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)

We have discovered a new class of transcripts of immunoglobulin kappa genes in RNA from B-lineage cells. These transcripts have the properties predicted of free introns excised from kappa mRNA precursors. RNA extracted from populations of normal mouse spleen cells polyclonally activated with B-cell mitogens contains four such transcripts; their electrophoretic mobilities correspond to the distances between the intron-exon boundary of the C kappa region and the four useable J kappa elements, and their relative abundance reflects the relative usage of those J segments. Analysis of RNA from monoclonal kappa-expressing cell lines reveals that one active locus produces one free intron, its size determined by which J element is used in that locus. Apart from their distinctive size, free introns are identified by their lack of polyadenylic acid and their ability to hybridize to cloned probes containing intron sequences, but not to the adjacent V or C exonic sequences. They have a characteristic subcellular distribution, being extractable from nuclei by treatment with nonionic detergent; nuclei thus treated retain most of the primary mRNA precursors, but few of the free introns. A high level of kappa gene expression is not a prerequisite of a cell containing detectable free kappa introns; the lymphoma 38c has only 5% or less of the amount of kappa mRNA that the plasmacytoma MCP-11 contains, yet the ratio of free intron to mRNA precursor is about the same in both cell lines. When analyzed by electrophoretic separation of sufficient resolving power, the free introns due to a single kappa locus resolve into two discrete species. We consider that this most likely reflects the existence of two conformers of the intron, one presumably a covalently intact circle and the other linear molecule.
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PMID:Introns excised from immunoglobulin pre-mRNAs exist as discrete species. 643 93

Group I Burkitt lymphoma (BL) lines retaining the original BL tumor cell phenotype are unable to present endogenously expressed antigens to HLA class I-restricted cytotoxic T cells (CTL) but can be recognized if the relevant HLA class I/peptide epitope complex is reconstituted at the cell surface by exogenous addition of synthetic target peptide. Endogenous antigen-processing function is restored in BL lines that have undergone Epstein-Barr virus (EBV)-induced drift in culture to the group III phenotype typically displayed by EBV-transformed lymphoblastoid cell lines (LCL) of normal B cell origin. We compared group I versus group III cells for their expression of proteasome components, transporter proteins and HLA-class I antigens, all of which are thought to be involved in the endogenous antigen processing pathway. By Western blot analysis, there were not consistent differences in the low molecular mass protein subunits of proteasomes (lmp)-2, lmp-7 and delta, although the mb-1 proteasome subunit was regularly present at higher levels in group I BL lines relative to group III lines or LCL. By contrast there were marked differences in the expression of peptide transporter-associated proteins (Tap), with down-regulation of Tap-1 and Tap-2 in 8/8 and 7/8 group I BL lines, respectively. Surface levels of HLA class I antigens were also consistently lower in group I cells; this was not associated with an intracellular accumulation of free HLA heavy chains, such as is seen in the Tap-deficient T2 processing-mutant line, but instead reflected a reduced rate of HLA class I synthesis in group I cells. Analysis of EBV gene transfectants of the B lymphoma lines BJAB and BL41 showed that the virus-encoded latent membrane protein-1 (LMP1), which is one of several EBV antigens expressed in group III but not in group I cells, was uniquely able to up-regulate expression both of the Tap proteins and HLA class I. Furthermore, this was accompanied by a restoration of antigen-processing function as measured by the ability of these cells to present an endogenously expressed viral antigen to CTL. These effects of LMP1 were similar to those induced in the same cell lines by interferon-gamma treatment. The results implicate both Tap and HLA class I expression as factors limiting the antigen-processing function of BL cells, and suggest that the accessibility of other EBV-associated malignancies to CTL surveillance may be critically dependent upon their LMP1 status.
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PMID:Restoration of endogenous antigen processing in Burkitt's lymphoma cells by Epstein-Barr virus latent membrane protein-1: coordinate up-regulation of peptide transporters and HLA-class I antigen expression. 777 41

A total of 42 adults with acute lymphoblastic leukemia were treated with an aggressive induction/consolidation chemotherapy (MCP-841) between June 1986 and December 1991. 32 patients (76.19%) achieved complete remission at the end of induction. There were 9 induction deaths, 6 of them due to infection. All patients received cranial irradiation in the dose of 20 Gy and intrathecal methotrexate for CNS prophylaxis. Twelve patients relapsed, 10 in the bone marrow, one case had isolated CNS relapse and the other relapsed in the bone marrow and CNS. The actuarial overall survival of all patients at the end of 5 years was 41.94%. Patient characteristics including age, sex, FAB morphology, phenotype, WBC count, platelet count and LDH did not influence survival significantly.
Leuk Lymphoma 1994 Jul
PMID:Adult acute lymphoblastic leukemia: results of an aggressive regimen in India. 795 Sep 17

The purpose of this study was to analyze the outcome of patients who completed therapy for acute lymphoblastic leukemia (ALL) and to study the role of an aggressive induction regimen in preventing post therapy relapses. Four hundred and twenty-two patients with ALL who completed therapy during the period 1975-1991 were followed. Two hundred and sixty patients received the aggressive MCP 841 protocol and 162 patients received various other less aggressive treatment regimens. Patients were followed with periodic examination and complete blood counts. The incidence of post therapy relapse was 27% in the less aggressive protocols and 15% in the MCP 841 protocol (p = 0.001). An higher percentage of relapses was seen in males (p = 0.05) and 89% relapses occurred within two years of stopping therapy. The relapse rate after 5 years of cessation of therapy was 0.59%. In conclusion, aggressive induction therapy is the most crucial factor in predicting relapses following cessation of therapy in ALL patients. However, relapses are unlikely to occur five years post therapy.
Leuk Lymphoma 1996 Jan
PMID:Survival of childhood acute lymphoblastic leukemia: results of therapy at Tata Memorial Hospital, Bombay, India. 862 72

Proteases play an important role in regulation of apoptosis. To elucidate the role of proteasome in apoptosis, we examined the effects of the proteasome inhibitors, carbobenzoxy-L-isoleucyl-gamma-t-butyl-L-glutamyl-L-alanyl-L-leucinal and carbobenzoxy-L-leucyl-L-leucyl-L-norvalinal on RVC lymphoma cells. Cells exposed to the proteasome inhibitors arrested at G2/M phase followed by internucleosomal DNA cleavage, chromatin condensation, and formation of apoptotic bodies dose- and time-dependently. Ubiquitinated histone H2A levels decreased in the exposed cells, suggesting a relationship between deubiquitination of histone H2A and the chromatin disarray seen in apoptosis. Northern blots showed an increase in expression of polyubiquitin genes early in the incubation. These findings suggest that the ubiquitin-mediated proteasome-proteolytic system is involved in regulating the cell cycle and apoptosis in RVC cells.
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PMID:Peptidyl aldehyde inhibitors of proteasome induce apoptosis rapidly in mouse lymphoma RVC cells. 913 24

c-Fos is a transcription factor that promotes cell growth, differentiation, and transformation. We found that c-Fos was degraded when WEHI7.2 mouse lymphoma cells were induced to undergo apoptosis with the calcium ATPase inhibitor, thapsigargin, or the glucocorticoid hormone, dexamethasone. The degradation of c-Fos preceded caspase-3 activation and apoptotic nuclear chromatin condensation and was inhibited by the proteasome inhibitors MG132, N-acetyl-leucyl-leucyl-norleucinal, and lactacystin. Stable transfection of WEHI7.2 cells with a mutant form of c-Fos that was not degraded by the proteasome inhibited apoptosis. Also, overexpression of Bcl-2 in WEHI7.2 cells blocked c-Fos degradation and inhibited apoptosis. The results indicate that proteasome-mediated degradation of c-Fos is an early, Bcl-2-regulated step in apoptosis induction by thapsigargin and dexamethasone. These findings suggest that c-Fos may have a protective action that is eliminated by proteasome-mediated degradation and preserved by Bcl-2.
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PMID:c-Fos degradation by the proteasome. An early, Bcl-2-regulated step in apoptosis. 973 57

One eukaryotic proteolytic complex--the proteasome--is classed as the major nonlysosomal protease, by its known and suspected functions, its size and its complexity. It seems improbable that other enzymes may be capable of substituting, even partially, for the potent proteasome, as this complex has a vital role in many cellular processes. Nevertheless, it is possible to adapt cultured EL-4 mouse lymphoma cells to survive in the presence of a specific inhibitor of the proteasome. The inhibition of the proteasome in these adapted EL-4 cells is accompanied by a dramatic increase in the activity of a new, as yet uncharacterized, large proteolytic complex. Here, we have presented evidence that a similar proteolytic activity is constitutively present in fission yeast, Schizosaccharomyces pombe, and that the yeast and mouse enzymes share basic physicochemical properties. We have shown that the S. pombe protease is found in two stable oligomeric forms, both of which are peptidases, although only the larger form acts as a proteinase. The relative amounts of the large and the small forms of the protease in the complex depended on the growth phase of the yeast culture and affected enzyme activity, suggesting that the activity of the enzyme is regulated by its oligomerization status. We refer to the new proteolytic complex as the 'multicorn' to indicate its analogy to the archaebacterial tricorn protease.
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PMID:A new large proteolytic complex distinct from the proteasome is present in the cytosol of fission yeast. 974 Aug 5

The HTLV-1 singly spliced open reading frame I protein, p12(I), is highly unstable and appears to be necessary for persistent infection in rabbits. Here we demonstrate that p12(I) forms dimers through two putative leucine zipper domains and that its stability is augmented by specific proteasome inhibitors. p12(I) is ubiquitylated, and mutations of its unique carboxy-terminus lysine residue to an arginine greatly enhance its stability. Interestingly, analysis of 53 independent HTLV-1 strains revealed that the natural p12(I) alleles found in ex vivo samples of tropical spastic paraparesis-HTLV-1-associated myelopathy patients contain a Lys at position 88 in some cases, whereas arginine is consistently found at position 88 in HTLV-1 strains from all adult T-cell leukemia-lymphoma (ATLL) cases and healthy carriers studied. This apparent segregation of different alleles in tropical spastic paraparesis-HTLV-associated myelopathy and ATLL or healthy carriers may be relevant in vivo, since p12(I) binds the interleukin-2 receptor beta and gammac chains, raising the possibility that the two natural alleles might affect differently the regulation of these molecules.
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PMID:A lysine-to-arginine change found in natural alleles of the human T-cell lymphotropic/leukemia virus type 1 p12(I) protein greatly influences its stability. 1040 Jul 40

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription-polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P =.001), the loss of p27 (P =. 002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P =.002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626) (Blood. 2000;95:619-626)
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PMID:Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. 1062 71

The c-myc proto-oncogene encodes a short-lived transcription factor that plays an important role in cell cycle regulation, differentiation and apoptosis. c-myc is often rearranged in tumors resulting in deregulated expression. In addition, mutations in the coding region of c-myc are frequently found in human lymphomas, a hot spot being the Thr58 phosphorylation site, a mutation shown to enhance the transforming capacity of c-Myc. It is, however, still unclear in what way this mutation affects c-Myc activity. Our results show that proteasome-mediated turnover of c-Myc is substantially impaired in Burkitt's lymphoma cells with mutated Thr58 or other mutations that abolish Thr58 phosphorylation, whereas endogenous or ectopically expressed wild type c-Myc proteins turn over at normal rates in these cells. Myc Thr58 mutants expressed ectopically in other cell types also exhibit reduced proteasome-mediated degradation, which correlates with a substantial decrease in their ubiquitination. These results suggest that ubiquitin/proteasome-mediated degradation of c-Myc is triggered by Thr58 phosphorylation revealing a new important level of control of c-Myc activity. Mutation of Thr58 in lymphoma thus escapes this regulation resulting in accumulation of c-Myc protein, likely as part of the tumor progression. (Blood. 2000;95:2104-2110)
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PMID:c-Myc hot spot mutations in lymphomas result in inefficient ubiquitination and decreased proteasome-mediated turnover. 1070 81


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