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)

Endothelial cells are critical elements in the evolution of all types of cutaneous inflammation. They participate through the synthesis and secretion of pro-inflammatory cytokines, including interleukin 1 (IL-1), IL-6, and IL-8, as well as M-CSF, G-CSF, GM-CSF, gro alpha, and MCP. They also express a series of cell-surface proteins and glycoproteins known as cell adhesion molecules that allow circulating leukocytes to bind to endothelial cells and allow endothelial cells to bind to matrix proteins. The regulated expression of these molecules, including those in the integrin, immunoglobulin gene, and selection families, allows for the precise trafficking of circulating leukocytes to sites of inflammation, injury, or immunologic stimulation in the skin. Furthermore, emerging evidence clearly indicates that selected differences exist between endothelial cells of the microvasculature and those that line large blood vessels. These include differences in secreted products, differences in the expression of cell adhesion molecules, and differences in cytokine-induced regulation of commonly expressed cell adhesion molecules, among others. Thus, a precise delineation of the biology of cutaneous microvascular endothelial cells is important to our understanding of cutaneous inflammation.
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PMID:Role of microvascular endothelial cells in inflammation. 842 79

Endothelial cells are critical elements in the evolution of all types of cutaneous inflammation. They participate the pathological process through the synthesis and secretion of pro-inflammatory cytokines, including interleukin 1 (IL1), IL6, IL8, and the three colony stimulating factors G-CSF, M-CSF, and GM-CSF and the two chemotactic factors gro-alpha and MCP. They also express a series of cell-surface proteins and glycoproteins known as cell adhesion molecules that allow circulating leukocytes to selectively bind to endothelial cells. In this paper we discuss the role of endothelial cells in the evolution of cutaneous necrotizing vasculitis, an immunologically mediated clinical disorder associated with segmental inflammation and fibrinoid necrosis of the dermal venules, through the release of cytokines or their response to cytokines locally produced from leukocytes themselves primarily involved in the endothelial cells injury. This interaction seems to involve and modulate other biologically active systems including the fibrinolytic system that can act amplifying and self-perpetuating the tissue damage through a non-immunologic mechanism.
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PMID:Cytokines, fibrinolysis and vasculitis. 860 38

The Rel/NF kappa B family of eukaryotic transcription factors are critical in immune and inflammatory processes regulating the expression of a wide variety of cytokines including IL-1, IL-2, IL-6, TNF-alpha and GM-CSF. Its ubiquitous distribution, rapid induction and regulation, the complexity of its subunits and its apparent involvement in several diseases has made this transcription factor a subject of intense study in normal cellular growth and cancer. Emerging studies have implicated a role for this transcription factor in the normal processes of aging. As significant declines in immune function is a natural concomitant to advancing age, the regulation of transcription factor NF kappa B appears to play a pivotal role in immune dysregulation during senescence, contributing to down regulation of both IL-2 and IL-2 receptor-alpha expression. Our studies have contributed to understanding the regulation of lowered NF kappa B induction in T cells during aging in humans and mice. Since we have shown that the lowered induction of NF kappa B in activated T cells from the elderly can be attributed to impaired degradation of the inhibitor I kappa B-alpha due to lowered proteasomal activity, we suspect that a similar alteration in proteasomal activity may be operative in age-dependent failure of immune function including the inability to initiate DNA synthesis following activation, skewing of T cell repertoire, lowered cytolytic activity and accumulation of aberrant proteins. Understanding the regulation of the proteasome pathway during immune senescence may provide new avenues for therapeutic intervention for immune based geriatric diseases.
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PMID:Regulation of transcription factor NF kappa B in immune senescence. 944 66

Fibroblasts from a variety of tissues interact with and influence the behavior of the cell types they are associated with by producing specific proteins that mediate these interactions. Thus, it is not surprising that fibroblasts have been shown to differ phenotypically and functionally depending on the tissue they are isolated from and its physiologic state. To study fibroblasts of hematopoietic tissues, cultures were established from human normal bone marrow (BM), and from non-myelometaplasic (NS) and myelometaplasic spleen (MMS) tissues and analyzed for phenotypic characteristics. The results are summarized as follows: (1) cytoskeletal elements: virtually all the MMS fibroblasts were stained positively for alpha-sm-actin while only a small fraction of BM and of NS fibroblasts were positive for this antigen; (2) extracellular matrix elements: MMS fibroblasts stained positively for ED-B fibronectin and tenascin while the other 2 fibroblast cell types did not; (3) cell surface molecules: NS and MMS fibroblasts expressed significantly higher levels of ICAM-1, VLA-4 and CD9 than BM fibroblasts. Moreover, MMS fibroblasts showed a higher expression of ICAM-1 and VLA-4 than NS fibroblasts; and (4) cytokines: IL-II, RANTES and MIP-1alpha were produced in higher amounts by BM than by NS fibroblasts. Conversely, production of GM-CSF, SCF, M-CSF and MCP-1alpha was elevated in NS compared with BM fibroblasts. The production of these cytokines was generally reduced in MMS cells. Overall, our results demonstrate that phenotypic characteristics can be identified to distinguish fibroblasts from normal and pathologic hematopoietic tissues. Such phenotypic characteristics suggest functional differences of each type of fibroblast in their influence on the blood cells with which they are associated.
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PMID:Phenotypic diversity in human fibroblasts from myelometaplasic and non-myelometaplasic hematopoietic tissues. 961 Jul 38

Human tumor cells frequently exhibit abnormalities in the major histocompatibility complex (MHC) class I surface expression which can be due to structural alterations and/or dysregulation of various components of the MHC class I antigen processing machinery, such as HLA class I heavy and light chains, the peptide transporter and the proteasome subunits. Although several cofactors critical for proper MHC class I assembly have been identified, their contribution to the immune escape phenotype of tumor cells has not been analyzed. In order to determine whether tapasin deficits are an integral part of immune escape mechanisms of human tumors, we studied the constitutive and cytokine-regulated expression pattern of tapasin in malignant cells of distinct histology. Heterogeneous and reduced expression levels of tapasin were found in small-cell lung carcinoma, pancreatic carcinoma, colon carcinoma, head an neck squamous cell carcinoma and renal cell carcinoma cell lines. Tapasin downregulation was also prominent in surgically removed tumor lesions when compared to normal controls. The impaired tapasin expression is often associated with low MHC class I cell surface expression. In addition, various cytokines, including interferon (IFN)-alpha, IFN-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4, but not granulocyte-macrophage colony stimulating factor (GM-CSF), transcriptionally upregulate to a distinct extent and in a time-dependent manner tapasin expression in tumor cells. Thus, deficient tapasin expression appears to be a frequent event in human tumor cells. Its restoration by cytokines further suggests that impaired tapasin expression in tumors is rather due to dysregulation than to structural alterations.
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PMID:Downregulation of the constitutive tapasin expression in human tumor cells of distinct origin and its transcriptional upregulation by cytokines. 1116 57

IL-5, IL-3, and GM-CSF are hematopoietic cytokines that are key mediators of the allergic inflammatory response. The receptors for these three cytokines consist of a cytokine-specific alpha (Ralpha) chain and a shared common beta (betac) chain. Herein, we demonstrate that agonistic ligation of these receptor subunits rapidly induces proteasomal degradation of the betac, but not the Ralpha, cytoplasmic domain, resulting in termination of signal transduction and yielding a truncated betac isoform ligated to the Ralpha subunit. Proteasomal degradation of the betac cytoplasmic domain was also a prerequisite for endocytosis and lysosomal degradation of the ligated receptor subunits. Moreover, proteasome-dependent termination of signaling induced by one betac-engaging cytokine resulted in cellular desensitization to signal transduction by subsequent stimulation with another betac-engaging cytokine. These data provide the first evidence for ligand-dependent proteasomal degradation of the betac cytoplasmic domain, and they establish a novel mechanism for heterotypic desensitization of shared cytokine receptor signaling.
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PMID:Proteasomal regulation of betac signaling reveals a novel mechanism for cytokine receptor heterotypic desensitization. 1174 63

Human CD46 (membrane cofactor protein, or MCP) and CDw150 (signaling lymphocyte activation molecule, or SLAM) serve as receptors for measles virus (MV), which induces marked host immune suppression. Although monocytes express CD46, they are considerably resistant to MV. Once monocytes differentiate into immature myeloid dendritic cells (iDCs) (GM-CSF + IL-4-treated), the cells become susceptible to MV. Therefore, we have identified CD46-adapted and CDw150-adapted strains of MV, and the dynamics of CD46 and CDw150 during monocyte-iDC conversion were examined in conjunction with MV susceptibility. Strikingly, CDw150 was not detected in monocytes and moderately induced in iDCs, while CD46 was constantly expressed in monocyte-to-iDC differentiation. Thus, iDCs were found to become highly permissive to CDw150-adapted MV strains via expression of CDw150. In fact, polyclonal and monoclonal antibodies that specifically blocked the MV receptor function of CD46 or CDw150 cancelled MV replication in iDCs according to the preferential usage of either CD46 or CDw150 in each strain of MV. Next, we showed that DCs that matured via stimulation of their Toll-like receptors (TLRs) 2 and/or 4 exhibited an approximately fivefold increase in CDw150 at the protein level, and concomitantly, higher levels of MV amplification were observed in mixed culture of lymphocytes than in iDCs without TLR2/4 stimuli. Hence, amplification of CDw150-dependent MV strains was augmented in DCs parallel with the levels of CDw150 in the presence of lymphocytes possessing CDw150. TLR-mediated functional potential of DCs may affect the degree of MV amplification through distinct MV strain-specific receptor usage of CDw150 or CD46.
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PMID:Susceptibility of human dendritic cells (DCs) to measles virus (MV) depends on their activation stages in conjunction with the level of CDw150: role of Toll stimulators in DC maturation and MV amplification. 1227 Jul 25

The global effect of ubiquitin-proteasome (UP) inhibitors on leukemic cell proteome was analysed. A total of 39 protein spots, affected by UP inhibitors, were identified, including 11 new apoptosis-associated proteins. They are involved in different cellular functions and four were associated with caspase-3 activation. Eukaryotic initiation factor 5A (eIF-5A) was identified in two spots; however, the peptide mass-fingerprinting for the accumulated one included a peptide with lysine50, indicating that hypusine formation was suppressed during UP inhibitor-induced apoptosis. Hypusine modification ensues immediately following translation of eIF-5A precursor, unless cells are treated with the modification inhibitors diaminoheptane. However, UP inhibitors induced a much stronger accumulation of unmodified eIF-5A compared to the effect of diaminoheptane. We further showed the unmodified eIF-5A was regulated in a proteasome-dependent manner. Inhibition of hypusine formation by diaminoheptane triggered apoptosis, but of particular interest is the finding that eIF-5A expression inhibition by antisense oligodeoxynucleotides significantly enhanced the stimulating effect of GM-CSF on cell growth. Therefore, the eIF-5A accumulation played important roles in the apoptosis induced by UP inhibitors. Moreover, hypusine inhibition in apoptosis was further revealed to be associated with the subcellular localization of eIF-5A. Our data pave the way to a better understanding of the mechanisms by which UP system has been linked to apoptosis.
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PMID:Proteomic analysis of ubiquitin-proteasome effects: insight into the function of eukaryotic initiation factor 5A. 1289 23

Pulmonary alveolar proteinosis (PAP) is a rare autoimmune lung disease characterized by abnormal surfactant accumulation within alveolar macrophages, and circulating auto-antibodies against granulocyte-macrophage colony stimulating factor (GM-CSF) resulting in functional GM-CSF deficiency. Monocyte/macrophage chemotactic protein-1 (MCP-1) is elevated in PAP, suggesting association with the pathophysiology. Because PAP has been associated with inflammatory pulmonary changes, we hypothesized that other MCP family chemokines would be present and that Chemokine Chemotaxis Receptor 2 (CCR2) would be elevated on PAP mononuclear cells. Here we show for the first time that MCP-2 and MCP-3, like MCP-1, are highly elevated in PAP. We also confirm that PAP alveolar macrophages and not epithelial cells produce MCP-1, and that MCP-1 from PAP lung has functional chemoattractant activity. Surprisingly, CCR2 expression is diminished in PAP lymphocytes and alveolar macrophages compared to controls. Further, MCP-1 from PAP lung suppresses CCR2 expression in vitro, suggesting that in PAP, MCP-1 participates in an autocrine regulatory network in vivo.
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PMID:Elevated monocyte chemotactic proteins 1, 2, and 3 in pulmonary alveolar proteinosis are associated with chemokine receptor suppression. 1559 12

We have identified human monocytic (THP-1) and myelogenous CD34+ (KG-1) leukemia cell lines that can be differentiated rapidly into mature dendritic cells (DCs) when cultured in serum-free medium containing GM-CSF, TNF-alpha, and ionomycin. These hematopoietic cell line-derived DCs are highly pure and monotypic, and display the morphologic, phenotypic, molecular, and functional properties of DCs generated from human donor-derived monocytes or CD34+ hematopoietic progenitor cells. During differentiation into mature DCs, the cells exhibit de novo cell-surface expression of CD83, CD80, CD86, CD40, CD206, CD209, CD120a, CD120b, and intracellular synthesis of IL-10, increase their endocytotic capacity, and acquire characteristic stellate morphology. To further define the cells as DCs, cytosolic induction and upregulation of RelB and RelA (p65), transcription factors of the NF-kappaB/Rel family essential for differentiation and maturation of DCs, as well as upregulation of the immunoproteasome subunits LMP2, LMP7, and MECL-1, and the proteasome activator PA28alpha, components essential for efficient MHC class I peptide antigen processing, were demonstrated during differentiation of the cells. In contrast to the cell lines, the cell line-derived mature DCs are capable of stimulating allogeneic CD4+ and CD8+ T cells, ultimately defining them as potent antigen-presenting cells. The approach to differentiate THP-1 and KG-1 cells into immature and mature DCs may serve as an experimental model to study molecular events and pathways that govern the differentiation of human malignant myeloid precursors, monocytes, and CD34+ hematopoietic progenitor cells into DCs.
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PMID:A cell line model for the differentiation of human dendritic cells. 1596 58


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