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)

We present an integrated model of hERalpha-mediated transcription where both unliganded and liganded receptors cycle on estrogen-responsive promoters. Using ChIP, FRAP, and biochemical analysis we evaluate hERalpha at several points in these cycles, establishing the ubiquitination status and subnuclear distribution of hERalpha, its mobility, the kinetics of transcriptional activation, and the cyclic recruitment of E3 ligases and the 19S regulatory component of the proteasome. These experiments, together with an evaluation of the inhibition of transcription and proteasome action, demonstrate that proteasome-mediated degradation and hERalpha-mediated transactivation are inherently linked and act to continuously turn over hERalpha on responsive promoters. Cyclic turnover of hERalpha permits continuous responses to changes in the concentration of estradiol.
...
PMID:Cyclic, proteasome-mediated turnover of unliganded and liganded ERalpha on responsive promoters is an integral feature of estrogen signaling. 1266 52

The potent oncoprotein and receptor tyrosine kinase ErbB2 is remarkable because it resists efficient downregulation. However, ErbB2 can be downregulated by the HSP-90 inhibitor geldanamycin, but the underlying cellular mechanisms are uncertain. Apparently, delivery of ErbB2 to lysosomes, cleavage of the ErbB2 kinase domain and proteasomal activity are all processes that are involved. Using a non-invasive confocal microscopical assay allowing quantitative analysis of ErbB2 internalization in cell populations, we show that whereas ErbB2 is resistant to internalization in untreated SK-BR-3 cells, geldanamycin stimulates internalization and subsequent degradation in lysosomes. This process depends on proteasomal activity, which is a regulatory upstream event in ErbB2 internalization rather than the actual mechanism of degradation. ErbB2 can be internalized as a full-length protein, thus cleavage of the ErbB2 kinase domain is not a requirement for geldanamycin-stimulated internalization. Moreover, as shown by FRAP (fluorescence recovery after photobleaching) and electron microscopy, geldanamycin induces an increase in the amount of mobile ErbB2 and a redistribution of ErbB2 in the plasma membrane making the receptor accessible to endocytosis. Cells with most ErbB2 endocytosis also have the highest fraction of mobile ErbB2. It is concluded that geldanamycin stimulates internalization of full-length ErbB2 in a proteasome-dependent manner leading to lysosomal degradation.
...
PMID:Geldanamycin stimulates internalization of ErbB2 in a proteasome-dependent way. 1635 62

Rapamycin and its analogues are being tested as new antitumor agents. Rapamycin binds to FKBP-12 and this complex inhibits the activity of FRAP/mammalian target of rapamycin, which leads to dephosphorylation of 4EBP1 and p70 S6 kinase, resulting in blockade of translation initiation. We have found that RAP inhibits the growth of HER-2-overexpressing breast cancer cells. The phosphorylation of mammalian target of rapamycin, p70 S6 kinase, and 4EBP1 is inhibited by rapamycin and cells are arrested in the G1 phase, as determined by growth assays, fluorescence-activated cell sorting analysis, and bromodeoxyuridine incorporation studies. Rapamycin causes down-regulation of cyclin D3 protein, retinoblastoma hypophosphorylation, loss of cyclin-dependent kinase (cdk) 4, cdk6, and cdk2 activity. The half-life of cyclin D3 protein decreases after rapamycin treatment, but not its synthesis, whereas the synthesis or half-life of cyclin D1 protein is not affected by the drug. Additionally, rapamycin caused accumulation of ubiquitinated forms of cyclin D3 protein, proteasome inhibitors blocked the effect of rapamycin on cyclin D3, and rapamycin stimulated the activity of the proteasome, showing that the effect of rapamycin on cyclin D3 is proteasome proteolysis dependent. This effect depends on the activity of HER-2 because Herceptin, a neutralizing antibody against HER-2, is able to block both the induction of proteasome activity and the cyclin D3 down-regulation due to rapamycin. Furthermore, inhibition of HER-2 gene expression by using small interfering RNA blocked the rapamycin effects on cyclin D3. These data indicate that rapamycin causes a G1 arrest in HER-2-overexpressing breast cancer cells that is associated with a differential destabilization and subsequent down-regulation of cyclin D3 protein.
...
PMID:Cyclin D3 is down-regulated by rapamycin in HER-2-overexpressing breast cancer cells. 1698 50

MR is a hormone-activated transcription factor that carries a strong synergy inhibitory function at its N-terminus. Using this region as bait in a yeast two-hybrid screening, we isolated major components of the sumoylation pathway, including the SUMO-1-conjugating enzyme Ubc9, and SUMO-1 itself. We found that MR interacts with both, Ubc9 and SUMO-1 in mammalian cells, and that the receptor is sumoylated at four acceptor sites which are clustered within its AF-1 domain. We observed that MR can be poly-ubiquitinated and that proteasome activity is essential for MR-activated transcription. Disruption of the SUMO-1 attachment sites abolished MR sumoylation but interfered with neither the poly-ubiquitination of the receptor nor its transactivation potential on MMTV. However, the hormone-activated mutant displayed enhanced synergistic potential on a compound promoter and delayed mobility in the nucleus. FRAP analysis further showed that proteasome inhibition immobilizes a subpopulation of unliganded MR receptors in the nucleus, a phenomenon that is significantly attenuated in the presence of aldosterone. Interestingly, the ability of the hormone to counteract the immobilizing effect of MG132 requires the sumoylation-competent form of MR. Moreover, increasing exogenously SUMO-1 cellular levels resulted in a selective, dose-dependent inhibition of the activity of the sumoylation-deficient MR. This effect was observed only on a synergy-competent promoter, revealing a mode for negative regulation of synergy that might involve sumoylation of factors different from MR. The data suggest that the overall transcriptional activity of MR can be modulated by its sumoylation potential as well as the sumoylation level of MR-interacting proteins, and requires the continuous function of the proteasome.
...
PMID:Sumoylation and proteasomal activity determine the transactivation properties of the mineralocorticoid receptor. 1731 4

The low molecular weight compound, PRIMA-1MET restores the transcriptional transactivation function of certain p53 mutants in tumor cells. We have previously shown that PRIMA-1MET induces nucleolar translocation of p53, PML, CBP and Hsp70. The Epstein-Barr virus encoded, latency associated antigen EBNA-5 (also known as EBNA-LP) is required for the efficient transformation of human B lymphocytes by EBV. EBNA-5 associates with p53-hMDM2-p14ARF complexes. EBNA-5 is a nuclear protein that translocates to the nucleolus upon heat shock or inhibition of proteasomes along with p53, hMDM2, Hsp70, PML and proteasome subunits. Here we show that PRIMA-1MET induces the nucleolar translocation of EBNA-5 in EBV transformed B lymphoblasts and in transfected tumor cells. The PRIMA-1MET induced translocation of EBNA-5 is not dependent on the presence of mutant p53. It also occurs in p53 null cells or in cells that express wild type p53. Both the native and the EGFP or DSRed conjugated EBNA-5 respond to PRIMA-1MET treatment in the same way. Image analysis of DSRed-EBNA-5 expressing cells, using confocal fluorescence time-lapse microscopy showed that the nucleolar translocation requires several hours to complete. FRAP (fluorescence recovery after photobleaching) and FLIP (fluorescence loss in photobleaching) measurements on live cells showed that the nucleolar translocation was accompanied by the formation of EBNA-5 aggregates. The process is reversible since the aggregates are dissolved upon removal of PRIMA-1MET. Our results suggest that mutant p53 is not the sole target of PRIMA-1MET. We propose that PRIMA-1MET may reversibly inhibit cellular chaperons that prevent the aggregation of misfolded proteins, and that EBNA-5 may serve as a surrogate drug target for elucidating the precise molecular action of PRIMA-1MET.
...
PMID:PRIMA-1MET induces nucleolar translocation of Epstein-Barr virus-encoded EBNA-5 protein. 1932 29

Virus-Induced Chaperone-Enriched (VICE) domains form adjacent to nuclear viral replication compartments (RC) during the early stages of HSV-1 infection. Between 2 and 3 hours post infection at a MOI of 10, host protein quality control machinery such as molecular chaperones (e.g. Hsc70), the 20S proteasome and ubiquitin are reorganized from a diffuse nuclear distribution pattern to sequestration in VICE domains. The observation that VICE domains contain putative misfolded proteins suggests that they may be similar to nuclear inclusion bodies that form under conditions in which the protein quality control machinery is overwhelmed by the presence of misfolded proteins. The detection of Hsc70 in VICE domains, but not in nuclear inclusion bodies, indicates that Hsc70 is specifically reorganized by HSV-1 infection. We hypothesize that HSV-1 infection induces the formation of nuclear protein quality control centers to remodel or degrade aberrant nuclear proteins that would otherwise interfere with productive infection. Detection of proteolytic activity in VICE domains suggests that substrates may be degraded by the 20S proteasome in VICE domains. FRAP analysis reveals that GFP-Hsc70 is dynamically associated with VICE domains, suggesting a role for Hsc70 in scanning the infected nucleus for misfolded proteins. During 42 degrees C heat shock, Hsc70 is redistributed from VICE domains into RC perhaps to remodel viral replication and regulatory proteins that have become insoluble in these compartments. The experiments presented in this paper suggest that VICE domains are nuclear protein quality control centers that are modified by HSV-1 to promote productive infection.
...
PMID:Virus-Induced Chaperone-Enriched (VICE) domains function as nuclear protein quality control centers during HSV-1 infection. 1981 71

In acute promyelocytic leukemia (APL), the promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha (RAR). Arsenic is an effective treatment for this disease as it induces SUMO-dependent ubiquitin-mediated proteasomal degradation of the PML-RAR fusion protein. Here we analyze the nuclear trafficking dynamics of PML and its SUMO-dependent ubiquitin E3 ligase, RNF4 in response to arsenic. After administration of arsenic, PML immediately transits into nuclear bodies where it undergoes SUMO modification. This initial recruitment of PML into nuclear bodies is not dependent on RNF4, but RNF4 quickly follows PML into the nuclear bodies where it is responsible for ubiquitylation of SUMO-modified PML and its degradation by the proteasome. While arsenic restricts the mobility of PML, FRAP analysis indicates that RNF4 continues to rapidly shuttle into PML nuclear bodies in a SUMO-dependent manner. Under these conditions FRET studies indicate that RNF4 interacts with SUMO in PML bodies but not directly with PML. These studies indicate that arsenic induces the rapid reorganization of the cell nucleus by SUMO modification of nuclear body-associated PML and uptake of the ubiquitin E3 ligase RNF4 leading to the ubiquitin-mediated degradation of PML.
...
PMID:Arsenic-induced SUMO-dependent recruitment of RNF4 into PML nuclear bodies. 2094 51

Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice.
...
PMID:Histone deacetylase inhibitors: clinical implications for hematological malignancies. 2270 87

BNIP3 (BCL2/adenovirus E1B 19 kDa interacting protein 3) is an atypical BH3-only protein that is induced by hypoxia-inducible factor 1 (HIF1) under hypoxia. BNIP3 is primarily regulated at the transcriptional level. However, little is known about the underlying mechanism of BNIP3 degradation. In this study, we found that BNIP3 was downregulated when hypoxia was accompanied by amino acid starvation. The BNIP3 downregulation did not occur at the transcription level and was independent of HIF1A. BNIP3 was primarily degraded by the proteasome, but BNIP3 was subjected to both proteasomal and autophagic degradation in response to starvation. The autophagic degradation of BNIP3 was dependent on ATG7 and MAP1LC3. We determined that autophagic degradation of BNIP3 was specifically regulated by ULK1 via the MTOR-AMPK pathway. Moreover, we confirmed that BNIP3 could play a protective role in tumor cells under hypoxia, and the treatment with Torin1, an MTOR inhibitor, decreased the BNIP3 level and enhanced the death of hypoxic tumor cells.
...
PMID:BNIP3 is degraded by ULK1-dependent autophagy via MTORC1 and AMPK. 2329 26

Proteasomal and autophagic pathways of protein degradation are two essential, endoplasmic reticulum (ER)-associated proteolytic systems involved in the ER stress response. The functional interaction between them has been shown by proteasome pharmacological inhibition. However, little data have been found concerning autophagy induction using an RNA interference approach due to the multisubunit composition of proteolytic systems. We suggested that silencing of single proteasome subunits can induce massive autophagy. Psmb7-specific small interference RNA added to isolated cardiomyocytes significantly affected mRNA expression of essential ER stress marker proteins, including DDIT3/CHOP and HSPA5/GRP78. mRNA expression of the key autophagy regulator MTOR was also increased. These findings were confirmed by single-cell reverse transcription real-time PCR on individual monodansylcadaverine (MDC)-labeled cardiomyocytes. RNA interference that decreased the levels of non-catalytic PSMB7 subunits of the proteasome had no influence on chymotrypsin- and trypsin-like activities, but significantly decreased peptidyl-glutamyl peptide-hydrolyzing activity. Immunohistochemical analysis showed increased levels of LC3-marked vacuoles in the cytoplasm of Psmb7-knockdown cells, and MDC staining showed significantly increased numbers of neonatal cardiomyocytes with autophagic vacuoles. After anoxia-reoxygenation, the number of cells with signs of autophagy after Psmb7 gene silencing was higher. Our results indicate that Psmb7 knockdown induces ER stress and autophagy in cardiomyocytes, which may be a useful approach to activate specific autophagy.
...
PMID:Knockdown of PSMB7 induces autophagy in cardiomyocyte cultures: possible role in endoplasmic reticulum stress. 2396 38


1 2 3 Next >>

---