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)

Huntington's disease (HD) and other polyglutamine (polyQ) neurodegenerative diseases are characterized by neuronal accumulation of the disease protein, suggesting that the cellular ability to handle abnormal proteins is compromised. As both a cochaperone and ubiquitin ligase, the C-terminal Hsp70 (heat shock protein 70)-interacting protein (CHIP) links the two major arms of protein quality control, molecular chaperones, and the ubiquitin-proteasome system. Here, we demonstrate that CHIP suppresses polyQ aggregation and toxicity in transfected cell lines, primary neurons, and a novel zebrafish model of disease. Suppression by CHIP requires its cochaperone function, suggesting that CHIP acts to facilitate the solubility of mutant polyQ proteins through its interactions with chaperones. Conversely, HD transgenic mice that are haploinsufficient for CHIP display a markedly accelerated disease phenotype. We conclude that CHIP is a critical mediator of the neuronal response to misfolded polyQ protein and represents a potential therapeutic target in this important class of neurodegenerative diseases.
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PMID:CHIP suppresses polyglutamine aggregation and toxicity in vitro and in vivo. 1620 74

Claspin is a Chk1-interacting protein that participates in the DNA replication checkpoint. Expression of Claspin fluctuates in a cell cycle-dependent manner, but the mechanisms involved in the regulation of Claspin protein levels have not been explored. In this study, we show that Claspin expression is downregulated by the proteasome-mediated degradation pathway and that Chk1 is required to maintain Claspin stability. Downregulation of Chk1 expression by siRNA or inhibition of Chk1 activity by UCN01 decreases Claspin levels in cells. Conversely, overexpression of Chk1 increases Claspin levels. These data indicate a role of Chk1 in regulating Claspin stability in the cell. Since Claspin has also been shown to participate in Chk1 activation following DNA damage, we further explored the exact role of Claspin during Chk1 activation following replication stress. We observed that while Rad17 is required for early Chk1 activation after hydroxyurea treatment, Claspin is only required to sustain Chk1 activation. Based on these findings, we propose that Claspin functions at late stages of Chk1 activation following DNA damage. Once Chk1 is activated, it stabilizes Claspin, which in turn helps to maintain Chk1 activation during replication stress. In summary, these data indicate that the interaction between Claspin and Chk1 is complex. These proteins regulate each other and thus ensure the proper cell cycle progression and replication checkpoint control.
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PMID:Chk1 is required to maintain claspin stability. 1650 6

PDGF is a potent chemotactic mitogen and a strong inductor of fibroblast motility. In Swiss 3T3 fibroblasts, exposure to PDGF but not EGF or IGF-1 causes a rapid loss of actin stress fibers (SFs) and focal adhesions (FAs), which is followed by the development of retractile dendritic protrusions and induction of motility. The PDGF-specific actin reorganization was blocked by inhibition of Src-kinase and the 26S proteasome. PDGF induced Src-dependent association between the multifunctional transcription/translation regulator hnRNP-K and the mRNA-encoding myosin regulatory light-chain (MRLC)-interacting protein (MIR), a E(3)-ubiquitin ligase that is MRLC specific. This in turn rapidly increased MIR expression, and led to ubiquitination and proteasome-mediated degradation of MRLC. Downregulation of MIR by RNA muting prevented the reorganization of actin structures and severely reduced the migratory and wound-healing potential of PDGF-treated cells. The results show that activation of MIR and the resulting removal of diphosphorylated MRLC are essential for PDGF to instigate and maintain control over the actin-myosin-based contractile system in Swiss 3T3 fibroblasts. The PDGF induced protein destabilization through the regulation of hnRNP-K controlled ubiquitin -ligase translation identifies a novel pathway by which external stimuli can regulate phenotypic development through rapid, organelle-specific changes in the activity and stability of cytoskeletal regulators.
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PMID:PDGF regulates the actin cytoskeleton through hnRNP-K-mediated activation of the ubiquitin E3-ligase MIR. 1661 33

Translation initiation factor 4E (eIF4E) is a cytoplasmic cap-binding protein that is required for cap-dependent translation initiation. Here, we have shown that eIF4E is ubiquitinated primarily at Lys-159 and incubation of cells with a proteasome inhibitor leads to increased eIF4E levels, suggesting the proteasome-dependent proteolysis of ubiquitinated eIF4E. Ubiquitinated eIF4E retained its cap binding ability, whereas eIF4E phosphorylation and eIF4G binding were reduced by ubiquitination. The W73A mutant of eIF4E exhibited enhanced ubiquitination/degradation, and 4E-BP overexpression protected eIF4E from ubiquitination/degradation. Because heat shock or the expression of the carboxyl terminus of heat shock cognate protein 70-interacting protein (Chip) dramatically increased eIF4E ubiquitination, Chip may be at least one ubiquitin E3 ligase responsible for eIF4E ubiquitination.
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PMID:Ubiquitination and proteasome-dependent degradation of human eukaryotic translation initiation factor 4E. 1672 May 73

CHIP (C terminus of Hsc-70 interacting protein) is an E3 ligase that links the protein folding machinery with the ubiquitin-proteasome system and has been implicated in disorders characterized by protein misfolding and aggregation. Here we investigate the role of CHIP in protecting from ataxin-1-induced neurodegeneration. Ataxin-1 is a polyglutamine protein whose expansion causes spinocerebellar ataxia type-1 (SCA1) and triggers the formation of nuclear inclusions (NIs). We find that CHIP and ataxin-1 proteins directly interact and co-localize in NIs both in cell culture and SCA1 postmortem neurons. CHIP promotes ubiquitination of expanded ataxin-1 both in vitro and in cell culture. The Hsp70 chaperone increases CHIP-mediated ubiquitination of ataxin-1 in vitro, and the tetratricopeptide repeat domain, which mediates CHIP interactions with chaperones, is required for ataxin-1 ubitiquination in cell culture. Interestingly, CHIP also interacts with and ubiquitinates unexpanded ataxin-1. Overexpression of CHIP in a Drosophila model of SCA1 decreases the protein steady-state levels of both expanded and unexpanded ataxin-1 and suppresses their toxicity. Finally we investigate the ability of CHIP to protect against toxicity caused by expanded polyglutamine tracts in different protein contexts. We find that CHIP is not effective in suppressing the toxicity caused by a bare 127Q tract with only a short hemagglutinin tag, but it is very efficient in suppressing toxicity caused by a 128Q tract in the context of an N-terminal huntingtin backbone. These data underscore the importance of the protein framework for modulating the effects of polyglutamine-induced neurodegeneration.
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PMID:CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. 1683 71

Mammalian Sprouty (Spry) gene expression is rapidly induced upon activation of the FGF receptor signaling pathway in multiple cell types including cells of mesenchymal and epithelial origin. Spry2 inhibits FGF-dependent ERK activation and thus Spry acts as a feedback inhibitor of FGF-mediated proliferation. In addition, Spry2 interacts with the ring-finger-containing E3 ubiquitin ligase, c-Cbl, in a manner that is dependent upon phosphorylation of Tyr55 of Spry2. This interaction results in the poly-ubiquitination and subsequent degradation of Spry2 by the proteasome. Here, we describe the identification of another E3 ubiquitin ligase, human Seven-in-Absentia homolog-2 (SIAH2), as a Spry2 interacting protein. We show by yeast two-hybrid analysis that the N-terminal domain of Spry2 and the ring finger domain of SIAH2 mediated this interaction. Co-expression of SIAH2 resulted in proteasomal degradation of Spry1, 2, and to a lesser extent Spry4. The related E3 ubiquitin-ligase, SIAH1, had little effect on Spry2 protein stability when co-expressed. Unlike c-Cbl-mediated degradation of Spry2, SIAH2-mediated degradation was independent of phosphorylation of Spry2 on Tyr55. Spry2 was also phosphorylated on Tyr227, and phosphorylation of this residue was also dispensable for SIAH2-mediated degradation of Spry2. Finally, co-expression of SIAH2 with Spry2 resulted in a rescue of FGF2-mediated ERK phosphorylation. These data suggest a novel mechanism whereby Spry2 stability is regulated in a manner that is independent of tyrosine phosphorylation, and provides an addition level of control of Spry2 protein levels.
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PMID:Regulation of Sprouty2 stability by mammalian Seven-in-Absentia homolog 2. 1688 1

Recent studies have shed light on the ligand-dependent transactivation mechanisms of nuclear receptors (NRs). When the ligand dose is reduced, the transcriptional activity of NRs should be downregulated. Here we show that a ubiquitin-proteasome pathway plays a key role in turning off transcription mediated by estrogen receptor beta (ERbeta). ERbeta shows estrogen-dependent proteolysis, and its degradation is regulated by two regions in the receptor. The N-terminal 37-amino acid-region is necessary for the recruitment of the ubiquitin ligase, i.e., the carboxyl terminus of HSC70-interacting protein (CHIP), to degrade ERbeta. In contrast, the C-terminal F domain protects ligand-unbound ERbeta from proteolysis to abrogate proteasome association. Suppression of CHIP by interfering RNA inhibited this switching off of receptor-mediated transcription when the ligand dose was reduced. Our results suggest that after ligand withdrawal, the active form of the NR is selectively eliminated via ligand-dependent proteolysis to downregulate receptor-mediated transcription.
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PMID:Turning off estrogen receptor beta-mediated transcription requires estrogen-dependent receptor proteolysis. 1694 Jan 84

The 26S proteasome is a multisubunit protease responsible for regulated proteolysis in eukaryotic cells. It is composed of one catalytic 20S proteasome and two 19S regulatory particles attached on both ends of 20S proteasomes. Here, we describe the identification of Adrm1 as a novel proteasome interacting protein in mammalian cells. Although the overall sequence of Adrm1 has weak homology with the yeast Rpn13, the amino- and carboxyl-terminal regions exhibit significant homology. Therefore, we designated it as hRpn13. hRpn13 interacts with a base subunit Rpn2 via its amino-terminus. The majority of 26S proteasomes contain hRpn13, but a portion of them does not, indicating that hRpn13 is not an integral subunit. Intriguingly, we found that hRpn13 recruits UCH37, a deubiquitinating enzyme known to associate with 26 proteasomes. The carboxyl-terminal regions containing KEKE motifs of both hRpn13 and UCH37 are involved in their physical interaction. Knockdown of hRpn13 caused no obvious proteolytic defect but loss of UCH37 proteins and decrease in deubiquitinating activity of 26S proteasomes. Our results indicate that hRpn13 is essential for the activity of UCH37.
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PMID:A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. 1699 Aug

The yeast UbL-UBA protein Dsk2 is thought to act as a shuttle protein that delivers polyubiquitinated proteins to the proteasome. Previously, we identified Xenopus Dsk2-related protein, XDRP1, as a cyclin A-interacting protein. Using Xenopus egg extracts, we further characterized its two isoforms, XDRP1L and XDRP1S, with respect to cyclin binding and its degradation. Polyubiquitinated cyclins bound to the UBA domain of XDRP1L and XDRP1S, whereas monomeric cyclins A and B bound to the UbL domain of XDRP1S but not to XDRP1L. Binding of XDRP1S with monomeric cyclins was affected by a Cdc2-mediated phosphorylation of either the XDRP1S UbL domain or cyclins. Degradation of cyclin B was also prevented by XDRP1S in a Cdc2-sensitive manner. Loss of the XDRP1S-cyclin interaction allowed cyclins to be degraded in calcium-treated CSF extracts. These results suggest that the shuttling pathway via the UbL-UBA protein XDRP1 participates in degradation of mitotic cyclins in Xenopus eggs.
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PMID:A Cdc2-sensitive interaction of the UbL domain of XDRP1S with cyclin B mediates the degradation of cyclin B in Xenopus egg extracts. 1702 25

Mitotic Aurora-A is an oncogene, which undergoes a cell-cycle-dependent regulation of both its synthesis and degradation. Overexpression of Aurora-A leads to aneuploidy and cellular transformation in cultured cells. It has been shown that the cell-cycle-dependent turnover of Aurora-A is mediated by Cdh1 (CDC20 homologue 1) through the anaphase-promoting complex/cyclosome (APC/C)-ubiquitin-proteasome pathway. We have described previously the identification of an Aurora-A kinase interacting protein, AURKAIP1 (formerly described as AIP), which is also involved in the destabilization of Aurora-A through the proteasome-dependent degradation pathway. In an attempt to investigate the mechanism of AURKAIP1-mediated Aurora-A degradation, we report here that AURKAIP1 targets Aurora-A for degradation in a proteasome-dependent but Ub (ubiquitin)-independent manner. AURKAIP1 inhibits polyubiquitination of Aurora-A. A non-interactive AURKAIP1 mutant that cannot destabilize Aurora-A restores ubiquitination of Aurora-A. An A-box mutant of Aurora-A, which cannot be targeted for proteasome-dependent degradation by Cdh1, can still be degraded by AURKAIP1. Inhibition of cellular ubiquitination either by expression of dominant negative Ub mutants or by studies in ts-20 (temperature sensitive-20) CHO (Chinese-hamster ovary) cell line lacking the E1 Ub activating enzyme at the restrictive temperature, cannot abolish AURKAIP1-mediated degradation of Aurora-A. AURKAIP1 specifically decreases the stability of Aurora-A in ts-20 CHO cells at the restrictive temperature, while cyclinB1 and p21 are not affected. This demonstrates that there exists an Ub-independent alternative pathway for Aurora-A degradation and AURKAIP1 promotes Aurora-A degradation through this Ub-independent yet proteasome-dependent pathway.
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PMID:Aurora-A kinase interacting protein 1 (AURKAIP1) promotes Aurora-A degradation through an alternative ubiquitin-independent pathway. 1712 67


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