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

---

Query: EC:3.4.25.1 (proteasome)
28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Polyglutamine diseases are characterized by neuronal intranuclear inclusions (NIIs) of expanded polyglutamine proteins, indicating the failure of protein degradation. UBB(+1), an aberrant form of ubiquitin, is a substrate and inhibitor of the proteasome, and was previously reported to accumulate in Alzheimer disease and other tauopathies. Here, we show accumulation of UBB(+1) in the NIIs and the cytoplasm of neurons in Huntington disease and spinocerebellar ataxia type-3, indicating inhibition of the proteasome by polyglutamine proteins in human brain. We found that UBB(+1) not only increased aggregate formation of expanded polyglutamines in neuronally differentiated cell lines, but also had a synergistic effect on apoptotic cell death due to expanded polyglutamine proteins. These findings implicate UBB(+1) as an aggravating factor in polyglutamine-induced neurodegeneration, and clearly identify an important role for the ubiquitin-proteasome system in polyglutamine diseases.
...
PMID:Accumulation of aberrant ubiquitin induces aggregate formation and cell death in polyglutamine diseases. 1519 95

To date, nine progressive neurodegenerative diseases are caused by expansion of the CAG repeat coding for polyglutamine, including Huntington's disease and several forms of spinocerebellar ataxia. Expanded polyglutamine causes dominant toxic gain-of-function related to its ability to aggregate. Polyglutamine aggregates inhibit the proteasome, suggesting that reduced degradation of misfolded proteins might contribute to polyglutamine toxicity. Moreover, several observations indicate that soluble proteins harboring expanded polyglutamine display altered turnover. To examine whether soluble polyglutamine interfered with proteasome-mediated degradation, we analyzed degradation of model proteasome substrates carrying either 103 or 25 glutamines in transfected cells. Expanded and normal size polyglutamine were degraded to completion and with similar efficiency. Moreover, targeting of expanded polyglutamine for proteasome-mediated degradation did not compromise proteasome activity. Thus, we propose that polyglutamine-containing disease proteins can be readily digested by the proteasome if they carried a degradation signal.
...
PMID:Proteasome degrades soluble expanded polyglutamine completely and efficiently. 1520 77

Neural proliferation and differentiation control protein-1 (NPDC-1) is a protein expressed primarily in brain and lung and whose expression can be correlated with the regulation of cellular proliferation and differentiation. Embryonic differentiation in brain and lung has classically been linked to retinoid signaling, and we have recently characterized NPDC-1 as a regulator of retinoic acid-mediated events. Regulators of differentiation and development are themselves highly regulated and usually through multiple mechanisms. One such mechanism, protein degradation via the ubiquitin/proteasome degradation pathway, has been linked to the expression of a number of proteins involved in control of proliferation or differentiation, including cyclin D1 and E2F-1. The data presented here demonstrate that NPDC-1 is likewise degraded by the ubiquitin/proteasome system. MG-132, a proteasome inhibitor, stabilized the expression of NPDC-1 and allowed detection of ubiquitinated NPDC-1 in vivo. A PEST motif (rich in proline, glutamine, serine, and threonine) located in the carboxyl terminus of NPDC-1 was shown to target the protein for degradation. Deletion of the PEST motif increased NPDC-1 protein stability and NPDC-1 inhibitory effect on retinoic acid-mediated transcription. NPDC-1 was phosphorylated by several kinases, including extracellular signal-regulated kinase. Phosphorylation of NPDC-1 increased the in vitro rate of NPDC-1 ubiquitination. The MEK inhibitor, PD-98059, an inhibitor of extracellular signal-regulated activation, also inhibited the formation of ubiquitinated NPDC-1 in vivo. Together these results suggest that retinoic acid signaling can be modulated by the presence of NPDC-1 and that the protein level and activity of NPDC-1 can be regulated by phosphorylation-mediated proteasomal degradation.
...
PMID:NPDC-1, a novel regulator of neuronal proliferation, is degraded by the ubiquitin/proteasome system through a PEST degradation motif. 1522 25

We reported (Yarasheski KE, Zachwieja JJ, Gischler J, Crowley J, Horgan MM, and Powderly WG. Am J Physiol Endocrinol Metab 275: E577-E583, 1998) that AIDS muscle wasting was associated with an inappropriately low rate of muscle protein synthesis and an elevated glutamine rate of appearance (Ra Gln). We hypothesized that high plasma HIV RNA caused dysregulation of muscle amino acid metabolism. We determined whether a reduction in HIV RNA (> or =1 log) increased muscle protein synthesis rate and reduced R(a) Gln and muscle proteasome activity in 10 men and 1 woman (22-57 yr, 60-108 kg, 17-33 kg muscle) with advanced HIV (CD4 = 0-311 cells/microl; HIV RNA = 10-375 x 10(3) copies/ml). We utilized stable isotope tracer methodologies ([13C]Leu and [15N]Gln) to measure the fractional rate of mixed muscle protein synthesis and plasma Ra Gln in these subjects before and 4 mo after initiating their first or a salvage antiretroviral therapy regimen. After treatment, median CD4 increased (98 vs. 139 cells/microl, P = 0.009) and median HIV RNA was reduced (155,828 vs. 100 copies/ml, P = 0.003). Mixed muscle protein synthesis rate increased (0.062 +/- 0.005 vs. 0.078 +/- 0.006%/h, P = 0.01), Ra Gln decreased (387 +/- 33 vs. 323 +/- 15 micromol.kg fat-free mass(-1).h(-1), P = 0.04), and muscle proteasome chymotrypsin-like catalytic activity was reduced 14% (P = 0.03). Muscle mass was only modestly increased (1 kg, P = not significant). We estimated that, for each 10,000 copies/ml reduction in HIV RNA, approximately 3 g of additional muscle protein are synthesized per day. These findings suggest that reducing HIV RNA increases muscle protein synthesis and reduces muscle proteolysis, but muscle protein synthesis relative to whole body protein synthesis rate is not restored to normal, so muscle mass is not substantially increased.
...
PMID:Reducing plasma HIV RNA improves muscle amino acid metabolism. 1536 96

To investigate changes in muscle metabolism during lactation, serial biopsy of the triceps brachii was conducted in first-parity sows subjected to three degrees of selective protein mobilization through restriction of dietary protein intake (see Clowes EJ, Aherne FX, Foxcroft GR, and Baracos VE. J Anim Sci 81: 753-764, 2003). Muscle biopsies were taken 7 days before parturition and at 12 and 23 days of lactation. The following changes occurred after parturition, were progressive, and were significantly magnified in animals under the greatest degree of dietary protein restriction and hence of protein mobilization. Decreased RNA-to-DNA ratio (capacity for protein synthesis) was observed. The presence of increased expression of several elements of the ubiquitin proteasome proteolytic pathway suggested a robust catabolic response. However, as lactation progressed, and especially under conditions of increased dietary protein restriction, protein mobilization increased, muscle RNA-to-DNA ratio fell further, protease gene expression continued to rise, tissue free glutamine levels rose dramatically, and essential amino acid levels, especially branched-chain amino acids and threonine, fell to below prepartum levels.
...
PMID:Skeletal muscle protein mobilization during the progression of lactation. 1550 37

At least nine neurodegenerative disorders are caused by expansion of polyglutamine repeats in various genes. This expansion induces the formation of nuclear inclusions (NI) within various cell types. In this study, we developed a model for polyglutamine diseases using primary cultures of sympathetic neurons from the superior cervical ganglia of prenatal rat pups. Transfection with a plasmid encoding 127 glutamine repeats causes NI to develop in approximately 70% of the sympathetic neurons within 6 days. In addition, it causes somatic atrophy and inhibits dendritic growth. The NIs contain ubiquitinated proteins and sequester the molecular chaperone heat shock protein 70 (Hsp70). We found that two specific proteasome inhibitors, lactacystin and CEP1612, suppress thezformation of polyglutamine-induced NI. In addition, lactacystin treatment induced the removal of preexisting NI. Western blotting and immunocytochemistry revealed that lactacystin and CEP1612 strongly induce the expression of Hsp70, whereas less specific proteasome inhibitor such as N-acetyl-Leu-Leu-Norleucinal does not. Coexpression of 127 glutamines with a plasmid encoding wild-type Hsp70 gene resulted in a marked reduction of the percentage of neurons containing NI. In addition, transfection with plasmids encoding mutant Hsp70 blocked the effects of lactacystin. These findings further implicate Hsp70 as a neuroprotective molecule and they suggest the potential utility of certain proteasome inhibitors in the treatment of polyglutamine diseases.
...
PMID:Proteasome inhibitors suppress formation of polyglutamine-induced nuclear inclusions in cultured postmitotic neurons. 1556 48

A major hallmark of the polyglutamine diseases is the formation of neuronal intranuclear inclusions (NIIs) of the disease proteins that are ubiquitinated and often associated with various chaperones and proteasome components. Recently, misfolding has come to be considered one of the primary factors for polyglutamine protein aggregation, although, the nature of misfolding and the relationship between misfolding and ubiquitination of the expanded polyglutamine protein is not yet known. By using ataxin-3, the defective gene product of SCA3/MJD, we demonstrate here that the misfolding propensity and the cellular toxicity of a polyglutamine protein is directly proportional to the length of the glutamine repeats and inversely dependent on the size of the corresponding protein. The size of the polyglutamine bearing protein also inversely influences the binding of 1C2 antibody (an antibody that selectively recognizes polyglutamine expansion) to the polyglutamine protein and determines the minimum length of glutamine expansion to be recognized by 1C2 antibody, which suggests that the critical pathological range of glutamine repeats could also be dependent on the size of the corresponding protein. Ataxin-3 (both full length and truncated) with normal glutamine repeats are not ubiquitinated, however, ataxin-3 with expanded polyglutamine is ubiquitinated and the ubiquitination depends on the misfolding propensity of the polyglutamine expanded ataxin-3.
...
PMID:Misfolding promotes the ubiquitination of polyglutamine-expanded ataxin-3, the defective gene product in SCA3/MJD. 1563 84

Kennedy disease, a degenerative disorder caused by an expanded glutamine tract, is mediated by misfolding of the mutant androgen receptor (AR) protein, a process that may disrupt proteasome function. We hypothesized that this might lead to endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR), a complex physiologic pathway that regulates cell survival. To test this hypothesis, we used aminoterminal fragments of wild type (AR16Q) or mutant (AR112Q) AR that triggered glutamine length-dependent cell death and activated an ER stress-inducible promoter. To evaluate the role of the UPR, we examined the contributions of three proximal sensors of ER stress: activating transcription factor 6 (ATF6), inositol requiring 1 (IRE1), and PKR-like endoplasmic reticulum kinase (PERK). AR112Q toxicity was significantly increased by a dominant negative ATF6 mutant and significantly decreased by a constitutively active ATF6 mutant, indicating that ATF6 promoted cell survival. In contrast, co-transfection with three separate IRE1alpha dominant negative mutants failed to alter glutamine length-dependent toxicity, suggesting that this arm of the UPR did not significantly affect AR112Q induced cell death. Activation of PERK, an ER transmembrane protein that functions as the third proximal UPR sensor, promoted glutamine length-dependent toxicity. Although nuclear localization sequence- and nuclear export sequence-targeted proteins both activated the UPR, this pathway more potently influenced toxicity when proteins were targeted to the cytoplasm. Taken together, our data demonstrate that the UPR is activated in cells expressing long glutamine tracts and that this pathway modulates polyglutamine toxicity.
...
PMID:The unfolded protein response modulates toxicity of the expanded glutamine androgen receptor. 1579 70

Polyglutamine (polyQ) expansions cause neurodegeneration that is associated with protein misfolding and influenced by functional properties of the host protein. The polyQ disease protein, ataxin-3, has predicted ubiquitin-specific protease and ubiquitin-binding domains, which suggest that ataxin-3 functions in ubiquitin-dependent protein surveillance. Here we investigate direct links between the ubiquitin-proteasome pathway and ataxin-3. In neural cells we show that, through its ubiquitin interaction motifs (UIMs), normal or expanded ataxin-3 binds a broad range of ubiquitinated proteins that accumulate when the proteasome is inhibited. The expression of a catalytically inactive ataxin-3 (normal or expanded) causes ubiquitinated proteins to accumulate in cells, even in the absence of proteasome inhibitor. This accumulation of ubiquitinated proteins occurs primarily in the cell nucleus in transfected cells and requires intact UIMs in ataxin-3. We further show that both normal and expanded ataxin-3 can undergo oligoubiquitination. Although this post-translational modification occurs in a UIM-dependent manner, it becomes independent of UIMs when the catalytic cysteine residue of ataxin-3 is mutated, suggesting that ataxin-3 ubiquitination is itself regulated in trans by its own de-ubiquitinating activity. Finally, pulse-chase labeling reveals that ataxin-3 is degraded by the proteasome, with expanded ataxin-3 being as efficiently degraded as normal ataxin-3. Mutating the UIMs does not alter degradation, suggesting that UIM-mediated oligoubiquitination of ataxin-3 modulates ataxin-3 function rather than stability. The function of ataxin-3 as a de-ubiquitinating enzyme, its post-translational modification by ubiquitin, and its degradation via the proteasome link this polyQ protein to ubiquitin-dependent pathways already implicated in disease pathogenesis.
...
PMID:Defining the role of ubiquitin-interacting motifs in the polyglutamine disease protein, ataxin-3. 1604 Jun 1

Huntington's disease (HD) is one of a group of neurodegenerative disorders caused by the pathological expansion of a glutamine tract. A hallmark of these so-called polyglutamine diseases is the presence of ubiquitylated inclusion bodies, which sequester various components of the 19S and 20S proteasomes. In addition, the ubiquitin-proteasome system (UPS) has been shown to be severely impaired in vitro in cells overexpressing mutant huntingtin. Thus, because of its fundamental housekeeping function, impairment of the UPS in neurons could contribute to neurotoxicity. We have recently proposed that the proteasome activator REGgamma could contribute to UPS impairment in polyglutamine diseases by suppressing the proteasomal catalytic sites responsible for cleaving Gln-Gln bonds. Capping of proteasomes with REGgamma could therefore contribute to a potential 'clogging' of the proteasome by pathogenic polyglutamines. We show here that genetic reduction of REGgamma has no effect on the well-defined neurological phenotype of R6/2 HD mice and does not affect inclusion body formation in the R6/2 brain. Surprisingly, we observe increased proteasomal 'chymotrypsin-like' activity in 13-week-old R6/2 brains relative to non-R6/2, irrespective of REGgamma levels. However, assays of 26S proteasome activity in mouse brain extracts reveal no difference in proteolytic activity regardless of R6/2 or REGgamma genotype. These findings suggest that REGgamma is not a viable therapeutic target in polyglutamine disease and that overall proteasome function is not impaired by trapped mutant polyglutamine in R6/2 mice.
...
PMID:Proteasome impairment does not contribute to pathogenesis in R6/2 Huntington's disease mice: exclusion of proteasome activator REGgamma as a therapeutic target. 1631 Dec 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---