Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the early phase of infection, the E1B-55K protein of adenovirus type 5 (Ad5) counters the E1A-induced stabilization of p53, whereas in the late phase, E1B-55K modulates the preferential nucleocytoplasmic transport and translation of the late viral mRNAs. The mechanism(s) by which E1B-55K performs these functions has not yet been clearly elucidated. In this study, we have taken a proteomics-based approach to identify and characterize novel E1B-55K-associated proteins. A multiprotein E1B-55K-containing complex was immunopurified from Ad5-infected HeLa cells and found to contain E4-orf6, as well as several cellular factors previously implicated in the ubiquitin-proteasome-mediated destruction of proteins, including Cullin-5, Rbx1/ROC1/Hrt1, and Elongins B and C. We further demonstrate that a complex containing these as well as other proteins is capable of directing the polyubiquitination of p53 in vitro. These ubiquitin ligase components were found in a high-molecular-mass complex of 800 to 900 kDa. We propose that these newly identified binding partners (Cullin-5, Elongins B and C, and Rbx1) complex with E1B-55K and E4-orf6 during Ad infection to form part of an E3 ubiquitin ligase that targets specific protein substrates for degradation. We further suggest that E1B-55K functions as the principal substrate recognition component of this SCF-type ubiquitin ligase, whereas E4-orf6 may serve to nucleate the assembly of the complex. Lastly, we describe the identification and characterization of two novel E1B-55K interacting factors, importin-alpha 1 and pp32, that may also participate in the functions previously ascribed to E1B-55K and E4-orf6.
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PMID:Analysis of the adenovirus E1B-55K-anchored proteome reveals its link to ubiquitination machinery. 1218 3

Hemorrhagic shock is a clinical syndrome that manifests as hypoperfusion, hypoxia, and ischemia initiating various cellular stress responses involved in the synthesis and release of an assortment of pro-inflammatory molecules, cytokines, chemokines, and reactive oxidant species (ROS). The ROS have been shown to oxidize and damage proteins making them targets for ubiquitination and proteasomal degradation. Cullin-5 (cul-5), an E3 ligase that binds ubiquitin to proteins targeted for degradation via the proteasome, was investigated for its gene expression during hemorrhagic shock. Male Long-Evans rats were subjected to volume controlled (27 ml kg-1) hemorrhage over 10 min and kept in shock for 60 min. Quantitative realtime polymerase chain reaction showed cul-5 mRNA levels were significantly increased in the brainstem and cerebellum, and decreased in the hypothalamus of rats as a result of hemorrhagic shock (n = 6) compared to sham-treated rats (n = 6). Cul-5 mRNA levels in the cerebral cortex, small intestine, kidney, liver, lung, or pituitary gland did not significantly change after hemorrhagic shock. This is the first report of cul-5 mRNA regulation by hemorrhagic shock. Evidence indicates this protein may have a regulatory role in ubiquitin-proteasomal protein degradation in response to hemorrhagic shock.
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PMID:Alterations of cullin-5 mRNA levels in the rat central nervous system following hemorrhagic shock. 1263 25

Cullin-5 (Cul-5), an E3 ubiquitin ligase that covalently binds ubiquitin to proteins targeted for degradation via the proteasome, was examined for its localization and distribution in the rat central nervous system (CNS). We showed cul-5 mRNA expression in rat neuronal, glial, and vascular endothelial cells by reverse transcription-polymerase chain reaction and corroborated these data by Cul-5 immunostaining in neurons, astrocytes, blood vessels, and choroid plexus of the laboratory rat. Widespread and ubiquitous expression of Cul-5 in the brain suggests that it may have a vital role(s) in cellular activities of the CNS.
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PMID:Cullin-5 is ubiquitous in the rat brain. 1282 Nov 86

Cullin-5 (Cul-5), a member of the cullin gene family of scaffold proteins of E3 ubiquitin-ligase complexes, has a role in proteolysis and cell cycle regulation. We recently demonstrated that cul-5 mRNA is ubiquitously expressed in the central nervous system. The present study used quantitative real time polymerase chain reaction and western blotting to measure changes in cul-5 mRNA and Cul-5 protein expression, respectively, in the injured CNS in response to traumatic brain injury (TBI). cul-5 mRNA levels were significantly decreased in the ipsilateral rat cerebral cortex on Days 1 and 7, but not on Day 3 following TBI. In the ipsilateral hippocampus, cul-5 mRNA was significantly reduced on Day 1 after TBI. Cul-5 protein levels were significantly decreased in the ipsilateral rat cerebral cortex on Days 1-7 post-TBI while levels were significantly lower in the ipsilateral hippocampus on Days 3-7 post-TBI. Since Cul-5 is ubiquitously expressed in eukaryotic cells and is linked to proteasome-mediated protein degradation, it may have a role in CNS cell fate determination under conditions of traumatic stress.
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PMID:Cullin 5 gene expression in the rat cerebral cortex and hippocampus following traumatic brain injury (TBI). 1701 May 17

Vif forms a complex with Elongin B/C, Cullin-5 and Rbx-1 to induce the polyubiquitination and proteasome-mediated degradation of human APOBEC3G (hA3G). These interactions serve as potential targets for anti-HIV-1 drug development. We have developed a cell culture-based assay to measure Vif-induced hA3G degradation. The assay is based on alpha-complementation, the ability of beta-galactosidase fragments to complement in trans. hA3G expressed with a fused alpha-peptide was enzymatically active, complemented a coexpressed omega-fragment and could be targeted for degradation by Vif. Vif reduced beta-galactosidase activity in the cell by 10-30-fold. The assay was validated by testing various hA3G and Vif point mutants. The assay accurately detected the effects of D128 in hA3G, and the BC box, Cul5 box and HCCH motifs of Vif. The results showed a strict association of Vif biological function with hA3G degradation. These findings support hA3G degradation as a requirement for Vif function. The Vif alpha-complementation assay may be a useful tool for the identification of Vif inhibitors.
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PMID:Analysis of Vif-induced APOBEC3G degradation using an alpha-complementation assay. 1704 78

Inducible nitric-oxide synthase (iNOS, NOS2) plays a prominent role in macrophage bactericidal and tumoricidal activities. A relatively large amount of NO produced via iNOS, however, also targets the macrophage itself for apoptotic cell death. To uncover the intrinsic mechanisms of iNOS regulation, we have characterized the SPRY domain- and SOCS box-containing protein 1 (SPSB1), SPSB2, and SPSB4 that interact with the N-terminal region of iNOS in a D-I-N-N-N sequence-dependent manner. Fluorescence microscopy revealed that these SPSB proteins can induce the subcellular redistribution of iNOS from dense regions to diffused expression in a SOCS box-dependent manner. In immunoprecipitation studies, both Elongin C and Cullin-5, components of the multi-subunit E3 ubiquitin ligase, were found to bind to iNOS via SPSB1, SPSB2, or SPSB4. Consistently, iNOS was polyubiquitinated and degraded in a proteasome-dependent manner when SPSB1, SPSB2, or SPSB4 was expressed. SPSB1 and SPSB4 had a greater effect on iNOS regulation than SPSB2. The iNOS N-terminal fragment (residues 1-124 of human iNOS) could disrupt iNOS-SPSB interactions and inhibit iNOS degradation. In lipopolysaccharide-treated macrophages, this fragment attenuated iNOS ubiquitination and substantially prolonged iNOS lifetime, resulting in a corresponding increase in NO production and enhanced NO-dependent cell death. These results not only demonstrate the mechanism of SPSB-mediated iNOS degradation and the relative contributions of different SPSB proteins to iNOS regulation, but also show that iNOS levels are sophisticatedly regulated by SPSB proteins in activated macrophages to prevent overproduction of NO that could trigger detrimental effects, such as cytotoxicity.
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PMID:Regulation of inducible nitric-oxide synthase by the SPRY domain- and SOCS box-containing proteins. 2119 76

The ubiquitin-proteasome pathway is an important regulatory system for the lifetime of inducible nitric-oxide synthase (iNOS), a high-output isoform compared to neuronal NOS (nNOS) and endothelial NOS (eNOS), to prevent overproduction of NO that could trigger detrimental effects such as cytotoxicity. Two E3 ubiquitin ligases, Elongin B/C-Cullin-5-SPRY domain- and SOCS box-containing protein [ECS(SPSB)] and the C-terminus of Hsp70-interacting protein (CHIP), recently have been reported to target iNOS for proteasomal degradation. However, the significance of each E3 ubiquitin ligase for the proteasomal degradation of iNOS remains to be determined. Here, we show that ECS(SPSB) specifically interacted with iNOS, but not nNOS and eNOS, and induced the subcellular redistribution of iNOS from dense regions to diffused expression as well as the ubiquitination and proteasomal degradation of iNOS, whereas CHIP neither interacted with iNOS nor had any effects on the subcellular localization, ubiquitination, and proteasomal degradation of iNOS. These results differ from previous reports. Furthermore, the lifetime of the iNOS(N27A) mutant, a form of iNOS that does not bind to ECS(SPSB), was substantially extended in macrophages. These results demonstrate that ECS(SPSB), but not CHIP, is the master regulator of the iNOS lifetime.
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PMID:The ECS(SPSB) E3 ubiquitin ligase is the master regulator of the lifetime of inducible nitric-oxide synthase. 2154

Cullin-5 (CUL5), a scaffold protein in active cullin-RING ubiquitin ligase (CRL) complexes, is a member of the cullin family of proteins. The CUL5-type ubiquitin ligase can target multiple proteins involved in ubiquitination and proteasome degradation. CUL5 plays positive roles in regulating cell growth, proliferation and physiological and other processes in the human body. It has been found that the expression of CUL5 is significantly downregulated in various cancer cells, which affects the course of the cancers. Here, we reviewed the current data on the expression and role of CUL5 in both normal and cancer cells, its possible mechanisms, and its potential as a therapeutic target for cancers.
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PMID:The functions and properties of cullin-5, a potential therapeutic target for cancers. 3219 10