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)

Complement-dependent cytotoxicity (CDC) mediated by a chimeric anti-Lewis Y monoclonal antibody (cH18A; human IgG1) was investigated in this study. Human lung adenocarcinoma cell lines (PC7, PC9, and PC14) were used as the target cells. PC7 and PC9 cells, expressed Lewis Y antigen and were lysed by cH18A as effectively as by the parent mouse anti-Lewis Y antibodies (mH18A) in a concentration-dependent manner. PC14 cells did not express Lewis Y antigen and were not lysed by either cH18A or mH18A. cH18A mediated CDC activity against PC7 and PC9 cells was enhanced by the combined use of monoclonal antibodies directed against CD46(MCP), CD55(DAF), and CD59. These molecules are complement-regulatory proteins which protect host cells from CDC. PC7 and PC9 cells, showed high levels of surface expression of these proteins, PC7 cells were more susceptible to cH18A-mediated CDC than PC9 cells. Use of multiple blocking antibodies to the complement-regulatory proteins produced more enhancement of cH18A-mediated CDC than a single antibody. Moreover, expression of CD55 and CD59 by PC7 and PC9 cells was decreased after treatment with PI-PLC, resulting in increased susceptibility to cH18A-mediated CDC. Although the reason is unknown, PC7 cells became more susceptible to CDC than PC9 cells after PI-PLC treatment even in the absence of cH18A. These data suggest that chimeric monoclonal antibodies can be used to induce CDC against lung adenocarcinoma, and that such CDC is potentiated by a variety of antibodies blocking compliment-regulatory proteins on the tumour cell surface.
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PMID:Augmented lung adenocarcinoma cytotoxicity by the combination of a genetically modified anti-Lewis Y antibody and antibodies to complement regulatory proteins. 754 16

The activity of insulin-degrading enzyme (IDE), a thiol metalloprotease degrading insulin in many insulin target cells, was determined in human colon adenocarcinoma (Caco-2) cells. Insulin-degrading activity was localized in the cytosol of Caco-2 cells, accounting for 88% of total activity. Western blots and immunoprecipitation showed that IDE was present in the cytosol of Caco-2 cells and contributed to more than 93% cytosolic insulin-degrading activity. Cytosolic insulin degradation was strongly inhibited by IDE inhibitors, including N-ethylmaleimide, 1,10-phenanthroline, p-chloromericuribenzoate, and EDTA, but was not significantly or not as extensively inhibited by strong inhibitors of proteasome, i.e., chymostatin, soybean trypsin inhibitor, leupeptin, and Dip-F. These results suggest that IDE is present in Caco-2 cells, that Caco-2 IDE has properties similar to those of its counterparts in insulin-target tissues, and that it significantly contributes to intracellular insulin degradation.
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PMID:Insulin-degrading enzyme in a human colon adenocarcinoma cell line (Caco-2). 759 85

Oncology of the hypertrophic prostate and histogenesis of the cancer. Histological examine of 286 hypertrophic prostates collected by suprapubic way, on histologic macrosections including the whole visceral area, with the "step section technique". N. 286 hypertrophic prostates collected through suprapubic way have been examined on histologic macrosections including the whole visceral area, with the step section technique. There have been used object holders slides measuring cm. 12 x 9 and cover objects measuring cm. 5 x 7. Colourings: hematoxylin-eosin , Goldner. Localisation of the tumours has been determined in the prostate area. The cases with the presence of tumours-microcarcinoma (MCP), with maximum axis up to 1 millimeter; small carcinoma (PCP), maximum axis from mm. 1.1 to mm. 5, and the classic carcinoma (CPcl) have been 232 (81%). CPcl appeared in 33 cases (11.53%). Histogenesis of the MCP has been ascertained (from terminal secretory micro-ducts of the prostate). Of PCP (from groups of MCP n. 56 in picture 7), and of CPcl (from PCP in progressive growth) or from grouping of MCP (in picture 14, 101 MCP of the 235 present in the area of mm2 40). CPcl has shows invading growth in ten cases; in 23 cases it consisted in infiltrating growth but limited, the border towards the prostatic tissue appears circumscribed by pseudocapsule, the cells show nucleoli of varying sizes. In seven cases it turned out to be adenocarcinoma with limited growth as said before, partly with pseudocapsules, and the cells appear seriously atypical, hypertrophic, hyperstained nuclei, thickening of the nuclear membrane, prominent nucleoli, in the absence of any invading tendency. Specific oncogenic agents are thought to transform the prostate cells into definite morphologic malignancy, while another oncogenic agent causes the invading proliferation.
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PMID:[Oncology of the hypertrophic prostate and study of the histogenesis of carcinoma. Histological analysis of 286 prostates obtained using the suprapubic route and examined using macro-sections including the entire visceral surface using the step-section technique]. 768 75

The levels of complement-regulatory molecules (complement receptor type one [CR1], decay-accelerating factor [DAF], membrane cofactor protein [MCP], and an inhibitor of membrane attack complex [CD59]) in lung cancer cells were analyzed to investigate the relation between their expression and histological subtypes, and the possibility of homologous complement deposition on cancer cells. In 25 cell lines (10 adenocarcinoma, 3 large-cell carcinoma, 7 small-cell lung cancer [SCLC], and 5 squamous cell carcinoma), flow cytometric analysis revealed that MCP was expressed in all cell lines, whereas none of the cell lines was CR1-positive. CD59 was detected in all cells. The DAF epitope defined by IA10 was expressed in all cells except one large cell carcinoma cell line. However, another epitope for anti-DAF monoclonal antibody, D17, was not detected in 5 (71.4%) SCLC and in 4 (22.2%) non-small-cell lung cancer. This disparity was seen in most cell lines, irrespective of histological subtypes. The loss of D17 reactivity seemed to be pertinent to malignant phenotype, because most of the normal pulmonary cells possessed the D17 epitope. Furthermore, a cell line lacking DAF (IA10-/D17-) allowed alternative pathway-mediated homologous complement (C3) deposition after pretreatment with anti-MCP antibody. This raises a new possibility for immunotargeting of cancer. These cell lines should be useful in studying the biology of lung cancer.
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PMID:Levels of complement regulatory molecules in lung cancer: disappearance of the D17 epitope of CD55 in small-cell carcinoma. 769 Mar 55

To avoid destruction by complement, normal and malignant cells express membrane glycoproteins that restrict complement activity. These include decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46) and protectin (CD59), which are all expressed on colonic adenocarcinoma cells in situ. In this study we have characterised the C3/C5 convertase regulators DAF and MCP on the human colonic adenocarcinoma cell line HT29. DAF was found to be a glycosyl-phosphatidylinositol-anchored 70-kDa glycoprotein. Blocking experiments with F(ab')2 fragments of the anti-DAF monoclonal antibody BRIC 216 showed that DAF modulates the degree of C3 deposition and mediates resistance to complement-mediated killing of the cells. The expression and function of DAF were enhanced by tumour necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta). Cells incubated with interferon gamma (IFN gamma) did not alter their DAF expression. Two MCP forms were expressed, with molecular masses of approximately 58 kDa and 68 kDa, the lower form predominating. MCP expression was up-regulated by IL-1 beta, but not by TNF alpha or INF gamma. Expression of DAF and MCP promotes resistance of colonic adenocarcinoma cells to complement-mediated damage, and represents a possible mechanism of tumour escape.
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PMID:Characterisation of the complement-regulatory proteins decay-accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46) on a human colonic adenocarcinoma cell line. 864 Aug 47

A proportion of familial breast cancer has recently been shown by genetic linkage analysis to map to chromosome l3q12 (Wooster et al, 1994). This locus contains a tumor suppressor gene BRCA2, mutations in which lead to tumorigenesis. Genetic alterations at this locus have also been shown in pancreatic adenocarcinoma and in hepatocellular carcinoma. In an effort to isolate the BRCA2 gene, we have cloned 73 non overlapping cDNAs from a set of nine YACs spanning 6 cM interval on chromosome 13q12 by using a direct cDNA selection method. One of the selected cDNAs corresponds to a region of the 3' portion of BRCA2 mRNA, the sequence of which was published recently (Wooster et al, 1995). Northern analysis of BRCA2 transcripts from a variety of cell lines showed altered sizes of the mRNA in a breast cancer cell line (MCF7) and a prostate carcinoma cell line (DU145). Furthermore, BRCA2 transcript was present in cDNA libraries from total fetus as well as adult human tissues. Fifteen unique cDNA fragments encode genes/ESTs that are already known, of which only two have been mapped to this region. The other 12 cDNAs include genes for RPL6/mRNA for TAX REB 107, elongation factor-1 delta, 26S protease S4 regulatory subunit, small cytoplasmic 7SL RNA, a full length open reading frame (ORFU), brain thiol specific antioxidant protein, ribosomal protein, L35, and lipoxygenase activating protein. Six cDNAs represent human homologs of genes known in other species, namely, mouse HSPE71, Rat RhoGAP protein, S cerevisiae leucyl tRNA synthetase and S cerevisiae chromosome II ORF YBLO44W. The remaining 52 cDNAs showed either weak similarity or no similarity to sequences in the nucleotide data base and hence would represent novel genes. The plausible functions of some of these genes based on their sequence similarity to other known genes is discussed.
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PMID:Isolation of expressed sequences that include a gene for familial breast cancer (BRCA2) and other novel transcripts from a five megabase region on chromosome 13q12. 870 May 50

HLA class I antigens of the human major histocompatibility complex play an important role in immune response. These molecules present foreign antigenic peptides to cytotoxic T lymphocytes and thereby play a role in the immune surveillance of cells infected with virus or other intracellular pathogens or altered by malignant transformation. A marked deficiency or lack of expression of these antigens has been reported in a variety of human neoplasms. In the present study, we examined the expression of class I alpha chain, beta 2-microglobulin, TAP (TAP1 and TAP2) and LMP (LMP2 and LMP7) genes in a number of human tumor cell lines including small-cell lung carcinoma, hepatocellular carcinoma, colon adenocarcinoma and basophilic leukaemia. These cell lines were deficient in expression of both class I alpha chain and beta 2-microglobulin gene products. In addition, these cell lines lacked the products of MHC-encoded proteasome subunit LMP2 as well as the putative peptide transporter TAP1 genes. In contrast, TAP2 and LMP7 genes were expressed in these cell lines. Treatment of cells with gamma-IFN markedly enhanced the expression of class I alpha chain, beta 2-microglobulin, TAP1 and LMP2 genes with a concomitant increase in cell-surface expression of class I molecules. The upregulation of TAP1 and LMP2 expression is associated with increased class I expression, suggesting that endogenous antigens, e.g. tumor antigens, could be presented by class I molecules following treatment of tumor cells with gamma-IFN.
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PMID:Markedly decreased expression of TAP1 and LMP2 genes in HLA class I-deficient human tumor cell lines. 880 12

Ovarian cancer has features that makes it well-suited for MAb adjuvant immunotherapy. Several of the MAbs used in clinical trials mediate cancer cell destruction by activation of complement (C). In this study, therefore, we examined the ability of ovarian-tumor cells to resist C attack. We found that the C regulators membrane cofactor protein (MCP, CD46) and protectin (CD59) were strongly expressed in the tumor cells in all 28 benign and malignant tumors examined. Decay-accelerating factor (DAF; CD55) was more heterogeneously expressed, and only 75% of the tumors exhibited a moderate amount of DAF in the tumor cells. In adenoma cells, CD59 and DAF were preferentially located apically, while in adenocarcinoma cells they were expressed also at the basolateral cell surface. The ovarian-carcinoma cell lines SK-OV-3, Caov-3, SW626 and PA-1 expressed both the 58- and the 68-kDa isoforms of MCP. DAF was present as a glycosyl-phosphatidylinositol(GPI)-anchored 70-kDa glycoprotein. The surface-expression level of DAF varied, and correlated with the vulnerability of the cells to C-mediated lysis. CD59 was expressed as a GPI-linked 19- to 25-kDa protein exhibiting multiple glycosylation variants. The surface expression of CD59 correlated with the amount of the main 1.9 + 2.1-kb CD59 mRNA transcripts. Neutralization of CD59 with an anti-CD59 MAb significantly enhanced C-mediated killing of the cell lines. Low expression of C regulators on the PA-1 teratocarcinoma cell line was associated with high sensitivity to C lysis. Thus, the expression of C regulators on malignant ovarian cells may constitute a tumor escape mechanism, and is a critical parameter to be examined when MAb therapy is being considered.
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PMID:Complement-regulatory proteins in ovarian malignancies. 898 85

In proliferating cells the turnover rate of proteins responsible for regulation of the cell cycle progression, namely cyclins and inhibitors of the cyclin-dependent kinases (CDKs) and phosphatases, is rapid and their cellular level is modulated at the transcriptional, translational and/or degradation (via proteasome pathway) stages. Inhibition of proteasome function results in accumulation of rapidly turning over proteins and, thus, causes an imbalance of the cell cycle regulatory components, and loss of their regulatory function. Indeed, it has been shown that proteasome inhibitors perturb the cell cycle progression. Onconase, a novel RNase which has anti-tumor activity and is in clinical trials, has previously been shown to suppress protein synthesis, presumably by degradation of intracellular RNA, preferentially tRNA. By interfering with regulation of expression of cyclins and/or CDK-inhibitors, onconase also may induce the imbalance of these proteins and potentiate the effect of proteasome inhibitors. In the present study, we observed that the combinations of onconase with peptide-aldehyde inhibitors of calpain and proteasome such as the N-acetyl-leucinyl-leucinyl-norleucinal (LLnL) and the N-acetyl-leucinyl-valinyl-phenylalaninal (LVP), but not N-acetyl-leucinyl-leucinyl-methioninal (LLM), were synergistic in suppressing cell proliferation and inducing apoptosis in three human tumor cell lines: A-549 lung adenocarcinoma, DU-145 prostatic carcinoma, and MDA-MB-231 breast carcinoma. The observed cytotoxicity may also be a result of prevention of the induction of the 'survival' genes by the nuclear factor kappaB (NFkappaB) by onconase and proteasome inhibitors. The data indicate that such combinations should be further tested as potential anti-cancer regimens.
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PMID:Enhanced in vitro cytotoxicity and cytostasis of the combination of onconase with a proteasome inhibitor. 973 89

The glucose-regulated stress response of cancer cells leads to a decreased expression of DNA topoisomerase IIalpha (topo IIalpha) and a cell cycle arrest at the G1 phase. In this study, we found that the topo IIalpha decrease occurred specifically during the G1 arrest in human colon adenocarcinoma HT-29 cells. The intracelluar level of topo IIalpha in HT-29 cells was relatively constant regardless of cell cycle position in the exponentially growing state, determined using a centrifugal elutriation technique and synchronizing the cells with a mitotic inhibitor nocodazole. Interestingly, when the cell cycle was arrested in the M phase by nocodazole, the topo IIalpha level remained high even in stressed cells. After the stressed cells were released from the M phase, topo IIalpha steeply decreased along with cell cycle progression followed by the next G1 arrest. This decrease in nuclear topo IIalpha protein was completely inhibited by selective inhibitors for proteasome. Furthermore, we found that proteasome activity was elevated three to fourfold in the nuclear extract of stressed cells over unstressed cells. Accordingly, there were increased amounts of nuclear proteasome subunits, although total intracellular content of the subunits did not change in stressed cells. These findings indicate that the expression of topo IIalpha in stressed cells is downregulated at the G1 phase by proteasome-mediated degradation and that the proteolysis of topo IIalpha can be facilitated by the nuclear accumulation of proteasome.
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PMID:Glucose-regulated stresses cause degradation of DNA topoisomerase IIalpha by inducing nuclear proteasome during G1 cell cycle arrest in cancer cells. 1036 22


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