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)

The COP9 signalosome is a highly conserved protein complex initially identified as a repressor of photomorphogenesis. Here, we report that subunit 6 of the Arabidopsis COP9 signalosome is encoded by a family of two genes (CSN6A and CSN6B) located on chromosomes V and IV, respectively. The CSN6A and CSN6B proteins share 87% amino acid identity and contain a MPR1p and PAD1p N-terminal (MPN) domain at the N-terminal region. The CSN6 proteins share homology with CSN5 and belong to the Mov34 superfamily of proteins. CSN6 proteins present only in the complex form and coimmunoprecipitate with other known subunits of the COP9 signalosome. Partial loss-of-function strains of the COP9 signalosome created by antisense and cosuppression with CSN6A exhibit diverse developmental defects, including homeotic organ transformation, symmetric body organization, and organ boundary definition. Protein blot analysis revealed that the defective plants accumulate significant amounts of ubiquitinated proteins, supporting the conclusion that the COP9 signalosome regulates multifaceted developmental processes through its involvement in ubiquitin/proteasome-mediated protein degradation.
...
PMID:Molecular characterization of subunit 6 of the COP9 signalosome and its role in multifaceted developmental processes in Arabidopsis. 1170 77

The COP9 signalosome (CSN) is an eight-subunit complex that regulates multiple signaling and cell cycle pathways. Here we link the CSN to the degradation of Cyclin E, which promotes the G1-S transition in the cell cycle and then is rapidly degraded by the ubiquitin-proteasome pathway. Using CSN4 and CSN5/Jab1 mutants, we show that the CSN acts during Drosophila oogenesis to remove Nedd8 from Cullin1, a subunit of the SCF ubiquitin ligase. Overexpression of Cyclin E causes similar defects as mutations in CSN or SCF(Ago) subunits: extra divisions or, in contrast, cell cycle arrest and polyploidy. Because the phenotypes are so similar and because CSN and Cyclin E mutations reciprocally suppress each other, Cyclin E appears to be the major target of the CSN during early oogenesis. Genetic interactions among CSN, SCF, and proteasome subunits further confirm CSN involvement in ubiquitin-mediated Cyclin E degradation.
...
PMID:The COP9 signalosome promotes degradation of Cyclin E during early Drosophila oogenesis. 1273 5

The COP9 signalosome (CSN) is composed of eight distinct subunits and is highly homologous to the lid sub-complex of the 26S proteasome. CSN was initially defined as a repressor of photomorphogenesis in Arabidopsis, and it has now been found to participate in diverse cellular and developmental processes in various eukaryotic organisms. Recently, CSN was revealed to have a metalloprotease activity centered in the CSN5/Jab1 subunit, which removes the post-translational modification of a ubiquitin-like protein, Nedd8/Rub1, from the cullin component of SCF ubiquitin E3 ligase (i.e., de-neddylation). In addition, CSN is associated with de-ubiquitination activity and protein kinase activities capable of phosphorylating important signaling regulators. The involvement of CSN in a number of cellular and developmental processes has been attributed to its control over ubiquitin-proteasome-mediated protein degradation.
...
PMID:The COP9 signalosome. 1457 May 71

DNA topoisomerase (topo) IIalpha, an essential enzyme for cell proliferation, is targeted to a proteasome-dependent degradation pathway when human tumor cells are glucose-starved. Here we show that the topo IIalpha destabilization depends on the newly identified domain, GRDD (glucose-regulated destruction domain), which was mapped to the N-terminal 70-170 amino acid sequence. Indeed, the deletion of GRDD conferred a stable feature on topo IIalpha, whereas the fusion of GRDD rendered green fluorescent protein unstable under glucose starvation conditions. Nuclear localization was a prerequisite for GRDD function, because the inhibition of nuclear translocation resulted in the suppression of GRDD-mediated topo IIalpha degradation. Further, GRDD was identified as an interactive domain for Jab1/CSN5, which promoted the degradation of topo IIalpha in a manner dependent on the MPN (Mpr1p/Prd1p N terminus) domain. Depleting Jab1/CSN5 by antisense oligonucleotide and treating cells with the CSN-associated kinase inhibitor, curcumin, inhibited topo IIalpha degradation induced by glucose starvation. These findings demonstrate that GRDD can act as a stress-activated degron for regulating topo IIalpha stability, possibly through interaction with the MPN domain of Jab1/CSN5.
...
PMID:Interaction between glucose-regulated destruction domain of DNA topoisomerase IIalpha and MPN domain of Jab1/CSN5. 1512 3

The COP9 signalosome (CSN) is a conserved multiprotein complex, with an important developmental role in several organisms, ranging from plants to mammalians. The influence of the CSN on several signaling and developmental processes has been ascribed to its ability to regulate degradation of a number of signaling proteins by the ubiquitin-proteasome system. The CSN controls the function of the SCF ubiquitin-ligase complex through an enzymatic activity that removes the small ubiquitin-like molecule NEDD8 from the cullin component of the SCF and that requires subunit 5 of the CSN (JAB1/CSN5). Mutants of the CSN display early embryonic lethality, a feature that has hindered further characterization of the role of the CSN at later stages of mammalian development. Here we report the analysis of JAB1/CSN5 expression pattern in the mouse embryo. At early stages of development, JAB1/CSN5 transcripts were present with low expression levels in all tissues. Preferential expression in selected tissues was detected starting at E11.5, with higher levels in dorsal root ganglia; at later stages, prominent expression of JAB1/CSN5 transcripts was observed in cranial nerve, spinal and sympathetic ganglia, as well as in selected epithelia, such as the oral and the olfactory epithelium. In the adult brain, additional areas of JAB1/CSN5 expression were the hippocampus and the Purkinjie layer of the cerebellum. We also analyzed the temporal and spatial expression pattern of NEDD8, and found that it substantially overlapped JAB1/CSN5 expression at all stages analyzed, supporting the model of a functional interaction between the two proteins during developmental processes.
...
PMID:Expression pattern of the JAB1/CSN5 gene during murine embryogenesis: colocalization with NEDD8. 1518 9

Recently, evidence is accumulating pointing to a function of the COP9 signalosome (CSN) in regulation of ubiquitination by specific ubiquitin ligases. Here, we demonstrate by mammalian two-hybrid analysis that the transcriptional regulators and substrates of the ubiquitin system Id1 and Id3, but not Id2 and Id4, bind to the CSN subunit CSN5. Pull-down experiments revealed that Id3 physically interacts with the CSN complex. Additional far Western and pull-down studies with Id3 support our two-hybrid data and show that the transcription regulator can bind to CSN5 and CSN7. Recombinant Id3 is not phosphorylated by the CSN-associated kinases CK2 and PKD. However, it inhibits c-Jun and CSN2 phosphorylation by the isolated CSN complex and by the recombinant CK2. The inhibitors of CSN associated kinases, curcumin and emodin, significantly induce ubiquitination and proteasome-dependent degradation of transiently expressed Id3 in HeLa cells. Proteasome-dependent degradation of endogenous Id1 in HeLa cells is also stimulated by treatment with curcumin or emodin. Ubiquitination of Id3 is shown directly by cotransfection of HeLa cells with Id3 and His-ubiquitin cDNA. Curcumin increased Id3-ubiquitin conjugate formation, as shown by Western blotting and His-pull-downs. In addition, overexpression of CSN2 leads to stabilization of Id3 protein. On the basis of these data, it is speculated that CSN-mediated phosphorylation inhibits ubiquitination of Id1 and Id3.
...
PMID:Ubiquitin-dependent degradation of Id1 and Id3 is mediated by the COP9 signalosome. 1545 66

Anti-HER2 antibody trastuzumab is emerging as a frontline therapy for patients with metastatic breast cancers that overexpress HER2. Understanding the molecular mechanisms by which the antibody inhibits tumor growth should permit the design of even more effective trastuzumab-based protocols. Several groups including our own have demonstrated that induction of cyclin-dependent kinase (CDK) inhibitor p27Kip1 protein is one of the key mechanisms of action of HER2-targeting antibodies. In this review, we discuss currently available data regarding the multiple signaling targets and pathways by which HER2-targeting antibodies upregulate p27Kip1 protein in breast cancer cells that overexpress HER2. Anti-HER2 antibodies inhibit HER2-mediated signaling in cancer cells, ultimately upregulating the levels and activity of p27Kip1 protein. At least six signaling targets and pathways are modulated by trastuzumab. By inhibiting CDK2 and decreasing Thr187 phosphorylation of p27Kip1, trastuzumab abrogates targeting of SCF-ubiquitin E3 ligase and minimizes proteasome degradation of p27Kip1. By inhibiting AKT and human kinase interacting stathmin (hKIS), trastuzumab blocks Thr157-, Thr198- and Ser10-induced p27Kip1 translocation from the nucleus to the cytosol, which increases the inhibitory effect of p27Kip1. By inhibiting Jun activation domain-binding protein 1 (Jab1) trastuzumab increases nuclear retention of p27Kip1. By inhibiting cyclin D and c-Myc, trastuzumab releases the sequestrated p27bKip1 protein from cyclin D-CDK4/6 complexes and increase the effect of p27Kip1 on CDK2-cyclin E complexes. By stimulating minibrain related kinase (MIRK), trastuzumab stabilizes p27Kip1 in the nucleus, which increases inhibitory action of p27Kip1 on CDK2. The targets and pathways affected by trastuzumab work in concert to maximize the expression and inhibitory effect of p27Kip1, which leads to cell cycle G1 arrest and growth inhibition.
...
PMID:HER2-targeting antibodies modulate the cyclin-dependent kinase inhibitor p27Kip1 via multiple signaling pathways. 1561 42

TRC8 encodes an E3-ubiquitin ligase disrupted in a family with hereditary renal cell carcinoma (RCC). We previously reported that Drosophila Trc8 (DTrc8) overexpression inhibits growth and that human and fly proteins interact with with the COP9 signalosome (CSN) subunit JAB1/CSN5. However, further mechanistic evidence linking DTrc8 growth suppression to CSN5 was lacking. Here, we show that haploinsufficiency of CSN5, or a T100I point mutation (CSN5(3)), relieved growth suppression by DTrc8, whereas CSN5(1) (E160V) and CSN5(2) (G147D) mutations had no effect. The strength of yeast two-hybrid interactions between DTrc8 and CSN5 were in complete agreement with the observed phenotypes. DTrc8 overexpression resulted in elevated levels of CSN5 and CSN7, but had no effect on NEDD8-modified Cul-1. In contrast to CSN5, heterozygosity for CSN4null had no effect on the DTrc8 phenotype. We also looked for genetic interactions between DTrc8 and other MPN domain proteins in the CSN and 26S proteasome lid. CSN6 haploinsufficiency restored growth, whereas reduction of proteasome subunits RPN8 or RPN11 had no effect. DTrc8 expression increased the level of digitonin-extractable CSN complex, consistent with elevated levels of CSN5 and 7. Our genetic results confirm that DTrc8-induced growth suppression is CSN5 (and CSN6) dependent. While there was no obvious influence on CSN deneddylation activity, the increase in CSN subunits and holocomplex suggests that TRC8 modulates signalosome levels or compartmentalization.
...
PMID:Growth suppression induced by the TRC8 hereditary kidney cancer gene is dependent upon JAB1/CSN5. 1573 86

Here, we show that estrogen receptor alpha (ERalpha) coimmunoprecipitates with CSN5/Jab1, a subunit of the COP9 signalosome (CSN), and that overexpression of CSN5/Jab1 causes an increase in ligand-induced ERalpha degradation. Inhibition of either the kinase activity associated with the CSN complex by curcumin or of nuclear export by leptomycin B (LMB) impaired estradiol-induced ERalpha degradation by the proteasome. Degradation of ERalpha induced by the pure antagonist ICI 182,780 (ICI) was blocked by curcumin but not by LMB, indicating that in the presence of ICI, ERalpha is degraded by a nuclear fraction of the proteasome. In addition, we observed that curcumin inhibited estradiol-induced phosphorylation of ERalpha. The use of three inhibitors of ERalpha degradation that target different steps of the estrogen response pathway (inhibition of the CSN-associated kinase, nuclear export, and proteasome) suggests that a phosphorylation event inhibited by curcumin is necessary for ERalpha binding to its cognate DNA target. Our results demonstrate that transcription per se is not required for ERalpha degradation and that assembly of the transcription-initiation complex is sufficient to target ERalpha for degradation by the proteasome.
...
PMID:CSN5/Jab1 is involved in ligand-dependent degradation of estrogen receptor {alpha} by the proteasome. 1589 41

To understand how cells respond to altered oxygenation, a frequent experimental paradigm is to isolate known components of bona fide oxygen responsive proteins. Recent studies have shown that a protein known as CSN5 or JAB1 interacts with both the HIF-1alpha oxygen-responsive transcription factor and its oxygen-dependent regulator, the Von Hippel-Lindau (pVHL) tumor suppressor. CSN5 is a component of the COP9 Signalosome (CSN) which is a multi-subunit protein that has high homology to the lid of the 19S lid of 26S proteasome. The exact function of the CSN5 interaction with pVHL and HIF-1alpha remains to be fully elucidated, but it is clear that the interaction is both oxygen dependent and that CSN5 may play different roles under oxic and hypoxic responses. Further, evidence has also been published indicating that pVHL can be potentially post-translationally modified by CSN5 (de-neddylation) and that CSN5 transcription is regulated by hypoxia as are many of the key pVHL/HIF-1alpha regulatory genes such as the PHDs and OS-9. This review will give a broad overview of known CSN5 and COP9 Signalosome functions and how these functions impact the pVHL/HIF-1alpha signaling complex and potentially other oxygen-sensitive response networks.
...
PMID:COPing with hypoxia. 1591 8


1 2 3 4 5 6 Next >>

---