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)

The recent discovery that the RING-finger domain is involved in mediating ubiquitin transfer from ubiquitin-conjugating enzymes to substrates have highlighted the importance of protein degradation through the ubiquitin-proteasome pathway in the regulation of different cellular processes. Two RING-finger-containing proteins, the promyelocytic leukemia protein (PML) from mammals and the constitutive photomorphogenic protein (COP1) from plants, show conspicuous similarities in their cellular distribution, dynamics and structure, indicating that they share a related function. Comparison of these two proteins suggests that they are involved in regulating the targeting of nuclear proteins to specific nuclear compartments for degradation through the ubiquitin-proteasome pathway.
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PMID:PML and COP1--two proteins with much in common. 1116 11

Human cytomegalovirus (HCMV) major immediate-early protein IE1 is an abundant 72-kDa nuclear phosphoprotein that is thought to play an important role in efficient triggering of the lytic cycle, especially at low multiplicity of infection. The best-known properties of IE1 at present are its transient targeting to punctate promyelocytic leukemia protein (PML)-associated nuclear bodies (PML oncogenic domains [PODs] or nuclear domain 10 [ND10]), with associated displacement of the cellular PML tumor suppressor protein into a diffuse nucleoplasmic form and its association with metaphase chromosomes. Recent studies have shown that the targeting of PML (and associated proteins such as hDaxx) to PODs is dependent on modification of PML by ubiquitin-like protein SUMO-1. In this study, we provide direct evidence that IE1 is also covalently modified by SUMO-1 in both infected and cotransfected cells, as well as in in vitro assays, with up to 30% of the protein representing the covalently conjugated 90-kDa form in stable U373/IE1 cell lines. Lysine 450 was mapped as the major SUMO-1 conjugation site, but a point mutation of this lysine residue in IE1 did not interfere with its targeting to and disruption of the PODs. Surprisingly, unlike PML or IE2, IE1 did not interact with either Ubc9 or SUMO-1 in yeast two-hybrid assays, suggesting that some additional unknown intranuclear cofactors must play a role in IE1 sumoylation. Interestingly, stable expression of either exogenous PML or exogenous Flag-SUMO-1 in U373 cell lines greatly enhanced both the levels and rate of in vivo IE1 sumoylation during HCMV infection. Unlike the disruption of PODs by the herpes simplex virus type 1 IE110(ICP0) protein, the disruption of PODs by HCMV IE1 proved not to involve proteasome-dependent degradation of PML. We also demonstrate here that the 560-amino-acid PML1 isoform functions as a transcriptional repressor when fused to the GAL4 DNA-binding domain and that wild-type IE1 inhibits the repressor function of PML1 in transient cotransfection assays. Furthermore, both IE1(1-346) and IE1(L174P) mutants, which are defective in displacing PML from PODs, failed to inhibit the repression activity of PML1, whereas the sumoylation-negative IE1(K450R) mutant derepressed as efficiently as wild-type IE1. Taken together, our results suggest that proteasome-independent disruption of PODs, but not IE1 sumoylation, is required for efficient IE1 inhibition of PML-mediated transcriptional repression.
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PMID:Proteasome-independent disruption of PML oncogenic domains (PODs), but not covalent modification by SUMO-1, is required for human cytomegalovirus immediate-early protein IE1 to inhibit PML-mediated transcriptional repression. 1160 10

Marinesco bodies (MBs) are ubiquitinated intranuclear inclusions observed in nigral pigmented neurons. They increase in number during aging, and their formation is considered to represent a cellular reaction to stress, but is not always associated with neuronal degeneration. We conducted immunohistochemical studies on MBs abundant in myotonic dystrophy brains and compared their nature with that of neuronal intranuclear inclusions (NIIs) in polyglutamine diseases. First, we examined the relationship between MBs and polyglutamine proteins and demonstrated that one of the polyglutamine proteins, ataxin-3, as well as a 19S proteasomal protein, was preferentially recruited into MBs even in the absence of expanded polyglutamine. This indicates that an alternative mechanism during the formation of MBs that is not related to polyglutamine expansion or neuronal degeneration may recruit ataxin-3 into nuclear inclusions in a protein-specific manner. Secondly, we investigated the relationship between MBs and promyelocytic leukemia protein (PML), a nuclear matrix-associated protein that is normally localized to intranuclear punctate structures (PML nuclear bodies) and is known to reorganize itself in association with polyglutamine aggregation. In nigral pigmented neurons in myotonic dystrophy, spherical, hemispherical or rod-like PML-immunoreactive structures, in addition to punctate structures, were observed in their nuclei. Similar PML redistribution was also observed in nigral pigmented neurons in aged controls and cases of hepatic encephalopathy, 2 other conditions in which abundant MBs are formed. Double immunofluorescence study revealed that these PML-positive structures undergo morphological changes in association with ubiquitin accumulation during MB formation. It is therefore indicated that PML reorganization does not represent a specific nuclear event involved in the pathogenesis of polyglutamine diseases, but may commonly occur during the formation of intranuclear inclusions as a reaction against various stresses that involve the ubiquitin-proteasome pathway.
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PMID:Promyelocytic leukemia protein is redistributed during the formation of intranuclear inclusions independent of polyglutamine expansion: an immunohistochemical study on Marinesco bodies. 1243 Jul 15

Polyglutamine diseases are inherited neurodegenerative diseases caused by the expanded polyglutamine proteins (polyQs). We have identified a novel guanosine triphosphatase (GTPase) named CRAG that contains a nuclear localization signal (NLS) sequence and forms nuclear inclusions in response to stress. After ultraviolet irradiation, CRAG interacted with and induced an enlarged ring-like structure of promyelocytic leukemia protein (PML) body in a GTPase-dependent manner. Reactive oxygen species (ROS) generated by polyQ accumulation triggered the association of CRAG with polyQ and the nuclear translocation of the CRAG-polyQ complex. Furthermore, CRAG promoted the degradation of polyQ at PML/CRAG bodies through the ubiquitin-proteasome pathway. CRAG knockdown by small interfering RNA in neuronal cells consistently blocked the nuclear translocation of polyQ and enhanced polyQ-mediated cell death. We propose that CRAG is a modulator of PML function and dynamics in ROS signaling and is protectively involved in the pathogenesis of polyglutamine diseases.
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PMID:A novel GTPase, CRAG, mediates promyelocytic leukemia protein-associated nuclear body formation and degradation of expanded polyglutamine protein. 1646 59

All-trans-retinoic acid and the tumor suppressor promyelocytic leukemia protein (PML) are potent regulators of the growth of cancer cells. This study investigates the individual and combined effects of PML, when overexpressed by the recombinant PML adenovirus, and all-trans-retinoic acid on the proliferation of human estrogen-receptor negative SKBR-3 and estrogen-receptor positive MCF-7 breast cancer cell lines. All-trans-retinoic acid caused a significant degree of cell death in SKBR-3 cells and MCF-7 cells, and PML elicited a similar incidence of or slightly more cell death in MCF-7 cells. Dual-treated cells displayed significantly less cell death than did single-treated cells in the same cell line. We concluded that PML and all-trans-retinoic acid cause cell death by different pathways: PML activates ERK1/2, p38 MAPK, and p21; arrests the cell cycle; and later causes cell death; and all-trans-retinoic acid activates proteasome function, caspase cleavage, and apoptosis. The combined use of all-trans-retinoic acid and PML gene therapy may not be the best treatment for patients with cancer, because the ubiquitinylation of PML and its subsequent proteasome-dependent degradation by retinoic acids occur before overexpressed PML exhibits tumor-suppressive activity.
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PMID:Retinoic acid attenuates promyelocytic leukemia protein-induced cell death in breast cancer cells by activation of the ubiquitin-proteasome pathway. 1674 Mar 59

Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 is a critical transcriptional regulator of energy metabolism. Here we found that PGC-1alpha is a short lived and aggregation-prone protein. PGC-1alpha localized throughout the nucleoplasm and was rapidly destroyed via the ubiquitin-proteasome pathway. Upon proteasome inhibition, PGC-1alpha formed insoluble polyubiquitinated aggregates. Ubiquitination of PGC-1alpha depended on the integrity of the C terminus-containing arginine-serine-rich domains and an RNA recognition motif. Interestingly, ectopically expressed C-terminal fragment of PGC-1alpha was autonomously ubiquitinated and aggregated with promyelocytic leukemia protein. Cooperation of the N-terminal region containing two PEST-like motifs was required for prevention of aggregation and targeting of the polyubiquitinated PGC-1alpha for degradation. This region thereby negatively controlled the aggregation properties of the C-terminal region to regulate protein turnover and intranuclear compartmentalization of PGC-1alpha. Exogenous expression of the PGC-1alpha C-terminal fragment interfered with degradation of full-length PGC-1alpha and enhanced its coactivation properties. We concluded that PGC-1alpha function is critically regulated at multiple steps via intramolecular cooperation among several distinct structural domains of the protein.
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PMID:Intramolecular control of protein stability, subnuclear compartmentalization, and coactivator function of peroxisome proliferator-activated receptor gamma coactivator 1alpha. 1762 Mar 42

REGgamma (also called PA28gamma or PSME3) is a proteasome activator involved in the degradation of several proteins that regulate cell cycle and transcription. Recently, we demonstrated that this protein has a role also in the maintenance of chromosomal stability and in the response to spindle damaging agents. Here we report for the first time that REGgamma interacts with the promyelocytic leukemia protein (PML), accumulates in PML nuclear bodies (PML-NBs), but it does not play any role in normal or arsenic-induced PML degradation. However, REGgamma seems to regulate PML-NBs number, since its deficiency causes an increase in PML-NBs, which can be overcome by increased levels of SUMO1, and its overexpression has the opposite effect. We additionally found that REGgamma interacts with the DNA damage checkpoint kinase Chk2, whose presence is necessary for the increase of PML-NBs induced by REGgamma deficiency, and that REGgamma depletion resulted in a partial restoration of PML-NBs in APL derived cells. Altogether, these results underline a new role for REGgamma in the control and regulation of PML subnuclear structures.
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PMID:REGgamma/PA28gamma proteasome activator interacts with PML and Chk2 and affects PML nuclear bodies number. 1955 97

The death-associated protein Daxx found in PML (promyelocytic leukemia protein) nuclear bodies (PML-NBs) is involved in transcriptional regulation and cellular intrinsic antiviral resistence against incoming viruses. We found that knockdown of Daxx in a nontransformed human hepatocyte cell line using RNA interference (RNAi) techniques results in significantly increased adenoviral (Ad) replication, including enhanced viral mRNA synthesis and viral protein expression. This Daxx restriction imposed upon adenovirus growth is counteracted by early protein E1B-55K (early region 1B 55-kDa protein), a multifunctional regulator of cell-cycle-independent Ad5 replication. The viral protein binds to Daxx and induces its degradation through a proteasome-dependent pathway. We show that this process is independent of Ad E4orf6 (early region 4 open reading frame 6), known to promote the proteasomal degradation of cellular p53, Mre11, DNA ligase IV, and integrin alpha3 in combination with E1B-55K. These results illustrate the importance of the PML-NB-associated factor Daxx in virus growth restriction and suggest that E1B-55K antagonizes innate antiviral activities of Daxx and PML-NBs to stimulate viral replication at a posttranslational level.
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PMID:Proteasome-dependent degradation of Daxx by the viral E1B-55K protein in human adenovirus-infected cells. 2048 9

Us3, a serine/threonine kinase encoded by all alphaherpesviruses, plays diverse roles during virus infection, including preventing virus-induced apoptosis, facilitating nuclear egress of capsids, stimulating mRNA translation and promoting cell-to-cell spread of virus infection. Given this diversity, the full spectrum of Us3 function may not yet be recognized. We noted, in transiently transfected cells, that herpes simplex virus type 2 (HSV-2) Us3 disrupted promyelocytic leukemia protein nuclear bodies (PML-NBs). However, PML-NB disruption was not observed in cells expressing catalytically inactive HSV-2 Us3. Analysis of PML-NBs in Vero cells transfected with pseudorabies virus (PRV) Us3 and those in Vero cells infected with Us3-null or -repaired PRV strains indicated that PRV Us3 expression also leads to the disruption of PML-NBs. While loss of PML-NBs in response to Us3 expression was prevented by the proteasome inhibitor MG132, Us3-mediated degradation of PML was not observed in infected cells or in transfected cells expressing enhanced green fluorescent protein (EGFP)-tagged PML isoform IV. These findings demonstrate that Us3 orthologues derived from distantly related alphaherpesviruses cause a disruption of PML-NBs in a kinase- and proteasome-dependent manner but, unlike the alphaherpesvirus ICP0 orthologues, do not target PML for degradation.
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PMID:The alphaherpesvirus serine/threonine kinase us3 disrupts promyelocytic leukemia protein nuclear bodies. 2143 51

TRAF and TNF receptor-associated protein (TTRAP) is a multifunctional protein that can act in the nucleus as a 5'-tyrosyl DNA phosphodiesterase and in the cytoplasm as a regulator of cell signaling. In this paper we show that in response to proteasome inhibition TTRAP accumulates in nucleolar cavities in a promyelocytic leukemia protein-dependent manner. In the nucleolus, TTRAP contributes to control levels of ribosomal RNA precursor and processing intermediates, and this phenotype is independent from its 5'-tyrosyl DNA phosphodiesterase activity. Our findings suggest a previously unidentified function for TTRAP and nucleolar cavities in ribosome biogenesis under stress.
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PMID:The PML nuclear bodies-associated protein TTRAP regulates ribosome biogenesis in nucleolar cavities upon proteasome inhibition. 2192 40


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