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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)

Vesicular monoamine transporter type 2 (VMAT2) is crucial for accumulation of monoamine neurotranmitters into neuronal secretory vesicles and histamine into secretory granules of the enterochromaffin-like cell in the acid-secreting gastric mucosa. Gastric VMAT2 expression is regulated by the antral hormone gastrin acting at the CCK(2) receptor. We demonstrate a gastrin response element (-56)ccgccccctc(-47) in the proximal VMAT2 promoter that binds in a gastrin-sensitive manner to nuclear proteins from gastric epithelial cell lines. Mutations within this sequence prevented nuclear protein binding and significantly reduced gastrin-stimulated expression of VMAT2 promoter-reporter constructs in gastric epithelial cells. In a yeast one-hybrid screen of an AR42J cell cDNA library, using the gastrin response element as bait, we identified a beta subunit of the 20 S proteasome, PSMB1, as a potential binding partner. In supershift assays, antibodies to PSMB1 and other proteasome beta subunits disrupted gastrin sensitive nuclear protein binding to the VMAT2 promoter. Moreover, RNA interference of PSMB1 significantly inhibited gastrin-mediated VMAT2 transcription. These data suggest that elements of the 20 S proteasome interact with the VMAT2 promoter to enhance G-protein-coupled receptor-mediated transcription.
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PMID:Identification of a gastrin response element in the vesicular monoamine transporter type 2 promoter and requirement of 20 S proteasome subunits for transcriptional activity. 1744 73

The cellular proteome is in a dynamic state of synthesis and degradation. Degradation of extracellular proteins is mainly mediated non-specifically by the lysosomes or due to released proteases, while the proteolysis of intracellular including nuclear proteins is catalyzed by the ubiquitin-proteasome pathway. Furthermore, the proteasomal system is largely responsible for the removal of unfolded and oxidatively damaged proteins. Taking into account the role of ubiquitin and proteasome system in protein metabolism, studies of its spatial organization within the cell are of great importance. For the understanding of cellular, including nuclear, protein maintenance the distribution of the proteasomes in both the nucleus and the cytosol and their response upon oxidative stress is of great interest. Although, the functional diversity of the cells is ensured by the three dimensional organization of the nucleus, nuclear proteins are also prone to oxidation and have to be removed from the cellular environment by the nuclear proteasome. Interestingly, nuclear proteins are partly degraded within the nucleus, whereas some are exported from the nucleus to the cytosol. Proteasomes are transported unidirectionally from the cytoplasm to the nucleus with a possible countervail during mitosis. This review is focused largely on the specifics of cellular proteasome distribution and on nuclear protein maintenance under physiological and oxidative stress conditions.
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PMID:The proteasome and its role in nuclear protein maintenance. 1753 63

Human repp86 is a nuclear protein that is expressed in a tightly limited period of time during the cell cycle and plays an essential role in its progression. Manipulation of repp86 expression by reduction of endogenous repp86 or overexpression of exogenous repp86 results in cell cycle arrest. We found that repp86 interacts with human Siah2, which is a known mediator for proteasomal degradation. Siah2 failed to interact with repp86 lacking the first 67 N-terminal amino acids. Overexpression of Siah2 reduced endogenous and exogenous repp86 at the protein level without affecting its mRNA, as shown by cotransfection and RT-PCR experiments. Furthermore, MG-132--a specific inhibitor of the proteasome--blocked the degradation of repp86 in Siah2 overexpressing cells. Moreover, transiently transfected Siah2 abrogated the mitotic arrest in repp86 overexpressing cells. Our data show that Siah2 is an important mediator of repp86 protein degradation.
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PMID:Regulation of repp86 stability by human Siah2. 1771 27

Proteasomes are large multisubunit, multicatalytic proteases responsible for most of the cytosolic and nuclear protein degradation, and their structure and functions are conserved in eukaryotes. Proteasomes were originally identified as the proteolytic module of the ubiquitin-dependent proteolysis pathway. Today we know that proteasomes also mediate ubiquitin-independent proteolysis, that they have RNAse activity, and play a non-proteolytic role in transcriptional regulation. Here we present an overview of the current knowledge of proteasome function and regulation in plants and highlight the role of proteasome-dependent protein degradation in the control of plant development and responses to the environment.
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PMID:Structure, function and regulation of plant proteasomes. 1782 68

The protein level of transcriptional coactivator p300, an essential nuclear protein, is critical to a broad array of cellular activities including embryonic development, cell differentiation and proliferation. We have previously established that histone deacetylase inhibitor such as valproic acid induces p300 degradation through the 26S proteasome pathway. Here, we report the roles of cellular trafficking and spatial redistribution in valproic acid-induced p300 turnover. Our study demonstrates that p300 is redistributed to the cytoplasm prior to valproic acid-induced turnover. Inhibition of proteasome-dependent protein degradation, does not prevent nucleo-cytoplasmic shuttling of p300, rather sequesters the cytoplasmic p300 to a distinct perinuclear region. In addition, the formation of p300 aggregates in the perinuclear region depends on functional microtubule networks and correlates with p300 ubiquitination. Our work establishes, for the first time, that p300 is also a substrate of the cytoplasmic ubiquitin-proteasome system and provides insight on how cellular trafficking and spatial redistribution regulate the availability and activity of transcriptional coactivator p300.
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PMID:Ubiquitin-dependent distribution of the transcriptional coactivator p300 in cytoplasmic inclusion bodies. 1796 93

The 26S proteasome (26SP) is a multi-subunit, multi-catalytic protease that is responsible for most of the cytosolic and nuclear protein turnover. The 26SP is composed of two sub-particles, the 19S regulatory particle (RP) that binds and unfolds protein targets, and the 20S core particle (20SP) that degrades proteins into small peptides. Most 26SP targets are conjugated to a poly-ubiquitin (Ub) chain that serves as a degradation signal. However, some targets, such as oxidized proteins, do not require a poly-Ub tag for proteasomal degradation, and recent studies have shown that the main protease in this Ub-independent pathway is free 20SP. It is currently unknown how the ratio of 26SP- to 20SP-dependent proteolysis is controlled. Here we show that loss of function of the Arabidopsis RP subunits RPT2a, RPN10 and RPN12a leads to decreased 26SP accumulation, resulting in reduced rates of Ub-dependent proteolysis. In contrast, all three RP mutants have increased 20SP levels and thus enhanced Ub-independent protein degradation. As a consequence of this shift in proteolytic activity, mutant seedlings are hypersensitive to stresses that cause protein misfolding, and have increased tolerance to treatments that promote protein oxidation. Taken together, the data show that plant cells increase 20SP-dependent proteolysis when 26SP activity is impaired.
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PMID:26S proteasome regulatory particle mutants have increased oxidative stress tolerance. 1797 Oct 41

The adaptation of animals to oxygen availability is mediated by a transcription factor termed hypoxia-inducible factor (HIF). HIF is an alpha (alpha)/beta (beta) heterodimer that binds hypoxia response elements (HREs) of target genes, including some of medicinal importance, such as erythropoietin (EPO) and vascular endothelial growth factor (VEGF). While the concentration of the HIF-beta subunit, a constitutive nuclear protein, does not vary with oxygen availability, the abundance and activity of the HIF-alpha subunits are tightly regulated via oxygen-dependent modification of specific residues. Hydroxylation of prolyl residues (Pro402 and Pro564 in HIF-1alpha) promotes interaction with the von Hippel-Lindau E3 ubiquitin ligase and, consequently, proteolytic destruction by the ubiquitin-proteasome pathway. This prolyl hydroxylation is catalyzed by the prolyl-hydroxylase domain (PHD) containing enzymes for which three isozymes have been identified in humans (1-3). Additionally, asparaginyl hydroxylation (Asn803 in HIF-1alpha) by factor-inhibiting HIF (FIH) ablates interaction of the HIF-alpha subunit with the coactivator p300, providing an alternative mechanism for down-regulation of HIF-dependent genes. Under hypoxic conditions, when oxygen-mediated regulation of the alpha-subunits is curtailed or minimized, dimerization of the alpha- and beta-subunits occurs with subsequent target gene upregulation. Therapeutic activation of HIF signaling has been suggested as a potential treatment for numerous conditions, including ischemia, stroke, heart attack, inflammation, and wounding. One possible route to achieve this is via inhibition of the HIF hydroxylases. This chapter details methods for the purification and assaying of PHD2, the most abundant PHD and the most important in setting steady-state levels of HIF-alpha. Assays are described that measure the activity of PHD2 via direct and indirect means. Furthermore, conditions for the screening of small molecules against PHD2 are described.
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PMID:Hypoxia-inducible factor prolyl-hydroxylase: purification and assays of PHD2. 1799 47

Protein degradation is a physiological process required to maintain cellular functions. There are distinct proteolytic systems for different physiological tasks under changing environmental and pathophysiological conditions. The proteasome is responsible for the removal of oxidatively damaged proteins in the cytosol and nucleus. It has been demonstrated that proteasomal degradation increases due to mild oxidation, whereas at higher oxidant levels proteasomal degradation decreases. Moreover, the proteasome itself is affected by oxidative stress to varying degrees. The ATP-stimulated 26S proteasome is sensitive to oxidative stress, whereas the 20S form seems to be resistant. Non-degradable protein aggregates and cross-linked proteins are able to bind to the proteasome, which makes the degradation of other misfolded and damaged proteins less efficient. Consequently, inhibition of the proteasome has dramatic effects on cellular aging processes and cell viability. It seems likely that during oxidative stress cells are able to keep the nuclear protein pool free of damage, while cytosolic proteins may accumulate. This is because of the high proteasome content in the nucleus, which protects the nucleus from the formation and accumulation of non-degradable proteins. In this review we highlight the regulation of the proteasome during oxidative stress and aging.
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PMID:Regulation of proteasome-mediated protein degradation during oxidative stress and aging. 1820 55

Light and gibberellins (GAs) mediate many essential and partially overlapping plant developmental processes. DELLA proteins are GA-signalling repressors that block GA-induced development. GA induces degradation of DELLA proteins via the ubiquitin/proteasome pathway, but light promotes accumulation of DELLA proteins by reducing GA levels. It was proposed that DELLA proteins restrain plant growth largely through their effect on gene expression. However, the precise mechanism of their function in coordinating GA signalling and gene expression remains unknown. Here we characterize a nuclear protein interaction cascade mediating transduction of GA signals to the activity regulation of a light-responsive transcription factor. In the absence of GA, nuclear-localized DELLA proteins accumulate to higher levels, interact with phytochrome-interacting factor 3 (PIF3, a bHLH-type transcription factor) and prevent PIF3 from binding to its target gene promoters and regulating gene expression, and therefore abrogate PIF3-mediated light control of hypocotyl elongation. In the presence of GA, GID1 proteins (GA receptors) elevate their direct interaction with DELLA proteins in the nucleus, trigger DELLA protein's ubiquitination and proteasome-mediated degradation, and thus release PIF3 from the negative effect of DELLA proteins.
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PMID:Coordinated regulation of Arabidopsis thaliana development by light and gibberellins. 1821 56

A detailed understanding of aging and senescence is limited by the complex interplay of the effects of extracellular and environmental stimuli on cellular metabolic, mutational, and epigenetic phenomena. For example, STASIS (stress or aberrant signaling-induced senescence) is affected by the exposure to free radicals and conditions that cause an increased cellular production of reactive oxygen species (ROS) during normal life span. In addition, progressive telomere erosion and telomeric dysfunction contribute to a cellular feature termed replicative or cellular senescence. To focus on distinct cellular pathways that contribute to these different forms of senescence, we investigated the reversible differentiation and aging process of the human U937 leukemia cell line. This was compared to cellular senescence that occurred in normal primary human mammary epithelial cells (HMECs). These two cell systems revealed an important role of the proteolytic activity of the 20S proteasome and its activation by the nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) during "retrodifferentiation" and rejuvenation of the leukemic cells. Moreover, reduced extracellular proteolytic activity of certain matrix metalloproteinases-for example, MMP-7-is associated with accelerated aging and senescence in normal HMECs.
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PMID:Matrix metalloproteinase-7 and the 20S proteasome contribute to cellular senescence. 1836 12


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