Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In HL-60 cells, retinoic acid (RA) and 9 cis-RA induce granulocytic differentiation, and calcitriol and sodium butyrate induce monocytic differentiation. To study the role of retinoid resistance on the response to these agents, we investigated their effects in HL-60 cells, retinoid-resistant HL-60R cells, and HL-60R+ cells in which retinoid sensitivity has been restored. In HL-60 cells, cathepsin D (ctsd) mRNA levels are increased by these agents and by cholera toxin after pretreatment with each agent. Calcitriol, 9 cis-RA, and sodium butyrate increase interleukin-8 (IL-8) mRNA expression, and pretreatment with these agents or RA potentiates the stimulation of IL-8 by phorbol ester (TPA). Pretreatment of HL-60 cells with all of the agents confers inducibility of cathepsin L (ctsl) mRNA by TPA in previously unresponsive cells. In HL-60R cells, none of the agents alone or in combination significantly enhances the expression of the ctsd, IL-8, or ctsl mRNAs. Retinoid stimulation (either alone or in combination with the other agents) of the three mRNAs is partially restored in the HL-60R+ cells. Calcitriol does not alter the expression of any of these mRNAs, and only the stimulation of IL-8 mRNA by sodium butyrate is recovered. Treatment with all of the agents inhibits proliferation and stimulates differentiation of the HL-60 cells. RA and calcitriol are unable to inhibit proliferation of the HL-60R cells, whereas only calcitriol fails to inhibit proliferation of the HL-60R+ cells. None of the agents induces differentiation in either the HL-60R or HL-60R+ cells. Therefore, the mutation of the RA receptor alpha is insufficient to account for the altered responses of the HL-60R cells, and there are likely defects in other signaling pathways in these cells. These cells may prove useful in examining the mechanism of cross-resistance between various differentiating agents.
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PMID:Comparative responsiveness of HL-60, HL-60R, and HL-60R+ (LRARSN) cells to retinoic acid, calcitriol, 9 cis-retinoic acid, and sodium butyrate. 767 94

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

Most of the increased protein degradation in muscle atrophy caused by starvation and denervation is due to activation of a non-lysosomal ATP-dependent proteolytic process. To determine whether expression of the ubiquitin-proteasome-dependent pathway is activated in atrophying muscles, we measured the levels of mRNA for ubiquitin (Ub) and proteasome subunits, and Ub content. After rats had been deprived of food for 1 or 2 days, the concentration of the two polyubiquitin (polyUb) transcripts increased 2-4-fold in the pale extensor digitorum longus muscle and 1-2.5-fold in the red soleus, whereas total muscle RNA and total mRNA content fell by 50%. After denervation of the soleus, there was a progressive 2-3-fold increase in polyUb mRNA for 1-3 days, whereas total RNA content fell. On starvation or denervation, Ub concentration in the muscles also rose by 60-90%. During starvation, polyUb mRNA levels also increased in heart, but not in liver, kidney, spleen, fat, brain or testes. Although the polyUb gene is a heat-shock gene that is induced in muscles under certain stressful conditions, the muscles of starving rats or after denervation did not express other heat-shock genes. On starvation or denervation, mRNA for several proteasome subunits (C-1, C-3, C-5, C-8 and C-9) also increased 2-4-fold in the atrophying muscles. When the food-deprived animals were re-fed, levels of Ub and proteasome mRNA in their muscles returned to control values within 1 day. In contrast, no change occurred in the levels of muscle mRNAs encoding cathepsin L, cathepsin D and calpain 1 on denervation or food deprivation. Thus polyUb and proteasome mRNAs increased in atrophying muscles in co-ordination with activation of the ATP-dependent proteolytic process.
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PMID:Increase in levels of polyubiquitin and proteasome mRNA in skeletal muscle during starvation and denervation atrophy. 774 90

These effects of polychlorinated biphenyl (PCB) were examined by light and electron microscopy and biochemical analysis of lysosomal enzyme activities. Several experimental protocols with dosage schedules of either 0.2, 2.0, or 20 mg/kg of PCB were used. Typical histological changes were observed in mice given 2 mg/kg of PCB in a single injection. There were no remarkable changes until 4 days after PCB administration; marked cytoplasmic vacuolation was observed in parotid acinar cells at 7 days. The activities of lysosomal enzymes increased after the PCB injection and their maximum values appeared consistently at 4 days after the treatment; the increases were threefold for acid phosphatase, twofold for beta-glucuronidase, threefold for cathepsin D, fivefold for cathepsin H and twofold for cathepsin L. As vacuolation was preceded by a large increase in lysosomal enzyme activities and the vacuoles co-localized with lysosomes, it is suggested that an increase in these activities induced by PCB may be closely related to the development of vacuolation in the parotid acinar cells as a subacute effect of PCB.
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PMID:Ultrastructural and biochemical studies of the effect of polychlorinated biphenyl on mouse parotid gland cells. 774 11

The recognition of lysosomal enzymes by UDP-GlcNAc: lysosomal-enzyme GlcNAc-1-phosphotransferase (phosphotransferase) is mediated by a protein structure on lysosomal enzymes. It has been previously demonstrated that lysine residues are required for phosphorylation of procathepsin L and are a common feature of the site on many lysosomal proteins. In this work, the procathepsin L recognition structure was further defined by identification of the region of the protein containing the structure and the critical lysine residues involved. Removal of the cathepsin L propeptide by low pH-induced autocatalytic processing abolished phosphorylation. The addition of either the purified propeptide or a glutathione S-transferase-propeptide fusion protein to the processed protein restored phosphorylation. Mutagenesis of individual lysine residues demonstrated that two propeptide lysine residues (Lys-54 and Lys-99) were required for efficient phosphorylation of procathepsin L. By comparison of the phosphorylation rates of procathepsin L, lysine-modified procathepsin L, and the procathepsin L oligosaccharide, lysine residues were shown to account for most, if not all, of the protein-dependent interaction. On this basis, it is concluded that the proregion lysine residues are the major elements of the procathepsin L recognition site. In addition, lysine residues in cathepsin D were shown to be as important for phosphorylation as those in procathepsin L, supporting a general model of the recognition site as a specific three-dimensional arrangement of lysine residues exposed on the surface of lysosomal proteins.
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PMID:Lysine-based structure in the proregion of procathepsin L is the recognition site for mannose phosphorylation. 779 59

The localization of cathepsins B, D, and L was studied in rat osteoclasts by immuno-light and -electron microscopy using the avidin-biotin-peroxidase complex (ABC) method. In cryosections prepared for light microscopy, immunoreactivity for cathepsin D was found in numerous vesicles and vacuoles but was not detected along the resorption lacunae of osteoclasts. However, immunoreactivity for cathepsins B and L occurred strongly along the lacunae, and only weak intracellular immunoreactivity was observed in the vesicles and peripheral part of the vacuoles near the ruffled border. In control sections that were not incubated with the antibody, no cathepsins were found in the osteoclasts or along the resorption lacunae of osteoclasts. At the electron microscopic level, strong intracellular reactivity of cathepsin D was found in numerous vacuoles and vesicles, while extracellular cathepsin D was only slightly detected at the base of the ruffled border but was not found in the eroded bone matrix. Most osteoclasts showed strong extracellular deposition of cathepsins B and L on the collagen fibrils and bone matrix under the ruffled border. The extracellular deposition was stronger for cathepsin L than for cathepsin B. Furthermore cathepsins B and L immunolabeled some pits and part of the ampullar extracellular spaces, appearing as vacuoles in the sections. Conversely, the intracellular reactivity for cathepsins B and L was weak: cathepsin-containing vesicles and vacuoles as primary and secondary lysosomes occurred only sparsely. These findings suggest that cathepsins B and L, unlike cathepsin D, are rapidly released into the extracellular matrix and participate in the degradation of organic bone matrix containing collagen fibrils near the tip of the ruffled border.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Localization of cathepsins B, D, and L in the rat osteoclast by immuno-light and -electron microscopy. 802 81

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

Cathepsins D, B, and L are acidic lysosomal proteinases involved in intracellular protein turnover. Increased levels of these enzymes have been reported to be indicators of aggressive tumor behavior in human and rodent tumors. In breast cancer increased levels of cathepsin D have been reported to be an independent prognostic factor in women with stage I disease. We used standard immunohistochemical techniques on formalin-fixed, paraffin-embedded tissue to examine the levels of cathepsins D, B, and L in 80 carcinomas of the breast and compared that with other indicators of aggressive tumor behavior, including stage of disease, tumor size, nuclear grade, estrogen receptor status, disease recurrence, and 5-year survival rates. Positive granular cytoplasmic staining was detected for cathepsin D in 90% of the tumors, for cathepsin B in two thirds of the tumors, and for cathepsin L in approximately one half of the tumors. Positive staining also was seen in normal breast epithelium, areas of apocrine metaplasia, stromal fibroblasts, and macrophages. Our results did not show a correlation between the expression of cathepsins D, B, and L and other indicators of aggressive tumor behavior. We conclude that the results obtained using polyclonal anticathepsin antibodies do not support the prognostic usefulness of immunohistochemical analysis of these three proteinases in tumor cells in human breast cancer.
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PMID:Immunohistochemical analysis of cathepsins D, B, and L in human breast cancer. 808 57

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

Immunohistochemical localization of cathepsins B, D and L in the osteoclasts of rat alveolar and femoral bones was investigated by using the avidin-biotin-peroxidase complex method for semithin, 1-micron-thick cryosections. Extracellular immunoreactivity for cathepsins B and L was clearly demonstrated along the bone resorption lacunae; the intensity of the extracellular immunoreactivity of cathepsin L was stronger than that of cathepsin B. However, the intracellular immunoreactivity of both cathepsins was weak compared with that of cathepsin D. The intracellular immunoreactivity of cathepsin D in the osteoclasts was clearly observed in the granules and/or vacuoles, but extracellular cathepsin D immunoreactivity was either negligible or not detected along the resorption lacunae. In the adjacent sections stained with anti-cathepsin L or D, extensive extracellular deposition of cathepsin L was found along the bone resorption lacunae, with or without osteoclasts, although the intracellular reactivity of cathepsin L was weak. This is the first morphological study in which cathepsins B and L have been demonstrated to be produced in the osteoclasts and extensively secreted into resorption lacunae, and in which cathepsin D was found to be present in the cells but scantily secreted into the lacunae. These findings suggest that cathepsins B and L directly and effectively participate in the degradation of the bone matrix.
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PMID:Immunohistochemical localization of cathepsins B, D and L in the rat osteoclast. 833 84


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