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 human T-cell leukemia virus type I (HTLV-I) has been etiologically associated with the development of the adult T-cell leukemia (ATL) as well as degenerative neurologic syndrome termed tropical spastic paraparesis (TSP). HTLV-I encodes a potent transactivator protein termed Tax that appears to play an important role in the process of T-cell immortalization. Even though the mechanisms by which Tax induces transformation are still unknown, it seems likely that the ability of Tax to alter the expression of many cellular genes plays an important part in this process. Tax does not bind directly to DNA but rather deregulates the activity of cellular transcription factors. One family of host transcription factors whose activity is altered by Tax includes NF-kappa B/Rel. These transcription factors are post-transcriptionally regulated by their assembly with a second family of inhibitory proteins termed I kappa B that serve to sequester the NF-kappa B/Rel complexes in the cytoplasm. Upon cellular activation, I kappa B alpha is phosphorylated, polyubiquitinated, and degraded in the proteasome. This proteolytic event liberates NF-kappa B, permitting its rapid translocation into the nucleus where it binds to its cognate enhancer elements. Similarly, the p105 precursor of the NF-kappa B p50 subunit is also post-translationally processed in the proteasome. The mechanisms by which Tax activates NF-kappa B remain unclear, and findings presented in the literature are often controversial. We identified a physical interaction between Tax and the HsN3 subunit of the human proteasome. This raises the intriguing possibility that physical association of the HsN3 proteasome subunit with HTLV-I Tax coupled with the independent interaction of Tax with either p100 or p65-I kappa B alpha targets these cytoplasmic NF-kappa B/Rel complexes to the proteasome for processing.
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PMID:Interaction of HTLV-I Tax with the human proteasome: implications for NF-kappa B induction. 879 8

The switch from short-term to long-term facilitation of the synapses between sensory and motor neurons mediating gill and tail withdrawal reflexes in Aplysia requires CREB-mediated transcription and new protein synthesis. We isolated several downstream genes, one of which encodes a neuron-specific ubiquitin C-terminal hydrolase. This rapidly induced gene encodes an enzyme that associates with the proteasome and increases its proteolytic activity. This regulated proteolysis is essential for long-term facilitation. Inhibiting the expression or function of the hydrolase blocks induction of long-term but not short-term facilitation. We suggest that the enhanced proteasome activity increases degradation of substrates that normally inhibit long-term facilitation. Thus, through induction of the hydrolase and the resulting up-regulation of the ubiquitin pathway, learning recruits a regulated form of proteolysis that removes inhibitory constraints on long-term memory storage.
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PMID:Ubiquitin C-terminal hydrolase is an immediate-early gene essential for long-term facilitation in Aplysia. 909 20

Activating transcription factor 2 (ATF2) is regulated by phosphorylation via the Jun N-terminal kinase, and its binding activity is markedly induced at late stages of T and B lymphocyte activation (Feuerstein, N., Firestein, R., Aiyer, N., Xiao, H., Murasko, D., and Cristofalo, V. (1996) J. Immunol. 156, 4582-4593). To identify proteins that interact specifically with ATF2 in lymphocytes, the yeast two-hybrid interaction system was employed using ATF2 cDNA as a "bait." In two separate screenings, a clone was identified that revealed a novel sequence with homology to several members of the ubiquitin-conjugating enzyme family. An identical sequence was recently reported as the human homolog of the yeast UBC9, hUBC9. Northern blot analysis revealed a 1.3-kilobase RNA transcript, which showed differential levels of expression in various human tissues and a moderate induction after a 48-h stimulation of peripheral blood T lymphocytes. An antibody that was generated against the bacterially expressed glutathione S-transferase-hUBC9 detected a approximately 19-kDa protein, which localizes predominantly in the nuclei of T cells. Further quantitative assays using the yeast two-hybrid system confirmed a high and specific level of interaction of hUBC9 with ATF2 and lack of interaction with lamin or control vectors. Two other cyclic AMP-responsive element-binding transcription factors, CREB and ATF1, also showed significant levels of interaction with hUBC9. However, this interaction was severalfold lower as compared with ATF2. Far Western blot analysis confirmed the specific binding of ATF2 and hUBC9 also in vitro. Evidence is presented that indicates a physiological significance for the interaction of hUBC9 with ATF2. (a) We show that ATF2 is ubiquitinated in vivo and in vitro, and (b) ATF2 ubiquitination in vitro is facilitated by addition of purified hUBC9. (c) ATF2 is shown to undergo a proteolytic process, which is rapidly regulated upon T cell activation concomitant with induction of ATF2 phosphorylation. (d) A proteasome inhibitor delays the down-regulation of ATF2 phophorylation after T cell activation. Taken collectively, these results implicate a role for hUBC9 and the ubiquitin/proteasome pathway in regulation of ATF2 in T cells.
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PMID:Association of activating transcription factor 2 (ATF2) with the ubiquitin-conjugating enzyme hUBC9. Implication of the ubiquitin/proteasome pathway in regulation of ATF2 in T cells. 948 27

The ubiquitin-proteasome pathway regulates gene expression through protein degradation. Here we show that the F-box protein betaTrCP, the receptor component of the SCF E3 ubiquitin ligase responsible for IkappaBalpha and beta-catenin degradation, is colocalized in the nucleus with ATF4, a member of the ATF-CREB bZIP family of transcription factors, and controls its stability. Association between the two proteins depends on ATF4 phosphorylation and on ATF4 serine residue 219 present in the context of DSGXXXS, which is similar but not identical to the motif found in other substrates of betaTrCP. ATF4 ubiquitination in HeLa cells is enhanced in the presence of betaTrCP. The F-box-deleted betaTrCP protein behaves as a negative transdominant mutant that inhibits ATF4 ubiquitination and degradation and, subsequently, enhances its activity in cyclic AMP-mediated transcription. ATF4 represents a novel substrate for the SCF(betaTrCP) complex, which is the first mammalian E3 ubiquitin ligase identified so far for the control of the degradation of a bZIP transcription factor.
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PMID:ATF4 degradation relies on a phosphorylation-dependent interaction with the SCF(betaTrCP) ubiquitin ligase. 1123 52

Spinal and bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) are representative motor neuron diseases in which selective neuronal degeneration occurs. In this paper, some molecular aspects are discussed related to the pathogenesis of the neuronal degeneration. SBMA is a an X-linked neurodegenerative disease caused by the expansion of a CAG repeat in the first exon of the androgen receptor (AR) gene. To date, eight CAG repeat diseases have been identified, including spinal and bulbar muscular atrophy (SBMA), Huntington's disease (HD), dentatorubralpallidoluysian atrophy (DRPLA), and five spinocerebellar ataxias (SCAs 1, 2, 3, 6, 7). These disorders very likely share a common pathogenesis caused by the gain of a toxic function associated with the expanded polyglutamine tract. Several mechanisms have been postulated as a pathogenic process for neurodegeneration caused by the expanded polyglutamine tract. In SBMA, nuclear inclusions (NIs) containing mutant AR protein have been observed in regions of SBMA central nervous system susceptible to degenerations. Transcriptional factors or their cofactors, such as CREB or creb-binding protein (CBP) sequestrated in NIs, may alter the major intracellular transcriptional signal transduction and ultimately may result in neuronal degeneration. The components in the ubiquitin-proteasome pathway also colocalized in NIs and contribute to the path-ogenesis of SBMA. We generated two types of transgenic mice expressing 239Q under the control of human AR promoter and full-size AR containing 97Q. Marked neurological symptoms and extensive nuclear inclusions were observed in both transgenic lines, but there was no neuronal cell death, suggesting that major neurological phenotype was due to neuronal dysfunction instead of neuronal cell death. As for the therapeutic strategies, the overexpression of Hsp70 and Hsp40 chaperones acted together to protect a cultured neuronal cell model of SBMA from inclusion formation and cell death by mutant AR with expanded polyglutamine tract. In regard to ALS, we are screening the gene expression profiles of the motor neurons from the human ALS and SOD transgenic mouse spinal cord. Motor neurons were microdissected from the spinal cord samples by a lazer-captured microdissection system. Gene expression profiles were screened by cDNA microarray and molecular indexing. Several new molecules were cloned and characterized for their function and relation to neuronal cell dysfunction. Some molecules characterized in this procedure were briefly described.
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PMID:[Molecular pathogenesis of motor neuron diseases]. 1140 Mar 22

Cellular CCAAT/enhancer binding protein alpha (C/EBPalpha) promotes cellular differentiation and has antimitotic activities involving cell cycle arrest at G(1)/S through stabilization of p21(CIP-1)/WAF1 and through transcriptional activation of the p21 promoter. The Epstein-Barr virus lytic-cycle transactivator protein ZTA is known to arrest the host cell cycle at G(1)/S via a p53-independent p21 pathway, but the detailed molecular mechanisms involved have not been defined. To further evaluate the role of ZTA in cell cycle arrest, we constructed a recombinant adenovirus vector expressing ZTA (Ad-ZTA), whose level of expression at a low multiplicity of infection in normal human diploid fibroblast (HF) cells was lower than or equal to the physiological level seen in Akata cells lytically induced by EBV (EBV-Akata cells). Fluorescence-activated cell sorting analysis of HF cells infected with Ad-ZTA confirmed that G(1)/S cell cycle arrest occurred in the majority of ZTA-positive cells, but not with an adenovirus vector expressing green fluorescent protein. Double-label immunofluorescence assays (IFA) performed with Ad-ZTA-infected HF cells revealed that only ZTA-positive cells induced the expression of both endogenous C/EBPalpha and p21 and blocked the progression into S phase, as detected by a lack of incorporation of bromodeoxyuridine. The stimulation of endogenous ZTA protein expression either through treatment with tetradecanoyl phorbol acetate in D98/HR1 cells or through B-cell receptor cross-linking with anti-immunoglobulin G antibody in EBV-Akata cells also coincided with the induction of both C/EBPalpha and p21 and their mRNAs, as assayed by Northern blot, Western blot, and IFA experiments. Mechanistically, the ZTA protein proved to directly interact with C/EBPalpha by coimmunoprecipitation in EBV-Akata cells and with DNA-bound C/EBPalpha in electrophoretic mobility shift assay experiments, and the in vitro interaction domain encompassed the basic leucine zipper domain of ZTA. ZTA also specifically protected C/EBPalpha from degradation in a protein stability assay with a non-EBV-induced Akata cell proteasome extract. Furthermore, both C/EBPalpha and ZTA were found to specifically associate with the C/EBPalpha promoter in chromatin immunoprecipitation assays, but the interaction with ZTA appeared to be mediated by C/EBPalpha because it was abolished by clearing with anti-C/EBPalpha antibody. ZTA did not bind to or activate the C/EBPalpha promoter directly but cooperatively enhanced the positive autoregulation of the C/EBPalpha promoter by cotransfected C/EBPalpha in transient luciferase reporter gene assays with Vero and HeLa cells as well as with DG75 B lymphocytes. Similarly, ZTA alone had little effect on the p21 promoter in transient reporter gene assays, but in the presence of cotransfected C/EBPalpha, ZTA enhanced the level of C/EBPalpha activation. This effect proved to require a previously unrecognized region in the proximal p21 promoter that contains three high-affinity C/EBPalpha binding sites. Finally, in C/EBPalpha-deficient mouse embryonic fibroblasts (MEF), Ad-ZTA was unable to induce either p21 or G(1) arrest, whereas it was able to induce both in wild-type MEF. Overall, we conclude that C/EBPalpha is essential for at least one pathway of ZTA-induced G(1) arrest during EBV lytic-cycle DNA replication and that this process involves a physical piggyback interaction between ZTA and C/EBPalpha leading to greatly enhanced C/EBPalpha and p21 levels through both transcriptional and posttranslational mechanisms.
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PMID:CCAAT/enhancer binding protein alpha interacts with ZTA and mediates ZTA-induced p21(CIP-1) accumulation and G(1) cell cycle arrest during the Epstein-Barr virus lytic cycle. 1250 63

Experience-dependent remodeling of the postsynaptic density (PSD) is critical for synapse formation and plasticity in the mammalian brain. Here, in cultured rat hippocampal neurons, I found long-lasting, global changes in the molecular composition of the PSD dictated by synaptic activity. These changes were bidirectional, reversible, modular, and involved multiple classes of PSD proteins. Moreover, activity-dependent remodeling was accompanied by altered protein turnover, occurred with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and required proteasome-mediated degradation. These modifications, in turn, reciprocally altered synaptic signaling to the downstream effectors CREB (cyclic AMP response element binding protein) and ERK-MAPK (extracellular signal regulated kinase-MAP kinase). These results indicate that activity regulates postsynaptic composition and signaling through the ubiquitin-proteasome system, providing a mechanistic link between synaptic activity, protein turnover and the functional reorganization of synapses.
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PMID:Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system. 3025 Feb 64

The major phosphorylation sites of the bovine papillomavirus E2 transactivator protein are two serine residues, 298 and 301, that are located in a flexible hinge region between the DNA binding and transactivation domains. Phosphorylation of serine residue 301 promotes ubiquitination and rapid degradation of the E2 protein by the proteasome pathway. To understand the mechanism through which phosphorylation regulates the intracellular levels of this unique papillomavirus regulatory protein, we have carried out an extensive mutational analysis of the region surrounding the phosphorylation sites of the E2 protein. Our results indicate that casein kinase II phosphorylates serine 301. However, phosphorylation of serine 301 is not a sufficient recognition motif for proteasomal degradation; other residues that directly surround the phosphorylation sites are crucial for E2 degradation. The phenotypes of E2 proteins mutated in this region indicate that phosphorylation of serine 301 induces a conformational change that leads to degradation of the E2 protein. In support of this model, circular dichroism studies of the conformational tendencies of peptides from this region indicate that phosphorylation at position 301 decreases the local thermodynamic stability of this region. Thus, this region appears to have evolved to display a marginal local thermodynamic stability that can be regulated by phosphorylation, leading to targeted degradation of the E2 protein.
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PMID:Casein Kinase II phosphorylation-induced conformational switch triggers degradation of the papillomavirus E2 protein. 1501 86

Human T-cell leukemia virus type 1 and type 2 (HTLV-1/2) are related retroviruses that infect T-lymphocytes. Whereas HTLV-1 infection can cause leukemia, HTLV-2 has not been demonstrated to be the agent of a hematological malignant disease. Nevertheless, the virally encoded Tax-1 and Tax-2 transactivators display a high percentage of similarity. Tax-1 is a shuttling protein that contains a noncanonical nuclear localization signal as well as a nuclear export signal. The presence of the nuclear localization signal and the nuclear export signal domains in the Tax-2 sequence has not been determined. The distribution of Tax-2 in infected cells is not known but has been assumed to be similar to that of Tax-1. By using a Tax-2-specific antibody, we report here that Tax-2 is located predominantly in the cytoplasm of the HTLV-2 immortalized or transformed infected T-cells. These results were confirmed after transient transfection of untagged Tax-1 and Tax-2 constructs, histidine tag Tax1/Tax2, GFP-Tax, and Tax-GFP fusion constructs in several cell lines. We show that this unanticipated localization is not due to a default in the Tax-2 nuclear localization signal functions nor to major differences in Tax-2 versus Tax-1 binding to the IKKgamma/NEMO protein. In addition, we demonstrate that inhibiting the proteasome results in a relocalization of Tax-1 in the cytoplasm, similar to that of Tax-2. By using a series of Tax-1/Tax-2 chimeras, we determined that the minimal domain that is necessary for Tax-2 peculiar distribution encompasses amino acids 90-100. Finally, we show a high correlation between intracellular localization of Tax and their NF-kappaB or CREB transactivating ability.
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PMID:A 10-amino acid domain within human T-cell leukemia virus type 1 and type 2 tax protein sequences is responsible for their divergent subcellular distribution. 1526 14

The CBP [CREB (cAMP-response-element-binding protein)-binding protein]/p300 acetyltransferases function as transcriptional co-activators and play critical roles in cell differentiation and proliferation. Accumulating evidence shows that alterations of the CBP/p300 protein levels are linked to human tumours. In the present study, we show that the levels of the CBP/p300 co-activators are decreased dramatically by continuous PDGF (platelet-derived growth factor) and Ras signalling pathway activation in NIH 3T3 fibroblasts. This effect occurs by reducing the expression levels of the CBP/p300 genes. In addition, CBP and p300 are degraded by the 26 S proteasome pathway leading to an overall decrease in the levels of the CBP/p300 proteins. Furthermore, we provide evidence that Mdm2 (murine double minute 2), in the presence of active H-Ras or N-Ras, induces CBP/p300 degradation in NIH 3T3 cells. These findings support a novel mechanism for modulating other signalling transduction pathways that require these common co-activators.
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PMID:The histone acetyltransferases CBP/p300 are degraded in NIH 3T3 cells by activation of Ras signalling pathway. 1670 73


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