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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 26S proteasome complex plays a general role in turnover of both short and long lived proteins by specifically degrading ubiquitinated proteins. Recent evidence suggests that this large protease has more specific functions in a number of important cellular processes, ranging from activation of the transcription factor NFkB and antigen processing to transit through mitosis. We have identified a component of the 26S proteasome that interacts specifically with MB67, an orphan member of the nuclear hormone receptor superfamily. MIP224 (MB67 interacting protein) was isolated using the yeast two hybrid system and is apparently identical to the human 26S proteasome component TBP7. MIP224/TBP7 is one of several proteasomal proteins that share a strongly conserved ATPase domain (CAD) which is also present in a rapidly expanding superfamily of proteins with diverse functions. In yeast, MIP224 interacts specifically with MB67 and another closely related orphan receptor, but does not interact with several other receptor superfamily members tested. In mammalian cells, coexpression of MIP224 inhibits transactivation by MB67. MIP224 also interacts in yeast with other CAD proteins, including MSS1, which is proteasomal, and TRIP1, which is associated with transcriptional activation. This interaction of a proteasomal protein with a transcriptional protein suggests a previously unexpected link between the processes of protein degradation and transcriptional regulation.
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PMID:A component of the 26S proteasome binds on orphan member of the nuclear hormone receptor superfamily. 860 43

The COP9 complex, genetically identified in Arabidopsis as a repressor of photomorphogenesis, is composed of multiple subunits including COP9, FUS6 (also known as COP11) and the Arabidopsis JAB1 homolog 1 (AJH1) ([1-3]; unpublished observations). We have previously demonstrated the existence of the mammalian counterpart of the COP9 complex and purified the complex by conventional biochemical and immunoaffinity procedures [4]. Here, we report the molecular identities of all eight subunits of the mammalian COP9 complex. We show that the COP9 complex is highly conserved between mammals and higher plants, and probably among most multicellular eukaryotes. It is not present in the single-cell eukaryote Saccharomyces cerevisiae, however. All of the subunits of the COP9 complex contain structural features that are also present in the components of the proteasome regulatory complex and the translation initiation factor eIF3 complex. Six subunits of the COP9 complex have overall similarity with six distinct non-ATPase regulatory subunits of the 26S proteasome, suggesting that the COP9 complex and the proteasome regulatory complex are closely related in their evolutionary origin. Subunits of the COP9 complex include regulators of the Jun N-terminal kinase (JNK) and c-Jun, a nuclear hormone receptor binding protein and a cell-cycle regulator. This suggests that the COP9 complex is an important cellular regulator modulating multiple signaling pathways.
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PMID:The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex. 970 2

The nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR) gamma is a ligand-activated transcription factor that regulates several crucial biological processes such as adipogenesis, glucose homeostasis, and cell growth. It is also the functional receptor for a new class of insulin-sensitizing drugs, the thiazolidinediones, now widely used in the treatment of type 2 diabetes mellitus. Here we report that PPARgamma protein levels are significantly reduced in adipose cells and fibroblasts in response to specific ligands such as thiazolidinediones. Studies with several doses of different ligands illustrate that degradation of PPARgamma correlates well with the ability of ligands to activate this receptor. However, analyses of PPARgamma mutants show that, although degradation does not strictly depend on the transcriptional activity of the receptor, it is dependent upon the ligand-gated activation function 2 (AF2) domain. Proteasome inhibitors inhibited the down-regulation of PPARgamma and ligand activation enhanced the ubiquitination of this receptor. These data indicate that, although ligand binding and activation of the AF2 domain increase the transcriptional function of PPARgamma, these same processes also induce ubiquitination and subsequent degradation of this receptor by the proteasome.
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PMID:Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. 1074 14

Nuclear hormone receptors (NHRs) represent a superfamily of structurally related ligand-activated transcription factors, which regulate diverse biological activities like growth, development, and homeostasis. Recently, it has been demonstrated that certain members of the NHR superfamily are degraded through the ubiquitin-proteasome pathway in a ligand-dependent manner. Though the signal for the down-regulation via the ubiquitin-proteasome pathway is not yet known, phosphorylation at specific amino acid residues or coactivator binding to receptors could lead to their degradation by the 26S proteasome. Activation and degradation seems to be an engineered cyclic mechanism, which provides tight control over diverse cellular processes. The degradation process involves extensive loss of proteins and requires expenditure of cellular ATP. That seems to be inevitable for a more important aim, that is efficient and appropriate regulation of transcription. Down-regulation of receptors would lead to an attenuated transcriptional response because the number of receptor molecules available to activate transcription would decrease over time. One of the obvious reasons for down-regulating NHRs thus seems to be to prevent the cell from overstimulation by the hormones or other activating signals. Nuclear receptor turnover may also reset the transcriptional apparatus in preparation for a subsequent response. Since inhibition of the ubiquitin-proteasome degradation pathway disturbs the transcriptional activitity of some of the nuclear receptors such as estrogen (ER) and progesterone (PR) receptors, it is also possible that the degradation of NHRs may enable recycling of components of receptor-cofactor complexes and general transcriptional machinary. Understanding the mechanism of nuclear hormone receptor degradation and its relation to transcription may lead to novel insights of therapuetic intervention.
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PMID:Importance of the regulation of nuclear receptor degradation. 1148 64

Nuclear receptor coactivators (NRCoAs) are nuclear hormone receptor-associated regulatory proteins that interact with members of the nuclear receptor superfamily in the presence of their cognate ligand, enhancing their transcriptional activity. The identification of ubiquitin-proteasome pathway proteins as coactivators provides evidence that ubiquitin-proteasome-mediated protein degradation plays an integral role in eukaryotic gene transcription. It has also been observed that nuclear receptors themselves are ubiquitinated and degraded in a hormone-dependent manner and that ubiquitin-proteasome function is essential for most nuclear receptors to function as transactivators. Here, we show that specific ubiquitin-proteasome pathway enzymes target specific NRCoA proteins in vivo and in vitro. First, using a temperature-sensitive cell line that contains a thermolabile ubiquitin-activating E1 enzyme, we confirmed that NRCoA proteins are targets of the ubiquitin-proteasome pathway. Then using coimmunoprecipitation studies, we also demonstrate that in vivo, NRCoA proteins are ubiquitinated. Finally, we illustrate that in vitro, NRCoA ubiquitination and degradation depend on the ubiquitin-activating enzyme (E1) and on specific ubiquitin-conjugating enzymes (E2) for each of the coactivators.
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PMID:Specific ubiquitin-conjugating enzymes promote degradation of specific nuclear receptor coactivators. 1266 42

The importance of the ubiquitin proteasome pathway in higher eukaryotes has been well established in cell cycle regulation, signal transduction, and cell differentiation, but has only recently been linked to nuclear hormone receptor-regulated gene transcription. Characterization of a number of ubiquitin proteasome pathway enzymes as coactivators and observations that several nuclear receptors are ubiquitinated and degraded in the course of their nuclear activities provide evidence that ubiquitin proteasome-mediated protein degradation plays an integral role in eukaryotic transcription. In addition to receptors, studies have revealed that coactivators are ubiquitinated and degraded via the proteasome. The notion that the ubiquitin proteasome pathway is involved in gene transcription is further strengthened by the fact that ubiquitin proteasome pathway enzymes are recruited to the promoters of target genes and that proteasome-dependent degradation of nuclear receptors is required for efficient transcriptional activity. These findings suggest that protein degradation is coupled with nuclear receptor coactivation activity. It is possible that the ubiquitin proteasome pathway modulates transcription by promoting remodeling and turnover of the nuclear receptor-transcription complex. In this review, we discus the possible role of the ubiquitin proteasome pathway in nuclear hormone receptor-regulated gene transcription.
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PMID:Urban renewal in the nucleus: is protein turnover by proteasomes absolutely required for nuclear receptor-regulated transcription? 1467 36

Over 25 years ago, eukaryotic cells were shown to contain a highly specific system for the selective degradation of short-lived proteins, this system is known as the ubiquitin-proteasome pathway. In this pathway, proteins are targeted for degradation by covalent modification by a small highly conserved protein named ubiquitin. Ubiquitin-mediated degradation of regulatory proteins plays an important role in numerous cell processes, including cell cycle progression, signal transduction and transcriptional regulation. Recent experiments have shown that the ubiquitin-proteasome pathway is also involved in nuclear hormone receptor (NR)-mediated transcriptional regulation. The idea that the ubiquitin-proteasome pathway is involved in NR-mediated transcription is strengthened by experiments showing that ubiquitin-proteasome components are recruited to NR target gene promoters. However, it is not clear how these components modulate NR-mediated chromatin remodeling and gene expression. In this review, we postulate the role of the ubiquitin-proteasome pathway on NR-mediated chromatin remodeling and gene regulation based on the current knowledge from studies implicating the pathway in chromatin structure modifications that are applicable to NR function. Since evidence from this laboratory, using the glucocorticoid receptor responsive mouse mammary tumor virus (MMTV) promoter organized as chromatin, suggest that the ubiquitin-proteasome system may be involved in the elongation phase of transcription, we particularly concentrate on chromatin modifications associated with the elongation phase.
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PMID:Linking the ubiquitin-proteasome pathway to chromatin remodeling/modification by nuclear receptors. 1582 Oct 97

The ubiquitin-proteasome pathway (UPP) is known to degrade short-lived and misfolded proteins. Its role in cell cycle regulation and signal transduction is well established. However, the importance of the UPP in nuclear hormone receptor-regulated gene transcription is relatively new. Nuclear hormone receptors (NHRs) are degraded by the UPP both in the presence or absence of their cognate ligands. In recent years, it has become evident that NHR degradation and NHR-dependent transcription are interdependent processes. The link between these two processes has become stronger with the discovery of a number of ubiquitin-pathway enzymes and components of the proteasome acting as modulators of NHR function. Also, UPP enzymes and components of the proteasome are recruited to the promoters of NHR-responsive genes. Interestingly both coactivators and corepressors (coregulators) of NHRs are also targeted to the UPP for degradation. Furthermore, additional evidence also indicates that the UPP may be involved in the turnover of transcription complexes, thereby facilitating proper gene transcription. In this review we discuss and provide an update on the role of UPP in NHR-dependent gene regulation.
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PMID:Nuclear hormone receptor degradation and gene transcription: an update. 1608 69

Peroxisome proliferator-activated receptor (PPAR) alpha, gamma, and delta belong to the nuclear hormone receptor superfamily of ligand-activated transcription factors. PPARs regulate metabolic, developmental, and differentiation pathways and play important roles in human diseases, such as diabetes, atherosclerosis, cancer, and chronic inflammation. PPARs are the targets of drugs of widespread clinical use and represent promising targets for discovery of new therapeutics. The interaction of PPARs with the ubiquitin-proteasome system (UPS) has been the subject of limited investigation. The UPS plays an important role in regulating the levels and modulating ligand-dependent and-independent activity of nuclear receptors. This review highlights the current knowledge regarding the interactions of the UPS with PPARs and focuses on the differential regulation of the level and activity of the PPAR isotypes by the UPS in response to selective ligands. Understanding the connections between the UPS and PPARs can provide insights in the actions of existing drugs and raise the possibilities for development of more effective PPAR-based therapeutics.
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PMID:Control of peroxisome proliferator-activated receptor fate by the ubiquitinproteasome system. 1711 5

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily that plays a pivotal role in regulating inflammatory gene expression. The purpose of this study was to investigate the effects of coffee extract, 3-methyl-1,2-cyclopentanedione (3-MCP) on PPARs in vitro. Western blotting and luciferase assays using the PPAR response element (PPRE) construct revealed that 3-MCP induced PPARgamma-selective activation in YPEN-1 cells and that treatment with the PPARgamma selective antagonist, GW9662, was associated with a decrease in 3-MCP-induced PPARgamma activity. The 3-MCP also was shown to suppress reactive species generation and pro-inflammatory transcription factor NF-kappaB activity through PPARgamma activation. Theses results indicate that 3-MCP is a novel PPARgamma agonist and suggests that this agent may have a potential to minimize inflammation.
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PMID:Peroxisome proliferator-activated receptor gamma agonist action of 3-methyl-1,2-cyclopentanedione. 1793 88


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