, leading to decreased Foxo1-dependent expression of orexigenic neuropeptide Agouti-related peptide and cessation of feeding.
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PMID:Induction of hypothalamic Sirt1 leads to cessation of feeding via agouti-related peptide. 2037 83

NAC (NAM, ATAF and CUC2) is one of the largest families of transcription factors in the plant genome, but the function and regulation of most NAC genes are still largely unknown. We recently isolated a gene encoding a NAC transcription factor designated ANAC078 from Arabidopsis plants and identified 166 genes up-regulated in ANAC078-overexpressing plants compared with the wild-type plants under high-light stress. The cyclic amplification and selection of targets (CASTing) technique showed that the ANAC078 recognition sequence contains T[A/T/C][A/T/G/C]C[T/G]TG[T/G]G as a DNA-binding site. The recognition sequence identified by this technique was detected in the promoter region of 52 up-regulated genes, including the gene for a transcription factor, proteasome subunits, peroxidase, and a protein kinase. The findings suggest these genes to be directly targeted by the ANAC078 protein.
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PMID:Identification of recognition sequence of ANAC078 protein by the cyclic amplification and selection of targets technique. 1988 40


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