Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of a thumb accounts for 60% decrease of functional value of the hand, thus any attempt of it's reconstruction is a priority in the field of hand surgery. Optimal reconstructive solution for subtotal thumb amputations has not been settled. The results of partial pollicization of ring finger in 5 adult men is presented. Four patients sustained distal subtotal thumb amputation (MCP joint level), one total amputation. In three patients the distal phalange of the ring finger was transferred with the DIP joint, FDP tendon and a fragment of extensor tendon. An effective movement of a newly created thumb's IP joint was achieved in two patients. In one patient with a total thumb amputation the transfer was followed by a pollicization of the second metacarpal with remnants of proximal phalange. The postoperative course was uneventful in all of the patients. The sensitivity tested on the pulp of the transferred finger equalized to the preoperative value, the hand strength was not diminished. The cosmetic result was excellent.
Chir Narzadow Ruchu Ortop Pol
PMID:[Transfer of the distal phalange of the ring finger as a method of reconstruction of the partially amputated thumb--preliminary report]. 1809 99

Thiazolidinediones are oral antidiabetic agents that activate peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and exert potent antioxidant and anti-inflammatory properties. It has also been shown that PPAR-gamma agonists induce G0/G1 arrest and apoptosis of malignant cells. Some of these effects have been suggested to result from inhibition of proteasome activity in target cells. The aim of our studies was to critically evaluate the cytostatic/cytotoxic effects of one of thiazolidinediones (pioglitazone) and its influence on proteasome activity. Pioglitazone exerted dose-dependent cytostatic/cytotoxic effects in MIA PaCa-2 cells. Incubation of tumor cells with pioglitazone resulted in increased levels of p53 and p27 and decreased levels of cyclin D1. Accumulation of polyubiquitinated proteins within cells incubated with pioglitazone suggested dysfunction of proteasome activity. However, we did not observe any influence of pioglitazone on the activity of isolated proteasome and on the proteolytic activity in lysates of pioglitazone-treated MIA PaCa-2 cells. Further, treatment with pioglitazone did not cause an accumulation of fluorescent proteasome substrates in transfected HeLa cells expressing unstable GFP variants. Our results indicate that pioglitazone does not act as a direct or indirect proteasome inhibitor.
Acta Biochim Pol 2008
PMID:Pioglitazone, a PPAR-gamma ligand, exerts cytostatic/cytotoxic effects against cancer cells, that do not result from inhibition of proteasome. 1832 3

Hexamethylene bis-acetamide-inducible protein 1 (HEXIM1) was identified earlier as an inhibitor of positive transcription elongation factor b (P-TEFb), which is a key transcriptional regulator of RNA polymerase II (Pol II). Studies show that more than half of P-TEFb in cells is associated with HEXIM1, which results in the inactivation of P-TEFb. Here, we identify a nucleolar protein, nucleophosmin (NPM), as a HEXIM1-binding protein. NPM binds to HEXIM1 in vitro and in vivo, and functions as a negative regulator of HEXIM1. Over-expression of NPM leads to proteasome-mediated degradation of HEXIM1, resulting in activation of P-TEFb-dependent transcription. In contrast, an increase in HEXIM1 protein levels and a decrease in transcription are detected when NPM is knocked down. We show that a cytoplasmic mutant of NPM, NPMc+, associates with and sequesters HEXIM1 in the cytoplasm resulting in higher RNA Pol II transcription. Correspondingly, cytoplasmic localization of endogenous HEXIM1 is detected in an acute myeloid leukemia (AML) cell line containing the NPMc+ mutation, suggesting the physiological importance of HEXIM1-NPMc+ interaction. Over-expression of NPM has been detected in tumors of various histological origins and our results may provide a possible molecular mechanism for the proto-oncogenic function of NPM. Furthermore, considering that 35% of AML patients are diagnosed with NPMc+ mutation, our findings suggest that in some cases of AML, RNA Pol II transcription may be disregulated by the malfunction of NPM and the mislocation of HEXIM1.
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PMID:Nucleophosmin interacts with HEXIM1 and regulates RNA polymerase II transcription. 1837 77

Transcription-coupled repair (TCR) plays a key role in the repair of DNA lesions induced by bulky adducts and is initiated when the elongating RNA polymerase II (Pol II) stalls at DNA lesions. This is accompanied by alterations in Pol II activity and stability. We have previously shown that the monofunctional adducts formed by irofulven (6-hydroxymethylacylfulvene) are exclusively recognized by TCR, without involvement of global genome repair (GGR), making irofulven a unique tool to characterize TCR-associated processes in vivo. Here, we characterize the influence of irofulven on Pol II activity, stability and mobility in living mammalian cells. Our results demonstrate that irofulven induces specific inhibition of nucleoplasmic RNA synthesis, an important decrease of Pol II mobility, coupled to the accumulation of initiating polymerase and a time-dependent loss of the engaged enzyme, associated with its polyubiquitylation. Both proteasome-mediated degradation of the stalled polymerase and new protein synthesis are necessary to allow Pol II recycling into preinitiating complexes. Together, our findings provide novel insights into the subsequent fate of the stalled RNA polymerase II and demonstrate the essential role of the recycling process for transcriptional reinitiation and viability of mammalian cells.
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PMID:Influence of irofulven, a transcription-coupled repair-specific antitumor agent, on RNA polymerase activity, stability and dynamics in living mammalian cells. 1838 15

Genetic analysis of the Drosophila leg-arista-wing complex (lawc) gene suggests a role for the Lawc protein in chromatin-related processes based on its classification as a trxG gene but the molecular mechanisms of its function remain elusive. We have found that Lawc is a small, cysteine-rich protein that is present in most of the interbands of polytene chromosomes. In agreement with this observation, Lawc co-localizes with RNA polymerase IIo (Pol IIo) and it is recruited to transcribed loci after elongation by Pol IIo has begun. Lawc interacts with the nuclear proteasome regulator dREGgamma in a yeast two-hybrid assay and both proteins co-localize on polytene chromosomes. In addition, a mutation in lawc interacts genetically with a mutation in a component of the proteasome. lawc mutants show decreased expression of some genes, while the levels of Pol IIoSer2 increase. We conclude that Lawc is required for proper transcription by RNA polymerase II in a process that involves the nuclear proteasome.
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PMID:The Lawc protein is required for proper transcription by RNA polymerase II in Drosophila. 1871 97

Ribosomal RNA (rRNA) is transcribed from the ribosomal DNA (rDNA) genes by RNA polymerase I (Pol I). Despite being responsible for the majority of transcription in growing cells, Pol I regulation is poorly understood compared to Pol II. To gain new insights into rDNA transcriptional regulation, we developed a genetic assay in Saccharomyces cerevisiae that detects alterations in transcription from the centromere-proximal rDNA gene of the tandem array. Changes in Pol I transcription at this gene alter the expression of an adjacent, modified URA3 reporter cassette (mURA3) such that reductions in Pol I transcription induce growth on synthetic media lacking uracil. Increases in Pol I transcription induce growth on media containing 5-FOA. A transposon mutagenesis screen was performed with the reporter strain to identify genes that play a role in modulating rDNA transcription. Mutations in 68 different genes were identified, several of which were already known to function in chromatin modification and the regulation of Pol II transcription. Among the other classes of genes were those encoding proteasome subunits and multiple kinases and phosphatases that function in nutrient and stress signaling pathways. Fourteen genes were previously uncharacterized and have been named as regulators of rDNA transcription (RRT).
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PMID:Genetic identification of factors that modulate ribosomal DNA transcription in Saccharomyces cerevisiae. 1927 Feb 72

Influenza viruses induce a host shut off mechanism leading to the general inhibition of host gene expression in infected cells. Here, we report that the large subunit of host RNA polymerase II (Pol II) is degraded in infected cells and propose that this degradation is mediated by the viral RNA polymerase that associates with Pol II. We detect increased ubiquitylation of Pol II in infected cells and upon the expression of the viral RNA polymerase suggesting that the proteasome pathway plays a role in Pol II degradation. Furthermore, we find that expression of the viral RNA polymerase results in the inhibition of Pol II transcription. We propose that Pol II inhibition and degradation in influenza virus infected cells could represent a viral strategy to evade host antiviral defense mechanisms. Our results also suggest a mechanism for the temporal regulation of viral mRNA synthesis.
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PMID:Mechanisms and functional implications of the degradation of host RNA polymerase II in influenza virus infected cells. 1987 44

Hypoxia-inducible factor-1 (HIF-1) is one of the major factors responsible for the activation of compensation processes during cell hypoxia. Hypoxia-inducible factor-1 is a dimeric protein complex and serves as a transcription factor regulator for many target genes. Under normoxic conditions it is constitutively produced and degraded by the ubiquitin-proteasome system. But under hypoxic conditions HIF-1 becomes stabilized. The expression of HIF-1 increases vascularization of the ischaemic area and regulates anaerobic metabolism. The same processes were observed in neoplastic tissues. Hypoxia-inducible factor-1 and its participation in neoplasia, the inhibition and stimulation of its transcriptional activity, attracts the attention of many scientists as the understanding of its function in tumour progression could be used in the future for preparation of new antineoplastic therapies.
Pol J Pathol 2009
PMID:Hypoxia-inducible factor-1, a new possible important factor in neoplasia. 1988 79

Adult rheumatoid arthritis (RA) is the most common of rheumatoid diseases, that may cause hand dysfunction in some patients. Its equivalent in children is juvenile chronic arthritis (JCA). The aim of our study was to evaluate differences in hand deformity between children with JCA and adults with RA. The prospective study was performed on two groups of patients: 15 with JCA (average age 13.1 years, range from 9 to 18 years) and 15 with RA (average age 53.6 years, range from 42 to 60 years). Both groups were similar in terms of Seyfried classification system and duration of the disease--7.9 years for children and 8.6 for adults. Clinical assessment was performed according to Swanson and Seyfrieda classification system. Patients with RA had only radial wrist "deviation" and those with JCA had both radial and ulnar wrist deviation. In MCP joints in adult's group fingers were always in ulnar position and in children's group finder position was opposite to wrist position. "Swan neck" deformity of fingers from II to V was found in both groups. "Buttonhole deformity" was more often seen in older group. Pain of wrist and in IP joints was more often found and was more severe in RA group. Hypertrophy of synovium and subluxation of IP and wrist joust were found with similar frequency in both groups. In other joints subluxation was rare. Concluding, radial wrist deviation is typical for RA patients. Children with JCA had both radial and ulnar wrist deviation. In MCP joints deformity is always opposite to wrist deviation.
Chir Narzadow Ruchu Ortop Pol
PMID:[Hand deformity in adult rheumatoid arthritis and juvenile chronic arthritis]. 2016 74

Advances in defining HIV-1 CD8+ T cell epitopes and understanding endogenous MHC class I antigen processing enable the rational design of polyepitope vaccines for eliciting broadly targeted CD8+ T cell responses to HIV-1. Here we describe the construction and comparison of experimental DNA vaccines consisting of ten selected HLA-A2 epitopes from the major HIV-1 antigens Env, Gag, Pol, Nef, and Vpr. The immunogenicity of designed gene constructs was assessed after double DNA prime, single vaccinia virus boost immunization of HLA-A2 transgenic mice. We compared a number of parameters including different strategies for fusing ubiquitin to the polyepitope and including spacer sequences between epitopes to optimize proteasome liberation and TAP transport. It was demonstrated that the vaccine construct that induced in vitro the largest number of [peptide-MHC class I] complexes was also the most immunogenic in the animal experiments. This most immunogenic vaccine construct contained the N-terminal ubiquitin for targeting the polyepitope to the proteasome and included both proteasome liberation and TAP transport optimized spacer sequences that flanked the epitopes within the polyepitope construct. The immunogenicity of determinants was strictly related to their affinities for HLA-A2. Our finding supports the concept of rational vaccine design based on detailed knowledge of antigen processing.
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PMID:Rational design based synthetic polyepitope DNA vaccine for eliciting HIV-specific CD8+ T cell responses. 2018 49


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