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 studied cytokine-related functional properties of four mouse endotheliomas from different anatomical sites obtained by transformation with middle T oncogene. We examined mRNA expression of IL-6, IL-1 alpha, macrophage-CSF, granulocyte/macrophage-CSF, and two members of an emerging super-family of chemotactic cytokines (JE/monocyte chemoattractant protein-1 (MCP-1) and KC). Exposure to IL-1 augmented or induced cytokine gene transcripts in three endothelioma lines (eEnd.1, sEnd.1, and tEnd) with maximal expression in tEnd.1 cells. Endothelioma cells also responded to TNF-alpha and LPS. Levels of IL-6 and monocyte chemotactic activity (a JE/MCP activity) correlated with mRNA expression. IL-1 also induced production of procoagulant activity and platelet-activating factor in endothelioma cells, with heterogeneity in the levels of response among individuals lines. Murine melanoma B16-F1, human colon carcinoma HT29 cells, CB33MT lymphoblastoid cells, and monocytes adhered to endothelioma monolayers and the adhesive properties of these cell lines were modulated by IL-1 beta, with marked differences among themselves. Murine EC derived from brain capillaries, used as control, shared several properties with bEnd.4 line. Endothelioma lines cause tumors by recruiting host cells. The capacity to produce cytokines that directly or indirectly attract host vascular cells, may play an important role in hemangioma induction in vivo. Murine endothelioma lines, generated by transformation with the polyoma middle T oncogene, retain functional properties of normal endothelium, and may represent an invaluable tool for analysis of the immunobiology and heterogeneity of EC in different tissues.
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PMID:Murine endothelioma cell lines transformed by polyoma middle T oncogene as target for and producers of cytokines. 191 46

The ubiquitin-proteasome pathway is the principal mechanism for the degradation of short-lived proteins in eukaryotic cells. Here we examine the possibility that ubiquitin-proteasome is involved in regulating the levels of Bcl-2, which is abundantly expressed in M-07e cells, a granulocyte/macrophage colony-stimulating factor (GM-CSF)-dependent human leukaemic cell line. Apoptosis in M-07e cells, induced by GM-CSF withdrawal, was associated with a gradual cleavage of Bcl-2 into a 22 kDa fragment. Treatment of M-07e cells with benzyloxycarbonyl-Leu-Leu-l-leucinal (Z-LLL-CHO; MG-132), a reversible ubiquitin-proteasome inhibitor, markedly accelerated the cleavage of Bcl-2 and promoted cell death through the apoptotic pathway. The cleavage of Bcl-2 was inhibited by a caspase-3 (CPP32)-specific inhibitor [acetyl-Asp-Glu-Val-Asp-CHO (DEVD-CHO)] but not caspase 1 inhibitor (acetyl-Tyr-Val-Ala-Asp-CHO), suggesting that Bcl-2 is a proteolytic substrate of a caspase-3-like protease activated during apoptosis. The simultaneous addition of recombinant human GM-CSF (rhGM-CSF) to M-07e cultures delayed the activation of caspase 3 and Bcl-2 cleavage triggered by Z-LLL-CHO, suggesting that the activation of the GM-CSF signalling pathway can partly overcome the apoptotic effect induced by Z-LLL-CHO. Apoptosis induced by inhibition of the proteasome pathway was verified in studies with lactacystin, a highly specific and irreversible proteasome inhibitor. Lactacystin-induced apoptosis in M-07e cells was remarkably similar to that induced by Z-LLL-CHO, which included caspase 3 activation, cleavage of Bcl-2 into a 22 kDa fragment and, ultimately, cell death. These results showed that inhibition of the ubiquitin-proteasome pathways can lead to the activation of a DEVD-CHO-sensitive caspase and induces Bcl-2 cleavage, which might have a role in mediating apoptosis in M-07e cells.
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PMID:Inhibition of ubiquitin-proteasome pathway activates a caspase-3-like protease and induces Bcl-2 cleavage in human M-07e leukaemic cells. 1022 67

The anticancer activity of the boronic acid dipeptide proteasome inhibitor PS-341 was examined in vitro and in vivo. PS-341 was a potent cytotoxic agent toward MCF-7 human breast carcinoma cells in culture, producing an IC90 of 0.05 microM on 24 h of exposure to the drug. In the EMT-6 tumor cell survival assay, PS-341 was equally cytotoxic administered p.o. or by i.p. injection up to a dose of 2 mg/kg. PS-341 was also toxic to the bone marrow colony-forming unit-granulocyte macrophage. PS-341 increased the tumor cell killing of radiation therapy, cyclophosphamide, and cisplatin in the EMT-6/Parent tumor, but was not able to overcome the in vivo resistance of the EMT-6/CTX and EMT-6/CDDP tumors. In the tumor growth delay assay, PS-341 administered p.o. had antitumor activity against the Lewis lung carcinoma, both primary and metastatic disease. In combination, regimens with 5-fluorouracil, cisplatin, Taxol and adriamycin, PS-341 seemed to produce primarily additive tumor growth delays against the s.c. tumor and was highly effective against disease metastatic to the lungs. The proteasome is an interesting new target for cancer therapy, and the proteasome inhibitor PS-341 warrants continued investigation in cancer therapy.
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PMID:The proteasome inhibitor PS-341 in cancer therapy. 1049 43

Monocytes and T-lymphocytes, both of which play a pivotal role in immune/inflammatory responses, can be attracted from the circulation into tissues by monocyte chemoattractant protein-1 (MCP-1), and monocytes can be further activated by colony-stimulating factors (CSFs), granulocyte/macrophage CSF (GM-CSF) or macrophage CSF (M-CSF). We examined whether either interleukin-6 (IL-6) or transforming growth factor-beta (TGF-beta), both of which are produced by thyroid follicular cells (TFC), can regulate the production of MCP-1 or CSF(s) in human TFC. IL-6, being effective only in the presence of soluble IL-6 receptor (sIL-6R), stimulated the expression of both MCP-1 and M-CSF, but was inhibitory on GM-CSF expression. On the other hand, TGF-beta stimulated the expression of both MCP-I and GM-CSF, but suppressed M-CSF expression. These results suggest a possible role of IL-6 or TGF-beta on the initiation and/or modulation of thyroid immune/inflammatory responses via MCP-1 production and differential production of GM-CSF or M-CSF by TFC.
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PMID:Interleukin-6 and transforming growth factor-beta regulate the expression of monocyte chemoattractant protein-1 and colony-stimulating factors in human thyroid follicular cells. 1050 48

Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evaluated in immature and mature stages of human monocyte-derived DC using semiquantitative RT-PCR and Western blot analyses. The IFN-gamma-responsive immunoproteasome subunits LMP2, LMP7 and MECL1 are up-regulated in immature DC, whereas the other components of the MHC class I presentation machinery, such as PA28, TAP, tapasin, and HLA heavy and light chains, were found to be more abundant in mature DC. These findings support the hypothesis that immature DC produced by the differentiation of monocytes in response to IL-4 and granulocyte macrophage colony stimulating factor first increase their capacity to capture antigens and process them into peptides, thereby switching from housekeeping to immunoproteasomes, while mature DC rather up-regulate the components required for peptide translocation and MHC class I-peptide complex formation, and thus specialize in antigen presentation. Our results establish that MHC class I, like MHC class II surface expression, is markedly regulated during DC development and maturation.
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PMID:Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation. 1171 92

Thrombopoietin (TPO), the primary regulator of platelet production, is composed of an amino-terminal 152 amino acids, sufficient for activity, and a carboxyl-terminal region rich in carbohydrates (183 residues) that enhances secretion of the molecule. Full-length TPO is secreted at levels 10-20-fold greater than truncated TPO. By introducing into mammalian cells a novel cDNA encoding the TPO secretory leader linked to its carboxyl-terminal domain (TPO glycan domain (TGD)), we tested whether TGD could function in trans to enhance secretion of TPO. The artificial TGD was secreted, inactive in proliferation assays, and did not inhibit TPO activity. However, when co-transfected with a cDNA encoding truncated TPO, TGD enhanced secretion 4-fold, measured by specific bioassay and immunoassay. TGD also enhanced secretion of granulocyte monocyte colony-stimulating factor and stem cell factor but did not affect the production of erythropoietin, interleukin-3, growth hormone, or of full-length TPO. To localize TGD function, we added an endoplasmic reticulum (ER) retention signal to TGD and, separately, deleted the secretory leader. Deletion of the secretory leader attenuated the secretory function of TGD, whereas addition of the ER retention signal did not alter its function. To investigate the physiologic role of TGD in folding and proteasomal protection, we tested full-length and truncated TPO in assays of protein refolding, and we examined protein stability in the presence of proteasome inhibitors. We found that truncated TGD re-folds readily and that proteasome-mediated degradation contributes to the poor secretion of truncated TPO. We conclude that TGD enhances secretion of TPO and can additionally function as an inter-molecular chaperone, in part because of its ability to prevent degradation of the hormone. The cellular location of TGD action is likely to be within the ER or earlier in the secretory pathway.
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PMID:The glycan domain of thrombopoietin (TPO) acts in trans to enhance secretion of the hormone and other cytokines. 1210 Nov 78

Several reports including those from this laboratory have demonstrated that bone marrow cells (BMC) downregulate in vitro both mixed leukocyte reaction and cytotoxic T lymphocyte reactions. We consequently hypothesized that a general property of immature cells of hematopoietic organs is their ability to suppress immune reactivity. As one of these suppressive activities, the lack of costimulatory molecules was proposed as a mechanism by which immature antigen presenting cells of the bone marrow might be involved. In the present report, we used two culture environments, each of which would regulate a different maturation pattern of human bone marrow-derived enriched dendritic antigen presenting cells (DC or APC) to determine the respective effects on in vitro immune regulatory function. Human BMC depleted of CD3+ cells were cultured with either: interleukin-4 (IL-4) and granulocyte macrophage-colony stimulating factor (GM-CSF), to maintain DC-enriched populations in an immature state (iAPC); or an interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNF-alpha), GM-CSF, LPS, and IL-6 cocktail to promote the maturation of DC-enriched APC (mAPC). These iAPC and mAPC were, respectively, phenotypically characterized and also tested in vitro for the following: (1) both direct and indirect-antigen presentation functions; (2) immune regulatory functions on the response of autologous and allogeneic peripheral blood lymphocytes (PBL); and (3) Western blot analysis determining the levels of both major histocompatibility complex (MHC) class I related cytoplasmic transporter molecules associated with antigen processing (TAP1) and as well as proteasome activator molecules (PA28alpha). The iAPC population expressed fewer dendritic cell markers (CD83 and DCsign), and costimulator molecules (CD86 and CD40) than the mAPC, such that there was an approximate threefold increase in expression of CD83, 2.5-fold increase in DCsign, and a threefold increase in CD40 and CD86 on mAPC than on iAPC (p=0.005 for CD83; p=0.001 for DCsign; p=0.001 for CD86; and p=0.001 for CD40). In lymphoproliferative assays, indirect and direct alloantigen presentation by iAPC was weaker than by mAPC (p=0.05 and 0.04). In addition, iAPC were able to downregulate allogeneic CTL responses. Also, after pulsing with Epstein-Barr virus (EBV) protein antigens, the iAPC were less efficient in their presentation to autologous EBV-specific T-cell lines, and caused an inhibition of EBV-CTL generation. The expression of TAP1 and PA28alpha was reduced in iAPC in comparison to mAPC. These findings support the notion that a maturation state of BMC-derived APC correlates with their capacity to present antigen. The observed in vitro deficiency of this function by immature bone marrow cells may therefore contribute to the immune downregulatory capacity seen in the BMC compartment.
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PMID:Antigen presentation and immune regulatory capacity of immature and mature-enriched antigen presenting (dendritic) cells derived from human bone marrow. 1496 64

Matrix metalloproteinase-9 (MMP-9) is considered to be an important component in the progression of inflammation. Monocytes/macrophages are prominent at inflammation sites, and activation of these cells by stimulants, such as lipopolysaccharide (LPS) or tumor necrosis factor alpha and granulocyte macrophage-colony stimulating factor, leads to the production of significant amounts of MMP-9. Here, we show that LPS stimulation of monocytes results in MMP-9 production through a phosphatidylinositol-3 kinase (PI-3K)/Akt/inhibitor of kappaB (IkappaB) kinase-alpha (IKKalpha)/nuclear factor (NF)-kappaB pathway. This new role for Akt in signaling leading to MMP-9 production was demonstrated by inhibitor and immunoprecipitation studies. LY294002 or wortmannin, inhibitors of PI-3K, suppressed LPS-induced Akt activity and MMP-9 production. Evidence for the participation of Akt in monocyte MMP-9 synthesis was demonstrated by the inhibition of MMP-9 by SH-5, a specific inhibitor of Akt. The mechanism by which Akt regulates MMP-9 is through the activation of NF-kappaB, as shown by coimmunoprecipitation of the phosphorylated form of IKKalpha and Akt as well as the SH-5 suppression of the dissociation of IkappaB from NF-kappaB and the activation of NF-kappaB p65. The role of NF-kappaB in regulation of MMP-9 was demonstrated further by the inhibition of MMP-9 production by proteasome inhibitors, lactacystin and MG-132, which prevented the ubiquitination and dissociation of IkappaB from NF-kappaB. This is the first demonstration that Akt is involved in the signaling pathway leading to the production of monocyte MMP-9 and provides an additional approach in the regulation of this enzyme in human primary monocytes.
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PMID:Production of matrix metalloproteinase-9 by activated human monocytes involves a phosphatidylinositol-3 kinase/Akt/IKKalpha/NF-kappaB pathway. 1580 29

Gfi1 is a transcriptional repressor essential during myeloid differentiation. Gfi1-/- mice exhibit a block in myeloid differentiation resulting in the accumulation of an immature myelo-monocytic cell population and the complete absence of mature neutrophils. Even though mRNA levels of Gfi1 appear to be very low in monocytes, Gfi1 might play a role in the monocytic lineage as Gfi1-/- mice exhibit diminished monocyte-derived dendritic cells and disturbed cytokine production by macrophages in response to LPS. We show here that Gfi1 protein levels are mainly regulated by the ubiquitin-proteasome system. Upon forced monocytic differentiation of U937 cells, Gfi1 mRNA levels dropped but protein levels increased due to diminished proteasomal turnover. Similarly, Gfi1 mRNA levels are low in primary monocytes whereas the protein is clearly detectable. Conversely, Gfi1 mRNA levels are high in granulocytes but the protein is swiftly degraded by the proteasome in these cells. Chromatin immunoprecipitation experiments showed that Gfi1 binds to the promoter of several granulocyte-specific genes in primary monocytes, including C/EBPalpha, neutrophil elastase, and Gfi1 itself. The binding of the repressor Gfi1 to these promoters correlated with low expression of these genes in monocytes compared with granulocytes. Our data fit a model in which Gfi1 protein levels are induced in primary monocytes, due to diminished proteasomal degradation, to repress genes that play a role in granulocytic differentiation.
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PMID:Diminished proteasomal degradation results in accumulation of Gfi1 protein in monocytes. 1688 99

Tribbles, an atypical protein kinase superfamily member, coordinates cell proliferation, migration, and morphogenesis during the development of Drosophila and Xenopus embryos. Although Tribbles are highly conserved throughout evolution, the physiological functions of mammalian Tribbles family remain largely unclear. Here we report that human TRB2 is a pro-apoptotic molecule that induces apoptosis of cells mainly of the hematopoietic origin. TRB2 mRNA is selectively induced by removal of granulocyte macrophage colony-stimulating factor (GM-CSF) or interleukin-2 from human erythroleukemia-derived TF-1 cell line or activated primary CD4(+) T cells, respectively. It is, however, not induced by many other treatments that trigger apoptosis of these two cell types. Overexpression of TRB2 activates many apoptotic events observed in GM-CSF-deprived TF-1 cells, including loss of mitochondrial membrane potential, Mcl-1 cleavage/degradation, and activation of Bax and a number of caspases. Specific knockdown of TRB2 significantly suppresses GM-CSF deprivation-induced apoptosis and all apoptotic events mentioned above. Finally, we demonstrate that TRB2-induced cleavage and degradation of Mcl-1 are mediated via a caspase-dependent but proteasome-independent mechanism, and overexpression of Mcl-1 or its upstream activator Akt can markedly overcome the apoptogenic effect of TRB2. Altogether, these results suggest that the TRB2-Mcl-1 axis plays an important role in survival factor withdrawal-induced apoptosis of TF-1 cells.
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PMID:Survival factor withdrawal-induced apoptosis of TF-1 cells involves a TRB2-Mcl-1 axis-dependent pathway. 1754 67


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