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 reported that proteasomes are expressed at abnormally high levels in various hematopoietic tumor cells (Kumatori, A., Tanaka, K., Inamura, N., Sone, S., Ogura, T., Matsumoto, T., Tachikawa, T., Shin, S., and Ichihara, A. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 7071-7075). In the present study, we examined changes in the expressions of proteasomes during growth of peripheral T-lymphocytes from healthy adults and differentiation of human leukemic cell lines. Up-regulation of mRNAs encoding multiple proteasome subunits was observed during proliferation of resting T-cells induced by mitogens such as phytohemagglutinin and interleukin-2. In contrast, in vitro terminal differentiation into monocytic, granulocytic, and erythroid cells of various immature leukemic cell lines, such as HL-60 promyelocytic leukemia cells and K562 erythroleukemia cells, by various inducing agents caused rapid and marked down-regulation of proteasomes expression, independently of the cell type, direction of differentiation, or type of signal. The syntheses of proteasome subunits of 21-31 kDa and their associated components of 35-110 kDa, measured by [35S]methionine incorporation, were much higher in mitogen-activated T-cells and unstimulated HL-60 cells, which grow rapidly, than in resting and differentiated cells, indicating apparent correlations of the mRNA levels of proteasomes with their translational activities. However, immunochemically, no detectable difference in the cellular contents of proteasomes was found in these cells in induced and uninduced states for proliferation and differentiation, suggesting accelerated turnover of proteasomes in rapidly proliferating cells. Inhibition of proteasome expression by an antisense oligodeoxynucleotide for the largest proteasome subunit, C2, caused partial arrest of cell cycle progression of T-lymphocytes, suggesting that up-regulation of proteasomes is indispensable for proliferation of the cells. We also observed that the nuclear fraction of proteasomes increased in proliferating T-cells and that proteasomes moved rapidly between the nucleus and cytoplasm during differentiation of HL-60 cells.
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PMID:Regulation of gene expression of proteasomes (multi-protease complexes) during growth and differentiation of human hematopoietic cells. 151 42

The present study was designed to examine the effect of Pseudomonas aeruginosa alkaline protease (AP) and elastase (Ela) on human natural killer (NK) cell activity in vitro. AP and Ela were found to inhibit NK cell function. Addition of alpha interferon and interleukin-2 did not abolish this inhibition of NK cell activity. Adhesion of effector to target cells was studied in a single-cell agarose assay of monocyte-depleted NK-cell-enriched cell populations. AP and Ela were shown to inhibit effector/target cell conjugate formation. Furthermore, AP and Ela inhibited the binding of the monoclonal antibody Leu-11, which reacts with the Fc receptor of NK cells. The inhibition of NK cell binding to the target cell by P. aeruginosa proteases is most likely due to proteolytic cleavage of the surface receptors involved in the binding of the effector cell to the target cell.
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PMID:Inhibition of human natural killer cell activity by Pseudomonas aeruginosa alkaline protease and elastase. 303 Sep 37

This study was undertaken to determine the effect of Pseudomonas aeruginosa alkaline protease (AP) and elastase (ELA) on human lymphocyte function. AP at 50 micrograms/ml and ELA at 12 micrograms/ml caused a 50% inhibition of phytohemagglutinin-induced proliferation. There was no difference in the effect of proteases on CD4- and CD8-positive cells. To determine the effect of proteases on interleukin-2 (IL-2)-induced cell proliferation, the proteases and IL-2 were added to the IL-2-dependent CTLL-2 cell line. AP and ELA inhibited the proliferation of these cells. When IL-2 was added in excess, the inhibition was partly reversed. ELA at 10 micrograms/ml cleaved IL-2, as judged by size chromatography of a reaction mixture containing 125I-labeled IL-2 and the proteases. The ELA-digested IL-2 exhibited a reduced binding capacity to IL-2 receptors on the lymphocytes. Furthermore, treatment of phytohemagglutinin-stimulated lymphocytes with AP and ELA resulted in inhibition of binding of intact IL-2 to IL-2 receptors on the stimulated lymphocytes. These results indicated that P. aeruginosa-derived enzymes are able to interfere with human lymphocyte function in vitro and that this effect might be due to cleavage of IL-2.
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PMID:Inhibition of human lymphocyte proliferation and cleavage of interleukin-2 by Pseudomonas aeruginosa proteases. 313 17

The biochemical properties of heretofore uncharacterized extracellular proteases of rat interleukin-2-activated natural killer (A-NK) cells were investigated. Following p-aminobenzamidine- and D-phenylalanine-agarose affinity chromatography both trypsin- and chymotrypsin-like protease activities were found. Zymography revealed "trypsin-like" activities, with apparent molecular weights of approximately 42 kDa to 20.5 kDa, and "chymotrypsin-like" activities of approximately 27 kDa, to 22 kDa. These proteases might contribute to diverse NK cell functions, and the characteristics of these proteolytic activities are compared with those of granzymes of lytic granules and the proteasome of A-NK cells.
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PMID:Zymographic analysis of extracellular, released and cell-associated proteases of rat interleukin 2-activated natural killer (A-NK) cells. 805 9

We have recently described nongranular, cytosolic, high-molecular-weight trypsin-like (A-NKP 1) and chymotrypsin-like (A-NKP 2) proteases of interleukin-2-activated rat natural killer (A-NK) cells. A functional correlation between the inactivation of A-NKP 2 and the inhibition of rat A-NK cell-mediated cytotoxicity was found. Herein we describe the 6,000-fold purification of A-NKP 2 to apparent homogeneity following: isopycnic sucrose gradient fractionation of postnuclear supernatants, molecular sieve chromatography, and heparin-Sepharose chromatography. We also report the novel finding that A-NKP 2 as well as A-NKP 1, derived from either rat A-NK cells or the rat NK leukemic cell line CRNK-16, are constituents of the multicatalytic proteinase (MCP/proteasome) complexes of these cells. Characteristic biochemical, biophysical, and electron microscopic/ultrastructural similarity to the rat liver proteasome was observed. However, Western blot analysis using polyclonal antibodies to the rat liver proteasome clearly indicated differences in the rat hepatic proteasome and the CRNK-16-derived proteasomal subunits. The identification, characterization, and purification of A-NKP 1 and A-NKP 2, described herein, now allow for further investigation of the potential role of these proteasome components in NK cell function. Moreover, the proteasome of NK and A-NK cells can now be compared and contrasted to the granzymes of lytic granules with respect to their role in cell-mediated cytotoxicity.
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PMID:Nongranular proteolytic enzymes of rat IL-2-activated natural killer cells. II. Purification and identification of rat A-NKP 1 and A-NKP 2 as constituents of the multicatalytic proteinase (proteasome) complex. 808 94

Interleukin-2 (IL-2) activates the receptor-associated Janus family tyrosine kinases, Jak1 and Jak3, which in turn phosphorylate and activate specific STAT proteins (signal transducers and activators of transcription), such as STAT5. Activation of Jak and STAT proteins by IL-2 is transient and the mechanism for the subsequent down-regulation of their activity is largely unknown. We report here that IL-2-induced DNA-binding activity and tyrosine phosphorylation of STAT5 are stabilized by a proteasome inhibitor MG132; however, no detectable ubiquitination of the STAT proteins is observed. This sustained STAT5 activation can be blocked by protein kinase inhibitors, which is consistent with the ability of the proteasome inhibitor to stabilize IL-2-induced tyrosine phosphorylation of Jak1 and Jak3. These results suggest that proteasome-mediated protein degradation modulates protein-tyrosine phosphatase activity that negatively regulates the Jak-STAT signaling pathways.
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PMID:Involvement of proteasomes in regulating Jak-STAT pathways upon interleukin-2 stimulation. 916 19

Optimal T cell activation and interleukin-2 production requires a second signal in addition to antigen-mediated T cell receptor (TCR) signaling. The CD28 molecule has been demonstrated to act as an effective costimulatory molecule upon binding by B7.1 or B7.2 present on antigen-presenting cells. The CD28 signal acts in concert with the TCR signal to significantly augment activation of the NF-kappaB family of transcription factors. The interleukin-2 gene is regulated by NF-kappaB among other transcription factors, in part, via a CD28 responsive element (CD28RE) present in the IL-2 promoter. Enhanced activation of NF-kappaB by CD28 is mediated by rapid phosphorylation and proteasome-mediated degradation of the NF-kappaB inhibitory proteins IkappaB alpha and IkappaB beta, which allows for accelerated nuclear expression of the liberated NF-kappaB. Herein, we provide evidence that the catalytic activities of two recently identified IkappaB kinases, IKKalpha and IKKbeta, are significantly elevated when T cells are stimulated through CD28 in addition to mitogen treatment. Catalytically inactive forms of IKKs are able to block the in vivo phosphorylation of IkappaB alpha induced by mitogen and CD28. Furthermore, CD28-mediated reporter gene transactivation of the CD28RE/AP-1 composite element is consistently attenuated by the IKK mutants. These findings suggest that cellular signaling pathways initiated at the TCR and CD28 converge at or upstream of IKK, resulting in more robust kinase activity and enhanced and prolonged NF-kappaB activation.
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PMID:IkappaB kinases serve as a target of CD28 signaling. 973 79

Recent studies have increasingly implicated the proteasome in the regulation of cell surface receptors. In the present study, we investigated the role of the proteasome for ligand-dependent endocytosis and degradation of the interleukin-2 (IL-2)-interleukin-2 receptor (IL-2R) complex. Proteasome inhibitors impaired internalization of IL-2.IL-2R and prevented the lysosomal degradation of this cytokine. Based on time-course studies, proteasome activity is primarily required after initial endocytosis of the IL-2.IL-2R. Proteasome function was also necessary for the lysosomal degradation of IL-2 internalized by IL-2R that were comprised of cytoplasmic tailless beta- or gamma c-subunits, suggesting that the target protein for the proteasome is independent of either the cytoplasmic tail of the IL-2R beta- or gamma c-subunits and their associated signaling components. Therefore, a functional proteasome is required for optimal endocytosis of the IL-2R/ligand complex and is essential for the subsequent lysosomal degradation of IL-2, possibly by regulating trafficking to the lysosome.
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PMID:The proteasome regulates receptor-mediated endocytosis of interleukin-2. 1103 38

The p27Kip1 cell cycle inhibitor (p27) has emerged as a critical mediator of normal cellular growth control. We report the expression of a 24 kD C-terminal variant of p27 in normal peripheral blood lymphocytes. This variant is rapidly degraded in a proteasome-dependent manner when lymphocytes are activated by interleukin-2 or by superantigen. Whereas p24 degradation is complete within 16 h of mitogen addition, full-length p27 is decreased only modestly over 72 h of mitogen exposure and is present in activated and cycling lymphocytes. Persistent p27 is present in a complex with cyclin D3 in activated lymphocytes, and is localized both in the nucleus and cytoplasm. These results indicate that lymphocytes exiting from quiescence use several mechanisms to overcome the p27Kip1-enforced cell cycle checkpoint, and that elimination of p27 is not required for cell cycle entry.
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PMID:Dynamic changes in p27kip1 variant expression in activated lymphocytes. 1159 7

VE-cadherin is an endothelial-specific cadherin that plays important roles in vascular morphogenesis and growth control. To investigate the mechanisms by which endothelial cells regulate cadherin cell surface levels, a VE-cadherin mutant containing the non-adhesive interleukin-2 (IL-2) receptor extracellular domain and the VE-cadherin cytoplasmic tail (IL-2R-VE-cadcyto) was expressed in microvascular endothelial cells. Expression of the IL-2R-VE-cadcyto mutant resulted in the internalization of endogenous VE-cadherin and in a dramatic decrease in endogenous VE-cadherin levels. The internalized VE-cadherin co-localized with early endosomes, and the lysosomal inhibitor chloroquine dramatically inhibited the down-regulation of VE-cadherin in cells expressing the IL-2R-VE-cadcyto mutant. Chloroquine treatment also resulted in the accumulation of a VE-cadherin fragment lacking the beta-catenin binding domain of the VE-cadherin cytoplasmic tail. The formation of the VE-cadherin fragment could be prevented by treating endothelial cells with proteasome inhibitors. Furthermore, inhibition of the proteasome prevented VE-cadherin internalization and inhibited the disruption of endothelial intercellular junctions by the IL-2RVE-cadcyto mutant. These results provide new insights into the mechanisms of VE-cadherin processing and degradation in microvascular endothelial cells.
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PMID:Mechanisms of VE-cadherin processing and degradation in microvascular endothelial cells. 1262 12


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