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:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the potential contribution of the lysosomal compartment in the processing of amyloid precursor protein (APP) to amyloid beta-peptides (A beta s), we stably overexpressed a series of lysosomal proteases (the cysteine proteases, cathepsins B, L and S, and the aspartic protease, cathepsin D) in a human kidney epithelial cell line (293) transfected to express high levels of beta APP. Preliminary experiments indicated that 293 cells endogenously synthesize cathepsins B, L and D, but not cathepsin S. A beta secretion was assessed by immunoprecipitation and ELISA and found to be increased approximately 2-fold following cathepsin S expression, but to be unchanged (cathepsins B, L) or decreased (cathepsin D) in the other double transfectants. E-64d, an inhibitor of lysosomal cysteine proteases, significantly reduced A beta secretion by the cathepsin S transfectants, but had no effect on cells expressing the other proteases. Radiosequencing of A beta secreted by cathepsin S-expressing cells revealed that a previously unreported variant beginning at Met -1 (relative to the most common A beta N-terminus, Asp -1) accounted for most of the increase in A beta secretion. Immunostaining of human brain sections revealed cathepsin S in cortical neurons and glia in samples of brain from patients with Alzheimer's disease. These results provide evidence in living cells for a pathway in which cathepsin S generates A beta from amyloidogenic fragments of beta APP in the endosomal/lysosomal compartment. This pathway appears to be inducible, distinct from a constitutive pathway used by 293 and other cells to generate A beta, and may be relevant to the pathogenesis of Alzheimer's disease.
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PMID:Lysosomal processing of amyloid precursor protein to A beta peptides: a distinct role for cathepsin S. 757 68

In cytosols of tumour and normal tissue of 53 patients suffering from head and neck carcinoma cathepsins D, B, H and L were measured using quantitative immunoreactive assays (ELISA). The values of cathepsins D, B and L were significantly higher in tumour tissue, whereas cathepsin H concentration was lower in tumour than in normal tissue. Median cathepsin D values were 27 pmol (tumour tissue) vs. 12 pmol (normal tissue) per mg of total protein, median cathepsin B values were 1.25 micrograms/mg (tumour tissue) vs. 0.23 micrograms/mg (normal tissue) and median cathepsin L values were 39.8 ng/mg (tumour tissue) vs. 20.0 ng/mg (normal tissue). Median cathepsin H values were 1.05 micrograms/mg and 2.20 micrograms/mg for tumour and normal tissue, respectively. Additionally, stefin A and stefin B were measured in tumour and normal tissue samples. In contrast to the cathepsins, the concentrations of these inhibitors of cysteine proteinases was not significantly different between tumour and normal samples. The concentrations of cathepsins D, B, H and L and stefins A and B measured in head and neck tumours, were independent of standard clinical and histological prognostic factors. Significant correlation of tumour tissue values was observed between cathepsins B and L and between both stefins.
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PMID:Lysosomal proteases cathepsins D, B, H, L and their inhibitors stefins A and B in head and neck cancer. 757 36

Chicken vitellogenin, a serum lipoprotein specific for laying hens, has been thought to be proteolytically cleaved into the heavy and light chain lipovitellins and phosvitin, the major yolk granule proteins, during or after transportation into oocyte. In this study, another proteolytic product of vitellogenin has newly been isolated from the 'beta-livetin' fraction of yolk plasma. It is a yolk glycoprotein of 40 kDa (YGP40) with asparagine-linked carbohydrate chain(s) recognized by Concanavalin A and castor bean lectin (RCA-I), and it is identified as a C-terminal cysteine-rich fragment of the major vitellogenin (vitellogenin II), the cysteine-rich domain homologous to D2 region of von Willebrand factor. Another yolk plasma glycoprotein of 42 kDa is suggested to be one of the proteolytic products of the minor vitellogenin (vitellogenin I). Both 40 kDa and 42 kDa glycoproteins were shown to be present in growing oocytes but absent in laying hen's serum. Limited proteolysis of vitellogenin II with cathepsin D produced a 40 kDa protein with reactivity to anti-YGP40 antibody. Gel filtration analysis of vitellogenin II digested with cathepsin D showed that YGP40 dissociated from lipovitellin-phosvitin complex after the proteolytic cleavage. These results suggest that after incorporation from serum via a specific receptor vitellogenin II is cleaved in the oocyte into four fragments, heavy and light chain lipovitellins, phosvitin and YGP40, and that YGP40 is released into the yolk plasma before or during compartmentation of lipovitellin-phosvitin complex into the yolk granule.
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PMID:Precursor-product relationship between chicken vitellogenin and the yolk proteins: the 40 kDa yolk plasma glycoprotein is derived from the C-terminal cysteine-rich domain of vitellogenin II. 759 59

Most native antigens require digestion by acidic proteases in order to be recognized in the context of major histocompatibility complex class II by T helper cells (Th). We have studied the roles of three different acidic proteases, cathepsin D, cathepsin B and cathepsin L, in the processing of ovalbumin (OVA) for presentation in the context of I-Ad. We report that digestion of OVA in vitro with the aspartyl protease cathepsin D generates the epitope OVA322-336, which is recognized by I-Ad-restricted OVA-specific Th in the presence of paraformaldehyde-fixed antigen-presenting cells (APC). In contrast, digestion of OVA with the cysteine proteases cathepsin B and L not only failed to generate an epitope, but also destroyed OVA322-336. In the presence of fixed APC expressing I-Ad. OVA322-336 was protected from destructive proteolysis by cathepsin L. These results illustrate the dependence of epitope selection on the intracellular proteolytic environment in APC, and suggest that mechanisms must exist for protection of epitopes from destructive proteolysis in the processing compartments.
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PMID:Destructive proteolysis by cysteine proteases in antigen presentation of ovalbumin. 762 59

Previous studies have indicated that acid-optimal cysteine proteinase(s) in the endosomal-lysosomal compartments, cathepsins, play a critical role in the proteolytic processing of endocytosed proteins to generate the antigenic peptides presented to the immune system on major histocompatibility complex (MHC) class II molecules. The presentation of these peptides and the expression of MHC class II molecules by macrophages and lymphocytes are stimulated by gamma-interferon (gamma-IFN). We found that treatment of human U-937 monocytes with gamma-IFN increased the activities and the content of the two major lysosomal cysteine proteinases, cathepsins B and L. Assays of protease activity, enzyme-linked immunosorbant assays (ELISA) and immunoblotting showed that this cytokine increased the amount of cathepsin B 5-fold and cathepsin L 3-fold in the lysosomal fraction. By contrast, the aspartic proteinase, cathepsin D, in this fraction was not significantly altered by gamma-IFN treatment. An induction of cathepsins B and L was also observed in mouse macrophages, but not in HeLa cells. These results suggest coordinate regulation in monocytes of the expression of cathepsins B and L and MHC class II molecules. Presumably, this induction of cysteine proteases contributes to the enhancement of antigen presentation by gamma-IFN.
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PMID:Gamma-interferon causes a selective induction of the lysosomal proteases, cathepsins B and L, in macrophages. 772 59

Study of the expression of the aspartyl cathepsin D-like and cysteine cathepsin L-like proteinases was carried out on a model system of rat embryo fibroblasts. The model system employed makes it possible to distinguish two discrete successive stages of transformation in vitro: immortalization and tumorigenic transformation. The dynamics of expression and subcellular distribution of proteinases throughout the transformation process was followed. It was shown that in immortalized and transformed cells the activities of the aspartyl and cysteine proteinases were expressed to a variable degree and the expression was dependent on the time of cell cultivation. The increase in both the aspartyl cathepsin D-like proteinase and cysteine cathepsin L- and B-like proteinase activities was correlated with the stage of fibroblast transformation. At all stages studied of transformation, the major part of cathepsin L-like proteinase activity was localized within the cell, while among secreted proteinases the cathepsin D-like proteinase was apparently predominant. It was found that the secreted cathepsin D-like proteinase in all cell cultures studied was complexed with the inhibitor.
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PMID:[Expression of cathepsins D and L during neoplastic transformation of fibroblasts]. 807 33

A procedure was developed for simultaneous isolation of aspartyl and cysteine proteinases as well as of the cysteine-proteinase inhibitors. Affinity chromatography using pepstatin-Sepharose enabled one to isolate aspartyl proteinases, while inhibitors of cysteine-proteinases were isolated by affinity chromatography on CM-papain-Sepharose; further purification of the enzymes was carried out using ion exchange chromatography and gel filtration. Partially purified preparations of cathepsin D as well as of cysteine-proteinases and their inhibitors were obtained. Some physicochemical and enzymatic properties of the enzymes and inhibitors obtained were studied.
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PMID:[A comparative study of aspartyl and cysteine proteinases and their inhibitors in human B- and T-cell leukemias]. 807 45

Malignant tumors derived from 60 patients with primary ovarian cancer were assayed for lysosomal cysteine proteinases--cathepsins B and L (Cat B, Cat L) and lysosomal aspartyl proteinase--cathepsin D (Cat D) as compared with benign ovarian tumors in controls. Malignant ovarian tumors exhibited significantly increased Cat B and Cat L activity (18.5- and 9-fold, respectively, p < 0.001) and moderately increased Cat D activity (1.5-fold, p < 0.01) as compared with those of benign tumors. The data obtained indicate that malignant ovarian tumors with a high Cat B activity (higher than the critical level of 723.5 +/- 100.0 Opmol/min. mg protein) proved to be more malignant in nature (low cell differentiated tumors predominated with early metastases spreading and relapses). Retrospective analysis of the disease development in 38 patients with ovarian tumors revealed that patients with early relapses (within the first year after surgery) demonstrated higher Cat B activity in tumors as compared with both the critical level and with that of patients without relapses; in the latter group the increase was found to be 2.4-fold (p < 0.01). The rate of CatB activity increases proved to be 56% and 8% in patients with and without relapses, respectively. Therefore, evaluation of the critical level of CatB activity in patients with primary ovarian cancer may be employed for prognostic purposes.
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PMID:[Prognostic significance of determining cathepsin B activity in malignant ovarian tumors]. 812 4

Altered cellular levels and localizations of four distinct intracellular proteinases, cathepsins D, E, B, and L, with aging were studied in various rat brain tissues by enzymatic and immunohistochemical methods using discriminative antibodies specific for each enzyme. With regard to two aspartic proteinases, cathepsin E was barely detectable in all the brain tissues of young adult rats, including the cerebral cortex, the hippocampus, the neostriatum, and the cerebellum, whereas cathepsin D was ubiquitously found in these tissues. Two cysteine proteinases, cathepsins B and L, also existed in these tissues of young rats at the relatively high levels of activities. In aged rats, the cathepsin D levels in all of the brain tissues examined were about twice those of young rats. Cathepsin E was markedly increased in the cerebral cortex and neostriatum of aged rats, but not in the other tissues. The levels of cathepsin B were also increased significantly in the neostriatum of aged rats, but not significantly in the other tissues. In contrast, the activity levels of cathepsin L were strikingly decreased in all the brain tissues of aged rats. At the light microscopic level, the increased immunoreactivity of cathepsins D and E in the brain tissues of aged rats was eminent in both the neurons and the glial cells. By double-immunostaining technique, the cathepsin D-positive glial cells were mainly associated with reactive astrocytes, whereas the cathepsin E-positive glial cells were largely reactive microglial cells. Western blot analyses revealed that the molecular forms of cathepsins D and E increasingly expressed in the cerebral cortex of aged rats were similar to those of the respective normal mature enzymes. The increased immunoreactivity of cathepsin B in the neostriatum of aged rats was also found in both the neurons and the glial cells. Despite the marked decrease of the cathepsin L activity in various brain tissues of aged rats, the immunostaining for this enzyme was not significantly changed, indicating the occurrence of the catalytically inactive form of the enzyme in these tissues. These results suggest that the increased levels of cathepsins D, E, and B and the decrease in cathepsin L activity in brain regions of aged rats are related to both the neuronal degeneration and the reactivation of glial cells during the normal aging process of the brain.
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PMID:Age-related changes in activities and localizations of cathepsins D, E, B, and L in the rat brain tissues. 815 22

Plasma cells secrete IgM only in the polymeric form: the C-terminal cysteine of the mu heavy chain (Cys575) is responsible for both intracellular retention and assembly of IgM subunits. Polymerization is not quantitative, and part of IgM is degraded intracellularly. Neither chloroquine nor brefeldin A (BFA) inhibits degradation, suggesting that this process occurs in a pre-Golgi compartment. Degradation of IgM assembly intermediates requires Cys575: the monomeric IgMala575 mutant is stable also when endoplasmic reticulum (ER) to Golgi transport is blocked by BFA. Addition of the 20 C-terminal residues of mu to the lysosomal protease cathepsin D is sufficient to induce pre-Golgi retention and degradation of the chimeric protein: the small amounts of molecules which exit from the ER are mostly covalent dimers. By contrast, when retained by the KDEL sequence, cathepsin D is stable in the ER, indicating that retention is not sufficient to cause degradation. Replacing the C-terminal cysteine with serine restores transport through the Golgi. As all chimeric cathepsin D constructs display comparable protease activity in vitro, their different fates are not determined by gross alterations in folding. Thus, also out of its normal context, the mu chain Cys575 plays a crucial role in quality control, mediating assembly, retention and degradation.
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PMID:Quality control of ER synthesized proteins: an exposed thiol group as a three-way switch mediating assembly, retention and degradation. 822 84


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