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)

Glucocorticoids signal enhanced proteolysis in various instances of muscle atrophy and increased gene expression of components of the lysosomal, Ca(2+)-dependent, and/or ubiquitin-proteasome proteolytic pathways in both rat skeletal muscle and myotubes. Cushing's syndrome is characterized by chronic excessive glucocorticoid production, which results in muscle wasting. We report here no change in messenger RNA levels for cathepsin D (a lysosomal proteinase), m-calpain (a Ca(2+)-activated proteinase), ubiquitin, 14-kDa ubiquitin-activating enzyme E2, and 20S proteasome subunits (i.e. critical components of the ubiquitin-proteasome proteolytic process) in skeletal muscle from such patients. Thus, in striking contrast with animal studies, glucocorticoids did not regulate the expression of muscle proteolytic genes in Cushing's syndrome. In humans, messenger RNA levels, for at least ubiquitin and proteasome subunits, are elevated in acute situations of muscle wasting, such as head trauma or sepsis. Because Cushing's syndrome is a chronic catabolic condition, we suggest that the lack of regulation of proteolytic genes in such patients may represent an adaptive regulatory mechanisms, preventing sustained increased protein breakdown and avoiding rapid muscle wasting.
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PMID:Glucocorticoids do not regulate the expression of proteolytic genes in skeletal muscle from Cushing's syndrome patients. 928 62

To understand the retinal changes in Alzheimer disease (AD) patients, pathological and immunocytochemical studies were performed on retinal cells in the chloroquine-treated rats at 0, 4, 8, 12, 16, 20, and 24 weeks after the initial injection, using anti-amyloid precursor protein (APP), -amyloid beta protein (A beta), -apolipoprotein E (apoE), -ubiquitin, and -cathepsin D antibodies. Pathological alterations consistent with chloroquine retinopathy were recognized in the ganglion cells of the ganglion cell layer (GCL) and the inner plexiform layer (IPL) 4 weeks after initial chloroquine injection. Rat retinal changes appear to have a direct relationship to the duration of chloroquine administration. Intense immunoreactivities for anti-APP, A beta, apoE (an associated protein), and ubiquitin co-localized in the swollen ganglion cells and Muller cells by 20-24 weeks together with the lysosomal enzyme cathepsin D. The present data indicate that the endosomal/lysosomal pathway plays an important role in the processing of APP in rat retina. This experimental model is considered to be a suitable neural model to understand retinal pathology and the processing of APP in terms of the pathogenesis of AD, whereas chloroquine-induced myopathy is a useful extra neuronal model.
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PMID:Amyloid precursor protein, A beta and amyloid-associated proteins involved in chloroquine retinopathy in rats--immunopathological studies. 929 26

To analyze the degradation system in epidermal cells during their generation, differentiation, and cell death, immunocytochemical localization of lysosomal cysteine and aspartic proteinases, an endogenous cysteine proteinase inhibitor, cystatin beta, and ubiquitin were examined using rat sole skin. By confocal laser microscopy, granular immunodeposits for lysosomal proteinases were well demonstrated in epidermal cells; immunoreactivity for cathepsins B and C was prominent in the lower spinous and basal layers, while that for cathepsins L and D was intense in the upper spinous and granular layers, although immunoreactivity for cathepsin D was also detected in the lower epidermal layers. Immunoreactivity for cathepsin H was weakly detected only in the spinous layer, where there were some intensely immunopositive cells with processes which were also immunopositive for S-100 alpha, indicating that these cells were Langerhans cells. Diffuse immunoreactivity for cystatin beta was intense in the spinous and granular layers and weak in the basal layer. In addition, we also examined the localization of ubiquitin, which is a signal peptide for cytosolic proteolysis; clear-cut granular immunodeposits for ubiquitin were detected in spinous and granular cells, and some were co-localized with cathepsin B immunoreactivity. In the basal layer, mitotic cells were strongly immunopositive for ubiquitin. These results suggest that cysteine and aspartic proteinases are involved in the lysosomal system of the epidermis, showing different distributions in the epidermal layers depending on the enzymes examined. Moreover, ubiquitin may be associated with the cell cycle-dependent degradation in basal cells while it also participates in the non-lysosomal proteolysis and probably, lysosomal proteolysis in the spinous and granular cells.
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PMID:Immunocytochemical localization of lysosomal cysteine and aspartic proteinases, and ubiquitin in rat epidermis. 937 75

Ultrastructural immunocytochemical studies were performed on sections of bone marrow from three patients with beta-thalassaemia major and two patients with haemoglobin H (HbH) disease. Some sections were reacted with either a polyclonal or a monoclonal anti-human-ubiquitin antibody and the reaction visualized using a gold-labelled secondary antibody. The inclusions of precipitated globin chains found within the erythropoietic cells of all five patients reacted much more strongly than the surrounding inclusion-free cytoplasm with both of the anti-ubiquitin antibodies, indicating that the precipitated globin chains were ubiquitinated. A non-specific reaction between the anti-ubiquitin antibodies and the inclusions was excluded by demonstrating that various other antibodies, including a polyclonal anti-human cathepsin D antibody, did not react with the inclusions. The data suggest that the ubiquitin proteolytic pathway is involved in the degradation of precipitated globin chains in alpha- and beta-thalassaemia.
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PMID:Evidence that the ubiquitin proteolytic pathway is involved in the degradation of precipitated globin chains in thalassaemia. 960 17

A mutant amyloid precursor protein (APP/RK) designed to interfere with processing by alpha-secretase caused a severe phenotype in transgenic mice, including behavioural abnormalities, i.e. neophobia, aggression, hypersensitivity to kainic acid, hyposensitivity to N-methyl-D-aspartate, and premature death [Moechars D. et al. (1996) Eur. molec. Biol. Org. J. 15, 1265-1274]. We now demonstrated that the APP/RK transgene did not disturb the expression of several other genes, i.e. endogenous amyloid precursor protein and amyloid precursor protein-like proteins, members of the low density lipoprotein receptor lipoprotein receptor family and several of their ligands, including apolipoprotein E, but expression of alpha-2-macroglobulin was never detected. Neither amyloid deposits nor neurofibrillary tangles were detected in the brain of APP/RK transgenic mice, even when 15-months-old. The tendency for seizures and hyposensitivity for N-methyl-D-aspartate was not due to or reflected in the distribution of the three major types of glutamate receptors. The major and consistent finding in transgenic APP/RK mice that died prematurely was extensive neurodegeneration and apoptosis, mainly in hippocampus and cortex, and accompanied by astrocytosis throughout the brain. Reduced synaptic density and dendritic damage was only observed in three transgenic mice that were killed shortly after positive observation of seizures. In addition, the distribution of cathepsin D and ubiquitin was abnormal in these mice.
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PMID:Premature death in transgenic mice that overexpress a mutant amyloid precursor protein is preceded by severe neurodegeneration and apoptosis. 1039 65

We assessed the effects of a long and severe period of underfeeding, followed by a rapid refeeding with a high-concentrate diet, on weight, protein mass, and cellularity of the splanchnic organs in adult ewes. Twenty-four ewes, allocated to four groups of six, were fed a forage diet (50% regrowth of natural grassland hay and 50% wheat straw) either at maintenance (groups M and MO) or at 40% maintenance (groups U and UO) for 78 d. Groups M and U were then slaughtered, and groups MO and UO were subsequently overfed a high-concentrate diet (52% hay, 20% barley, 16% rapeseed meal, 4% fish meal, and 8% Megalac) at 236% maintenance for 26 d before being slaughtered. During the experiment, feed was adjusted to maintain feed supply at a constant percentage of animal requirements. After slaughter, fresh weight, dry weight, and protein mass of the reticulorumen, omasum, abomasum, small intestine, large intestine, and liver were measured. Cellularity was assessed from nucleic acids and protein contents for both ruminal mucosa and muscular-serosa layers, jejunum, and liver. The concentrations of ubiquitin and cathepsin D mRNA were measured in ruminal mucosa and muscular-serosa layers and in jejunum. Underfeeding decreased protein mass of splanchnic organs, especially in liver (-29%) and reticulorumen (-39%). Refeeding previously underfed animals increased protein mass of liver (+102%) and small intestine (+59%). No carry-over effect of the previous level of intake (UO vs. MO) was observed on the protein mass of splanchnic tissues after 26 d of refeeding. Variations in liver mass were mainly due to hypertrophy, as determined by the protein:DNA ratio, whereas variations in small intestinal mass were mainly due to hyperplasia, as determined by the amount of DNA. By contrast, changes in rumen mass associated with increasing ME intake seemed to be related to hypertrophy in the muscular-serosal component and hyperplasia in the epithelial component. The concentrations of ubiquitin and cathepsin D mRNA in the rumen and jejunum were not modified by feeding level, demonstrating that the expression of these genes for proteolytic enzymes was unchanged under these conditions.
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PMID:Effects of underfeeding and refeeding on weight and cellularity of splanchnic organs in ewes. 1046 9

An expansion of polyglutamines in the N terminus of huntingtin causes Huntington's disease (HD) and results in the accrual of mutant protein in the nucleus and cytoplasm of affected neurons. How mutant huntingtin causes neurons to die is unclear, but some recent observations suggest that an autophagic process may occur. We showed previously that huntingtin markedly accumulates in endosomal-lysosomal organelles of affected HD neurons and, when exogenously expressed in clonal striatal neurons, huntingtin appears in cytoplasmic vacuoles causing cells to shrink. Here we show that the huntingtin-enriched cytoplasmic vacuoles formed in vitro internalized the lysosomal enzyme cathepsin D in proportion to the polyglutamine-length in huntingtin. Huntingtin-labeled vacuoles displayed the ultrastructural features of early and late autophagosomes (autolysosomes), had little or no overlap with ubiquitin, proteasome, and heat shock protein 70/heat shock cognate 70 immunoreactivities, and altered the arrangement of Golgi membranes, mitochondria, and nuclear membranes. Neurons with excess cytoplasmic huntingtin also exhibited increased tubulation of endosomal membranes. Exogenously expressed human full-length wild-type and mutant huntingtin codistributed with endogenous mouse huntingtin in soluble and membrane fractions, whereas human N-terminal huntingtin products were found only in membrane fractions that contained lysosomal organelles. We speculate that mutant huntingtin accumulation in HD activates the endosomal-lysosomal system, which contributes to huntingtin proteolysis and to an autophagic process of cell death.
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PMID:Huntingtin expression stimulates endosomal-lysosomal activity, endosome tubulation, and autophagy. 1100 84

Muscle wasting is a common and prominent feature of advanced cancer, including lung cancer. Evidence from animal experiments suggests that accelerated proteolysis via the ubiquitin--proteasome pathway is the primary cause of cancer-related cachexia. However, there are few data on the role of this pathway in determining muscle wasting in human cancer. The present study was designed to measure whether skeletal muscle gene expression of components of the ubiquitin-proteasome pathway and/or the lysosomal proteolytic pathway was increased in patients with early lung cancer. A total of 36 patients with lung cancer referred for curative resection and 10 control subjects had biopsies of latissimus dorsi muscle taken at operation. mRNA levels of four components of the ubiquitin-proteasome pathway, i.e. polyubiquitin, C2 alpha proteasome subunit, 14 kDa ubiquitin-carrier protein and ubiquitin-activating protein, and of two lysosomal proteolytic enzymes, i.e. cathepsin B and cathepsin D, were measured using quantitative Northern blotting. mRNA levels for cathepsin B, but not for components of the ubiquitin--proteasome pathway, were higher in patients with cancer compared with controls (P=0.01). Among lung cancer patients, cathepsin B mRNA levels correlated with fat-free mass index (r = -0.57, P=0.003) and tumour stage (r(s)=0.45, P=0.03), and were higher in smokers (P=0.04). Thus gene expression of the lysosomal protease cathepsin B is increased in the skeletal muscle of patients with early lung cancer, and the strong inverse relationship with fat-free mass suggests that cathepsin B may have a role in inducing muscle wasting in the early stages of lung cancer.
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PMID:Skeletal muscle mRNA levels for cathepsin B, but not components of the ubiquitin-proteasome pathway, are increased in patients with lung cancer referred for thoracotomy. 1186 77

Butyrate, a 4-carbon fatty acid, has been shown to cause growth arrest and apoptosis of cancer cells in vitro and in vivo. The signaling pathways leading to changes in cell growth are unclear. We used a functional proteomics approach to delineate the pathways and mediators involved in butyrate action in HT-29 cells at 24 hr posttreatment. Using 2-dimensional gel electrophoresis, we showed that butyrate treatment resulted in alterations in the proteome of HT-29 cells. MALDI-TOF mass spectrometry was used to identify butyrate-regulated spots. First, our results revealed that the expression of various components of the ubiquitin-proteasome system was altered with butyrate treatment. This suggests that, in addition to the regulation of gene expression through the histone deacetylase pathway, proteolysis could be a means by which butyrate may regulate the expression of key proteins in the control of cell cycle, apoptosis and differentiation. Second, we found that both proapoptotic proteins (capase-4 and cathepsin D) and antiapoptotic proteins (hsp27, antioxidant protein-2 and pyruvate dehydrogenase E1) were simultaneously upregulated in butyrate-treated cells. Western blotting was carried out to confirm butyrate regulation of the spots. Both cathepsin D and hsp27 showed a time-dependent increase in expression with butyrate treatment in HT-29 cells. However, in HCT-116 cells, which were 5-fold more sensitive to butyrate-induced apoptosis, the upregulation of cathepsin D with time was not accompanied by a similar increase in hsp27 levels. Thus, the simultaneous upregulation of both proapoptotic and antiapoptotic proteins in HT-29 cells may account for their relative resistance to butyrate-induced apoptosis.
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PMID:Proteome analysis of butyrate-treated human colon cancer cells (HT-29). 1192 Jun 11

Cells cultured from Alzheimer disease leptomeninges or skin were grafted into the cortex of adult thymectomized rats. At 3 days post-implant, plaque-like aggregates were found in the cortex, corpus callosum, septum and caudate nucleus. These structures were immunopositive for human amyloid precursor protein (APP), human amyloid beta peptide (Abeta), cathepsin D, apolipoprotein E and ubiquitin. Aberrant tau+ neurites, reactive astrocytes and microglia were associated with many aggregates. Although birefringent amyloid occupied the central area of most aggregates, these structures had disappeared by l month post-implant. Abeta and APP produced by grafted non-neural human cells can penetrate rat brain and form plaque-like structures, which can be effectively cleared by the rat.
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PMID:Transient appearance of amyloid precursor protein plaques in the brain of thymectomized rats after human leptomeningeal cell grafts. 1195 44


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