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)

Eighteen clones of a methylcholanthrene-induced murine fibrosarcoma (3AM) which were heterogeneous with respect to metastatic potentials and in vivo growth rates were examined for five different protease activities: acid protease (cathepsin D), BANA hydrolase (cathepsin B), neutral protease, collagenase, and plasminogen activator. Homogenates of the solid tumors produced by the clones were heterogeneous with respect to the activities of the proteases; these activities were in all cases (except plasminogen activator) higher than those obtained for normal muscle tissue. There was, however, no correlation between any of these protease activities and the metastatic potential or in vivo growth rates. The cathepsin B activity has also been evaluated on the cultured cells of the various clones. Results similar to that of the in vivo study were obtained. Analysis of the enzyme activity of the cell culture and of organ culture media, however, revealed no cathepsin B activity. It is concluded that the measurement of any one biochemical parameter such as proteolysis may not be sufficient to establish a correlation with the overall process of metastasis; a more precise dissection of the individual steps culminating in metastasis may provide a more fruitful approach to this problem.
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PMID:Proteolytic and metastatic activities of clones derived from a methylcholanthrene-induced murine fibrosarcoma. 610 Aug 5

The activity of collagenase, cathepsin B1, cathepsin D and Hyaluronidase was determined in skin, bone, liver, kidney, spleen and serum of adjuvant induced arthritic rats during the acute and chronic phase of the disease. Collagenase was assayed directly in tissue extract by a solution method using radioactive labelled substrate. The activity of collagenase, cathepsin B1 and D was found to increase significantly at both phases of the disease. The activity of hyaluronidase decreased significantly in liver, kidney and spleen of arthritic rats, while in skin, bone and serum no significant change was observed. The results are discussed with respect to catabolism of collagen in adjuvant induced arthritis. Prednisolone and L-thyroxine were administered to arthritic rats and the activity of collagenase, cathepsin B1, cathepsin D and hyaluronidase was determined in the treated groups during the acute and chronic phase of the disease. Prednisolone was found to suppress the development of arthritis which, in turn, decreased the increased activity of collagenase and lysosomal enzymes cathepsin B1 and D in tissues and serum of arthritic rats. L-Thyroxine was found to slowly diminish the development of inflammation and its beneficial action was found in mesenchymal tissues and skin of arthritic rats but not in bone.
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PMID:Effect of adjuvant arthritis on collagenase and certain lysosomal enzymes in relation to the catabolism of collagen. 624 97

Both malignant (adenocarcinomas) and nonmalignant (fibroadenomas and normal tissue) human breast tissues were maintained in organ culture for up to 10 days to study the secretion of lysosomal and neutral proteinases. Little difference was observed between the different tissue groups in the release of the lysosomal proteinase cathepsin D into the culture medium. Similar results were obtained when media were tested for plasminogen activator activity. The secretion of collagenolytic activity was investigated with fibroadenoma and adenocarcinoma explants and found to be very low for both tissue groups. The average accumulation of collagenase activity during a 2-day period was 0.002 units/microgram DNA for adenocarcinomas and 0.008 units/microgram DNA for fibroadenomas. The only proteinase that was secreted in substantially higher amounts from explants of malignant tissue was a cathepsin B-like thiol proteinase. Media from adenocarcinoma explants (n = 38) contained on the average 11 times more activity than did media from fibroadenoma (n = 20) and normal tissue explants (n = 8). Metastases of mammary adenocarcinomas (n = 7) secreted the thiol proteinase at about one third of the rate of primary tumors. The secretion of this enzyme is dependent upon protein synthesis as its release was completely inhibited 24 hr after the addition of cycloheximide. In some cases, it was also observed that the presence of sheep serum in the tissue culture medium reduced the accumulation of activity.
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PMID:Secretion of proteinases from malignant and nonmalignant human breast tissue. 625 82

The proteolytic activity in homogenates and extracts of subcellular fractions prepared from subcutaneous Lewis lung carcinoma was determined using proteins and synthetic peptides as substrates. The presence of cathepsin D, plasminogen activator, cathepsin B-, cathepsin G- and elastase-like enzymes was observed. No difference was revealed between the proteolytic activity in homogenates of Lewis lung carcinoma, at the growth stage examined, and in homogenates of normal lung. High specific activities were found in the lysosomal extract, whereas decreasing activities were found in the nuclear extract, the homogenate and the postlysosomal mitochondrial supernatant; no active or trypsin-activatable collagenase activity was detected. The presence in the tumor tissue of these enzymatic activities is in agreement with their proposed role in the process of metastasis. The lack of differences between homogenates of tumor and normal lung tissue suggests that the use of whole cells is required to selectively study tumor proteinases specifically involved in tumor malignancy.
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PMID:Methodologic problems encountered in the assay of proteinases in Lewis lung carcinoma, a mouse metastasizing tumor. 629 35

The activity of collagenase and certain lysosomal hydrolases (cathepsin B1, cathepsin D, beta-glucuronidase and beta-N-acetyl glucosaminidase) was studied in serum and tissues of rats with streptozotocin- or alloxan-induced diabetes. The activity of serum lysosomal enzymes was increased in both groups (p less than 0.05). Both streptozotocin- and alloxan-diabetic animals showed significantly higher dermal collagenase activity than those of controls (p less than 0.01), but the liver and spleen showed similar activities; there was a significant decrease in the renal collagenase activity of streptozotocin-diabetic rats (p less than 0.05). Comparison of the alloxan- or streptozotocin-treated groups with control animals showed an increase in lysosomal enzymes (cathepsin B1, cathepsin D, beta-glucuronidase and beta-N-acetyl glucosaminidase in skin, liver and spleen) (p less than 0.05) but beta-N-acetyl glucosaminidase was unchanged in the spleen of streptozotocin-diabetic rats. There was no difference in renal cathepsin B1 and D in control versus alloxan-diabetic rats, but there was an increase in beta-glucuronidase and beta-N-acetyl glucosaminidase (p less than 0.05). The streptozotocin-diabetic animals showed decreased activities of renal lysosomal enzymes (p less than 0.05), but similar activity of cathepsin D to the control animals.
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PMID:Influence of streptozotocin- and alloxan-induced diabetes in the rat on collagenase and certain lysosomal enzymes in relation to the degradation of connective tissue proteins. 630 89

Medium conditioned by the culture of porcine gingival explants was shown to contain, in addition to collagenase, proteolytic activity capable of releasing small fragments, devoid of hydroxyproline but containing hydroxynorleucine, from reduced (tritiated) type I collagen in solution at neutral pH. Quantitative comparison of this effect with that of cathepsin D, at pH 4, revealed that the fragments were derived at least in part from the carboxy-terminal, extra-helical portion of the collagen alpha 1-chains. Incubation of concentrated conditioned medium with fibrillar acetic acid-insoluble collagen resulted in the solubilization of the TC 3/4 and TC 1/4 fragments characteristic of the action of collagenase. However, alpha 1-chain fragments isolated from the latter were found to lack the antigenic determinant normally present on the amino-terminal side of the (hydroxy-)lysine residue which is known to be involved in intermolecular cross-linking. It is therefore suggested that the proteolytic activity described above was involved in the solubilization process. Both the release of low molecular fragments from soluble collagen and the solubilization effect were abolished by ethylenediaminetetra-acetic acid.
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PMID:Cleavage of the carboxy-terminal cross-linking region of type I collagen by proteolytic activity from cultured porcine gingival explants. 631 80

Local or systemic prostaglandin (PG) administration leads to the known softening and dilatation of the cervix uteri. Lysosomal enzymes are involved in connective tissue degradation. The question arises whether the effect of PG on the cervix uteri is mediated by lysosomes. Five pregnant women (volunteers after informed consent) in the first trimester received 500 micrograms of PGE2-derivative (Nalador) i.m. at 12 and 8 h before termination by curettage. Five pregnant women without PG-treatment served as controls. Small biopsies were obtained from the endocervical canal and were immediately immersed in cold 2.5% glutaraldehyde and after further preparations examined under a Zeiss electron microscope 9S-2. A second portion of tissue was sliced and prepared for histochemical analysis of the acid phosphatase on lysosomes. Examination of the ultrastructure of the cervix uteri showed vesicles in the extracellular matrix. These were surrounded by a single membrane and contained either fine granular material of myelin-like whorls of membranes. These vesicles lay between collagen fibers, showed the reaction product of acid phosphatase and were often surrounded by an electron-lucent halo. We conclude that these matrix vesicles were "matrix lysosomes" extruded from the cervical myo-fibrocytes into the extracellular space as a result of the PG-E2-administration. Here they are not under cellular control and can initiate the proteolytic degradation of connective tissue. This might be the crucial step in cervical dilatation which, on ultrastructural examination, can be seen as decreasing electron density of the extracellular ground substance near the matrix lysosomes. The relationship between PGE2 and collagenase production is generally accepted. If one believes that lysosomal cathepsin D and cathepsin B act synergistically with collagenase, it can be assumed that PGE2 is involved in a lysosomal degradation of the connective tissue. The morphological sign of this occurrence is the release of matrix lysosomes by PGE2 as described in the present study. Extracellular lysosomes and their physiological significance in cervical function are discussed in detail.
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PMID:The effect of prostaglandins on the lysosomal function in the cervix uteri. 666 Sep 24

beta A4 amyloid peptide, the main constituent of amyloid plaques and cerebrovascular amyloid deposits associated with Alzheimer's disease, derives from a large precursor protein (APP) by the action of beta- and gamma-secretases, the unidentified endoproteases which release the amino and carboxyl termini of beta A4, respectively. Several gamma-secretase cleavage sites exist which yield the more soluble (1-39/40) forms of beta A4 and the longer forms (1-42/43) which have a greater tendency to aggregate into amyloid plaques. gamma-Secretase activity may therefore be critical in amyloid formation. In this study, a synthetic peptide which encompasses the various gamma-secretase cleavage sites was used as a substrate to probe proteases of various classes and specificities. Elastase, collagenase, and cathepsin D cleaved at the amyloidogenic sites (after Ala42 or after Thr43) to release the carboxyl termini of the aggregating forms. In addition, collagenase and pepsin released the carboxyl terminus of the more soluble forms. Human brain fractions enriched in lysosomes contained a proteolytic activity that cleaved the substrate at the amyloidogenic site(s). This activity was more active at acidic pH and was inhibited by pepstatin, two characteristics of the lysosomal aspartyl proteinase cathepsin D. The same lysosomal fractions were found to contain APP carboxyl-terminal fragments which are potentially amyloidogenic. These were degraded, only in acidic conditions, by an endogenous protease activity inhibited by pepstatin. Thus, a cathepsin D-like activity from human brain is a candidate for APP gamma-secretase(s).
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PMID:Candidate gamma-secretases in the generation of the carboxyl terminus of the Alzheimer's disease beta A4 amyloid: possible involvement of cathepsin D. 757 16

Abnormalities in extracellular matrix degradation may play a pathogenetic role in diabetic nephropathy. Cultured renal mesangial cells are known to synthesize increased amounts of matrix proteins when incubated in high glucose media (e.g., 30 mmol/l). However, the effect of glucose loading on degradative enzymes is unknown. Primary cultures of rat mesangial cells were grown until confluent in the presence of fetal calf serum (FCS) and insulin (0.67 U/ml). Cells were then cultured for 7 days in plastic wells in either 10 or 30 mmol/l glucose media containing neither FCS nor insulin. Collagenase activity in media were determined by zymography and quantitative spectrofluorometry. Cathepsin B and D activities in cell extracts were measured by spectrofluorometry (using the fluorescent substrate Z-Arg-Arg-7-amido-4-methylcoumarin) and 125I-labeled hemoglobin digestion, respectively. Gelatin-degrading activity of live mesangial cells was also determined. mRNA levels for collagenase IV, cathepsin B, and cathepsin D were determined by Northern analysis. A major band of collagenase activity with a molecular size of 72 kDa was observed in all mesangial cell media. Exposure of cells to high glucose media resulted in significant reductions in collagenase and cathepsin B activities as well as impairment in gelatin-degrading activity. Collagenase IV and cathepsin B and D mRNA levels were also decreased by glucose loading. To exclude the possibility that glucose loading was injurious to cells, 3H-leucine uptake (as a measure of protein synthesis) and membrane alkaline phosphatase activity (as a biochemical marker of viability) were not affected by the high glucose condition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased degradative enzymes in mesangial cells cultured in high glucose media. 762 99

Clinical and histopathological features do not reliably distinguish between benign and malignant pheochromocytomas. Additional markers that might be useful prognostic indicators in the pathological assessment of these tumors are sought. Immunohistochemical expression of MIB-1, Bcl-2, cathepsin B, cathepsin D, basic fibroblast growth factor (bFGF), c-met, and type IV collagenase were studied on formalin-fixed tissue from 33 nonconsecutive cases of pheochromocytoma, selected on the basis of reliable long-term follow-up, to determine associations with malignancy. The study group included 33 patients, 19 men and 14 women, with a mean age of 45 years, including five cases of neurofibromatosis (NF), three familial, and one MEN IIb. Mean follow-up was 63.2 months. Ten patients were determined to have malignant pheochromocytomas by the presence of metastatic disease. Features found to be associated with malignancy included MIB-1 labeling index (5% vs 1%) (P = .0009), male gender (90% vs 43%) (P = .008), extra-adrenal location (40% vs 9%) (P = .03), tumor weight (481 g vs 124 g) (P = .05), and young age (38 years vs 49 years) (P = .05). None of the five cases with NF were malignant (P = .04). S-100 positivity showed a significant (P = .02) but nonlinear association with benign tumors. Absent S-100 correlated with greater tumor weight. Malignancy was not associated with right versus left side or bilaterality, although bilateral tumors were smaller. C-met, bFGF, cathepsin B, cathepsin D, and collagenase were strongly expressed in most tumors and were not predictive of outcome, nor was bcl-2, which was variably expressed. Using multiple logistic regression with malignancy as the dependent variable, MIB-1 continued to show a significant association with malignancy (P = .005) independent of any association with sex, age, or extra-adrenal location. Using a cutoff value of MIB-1 labeling of greater than 3% yielded a specificity of 100% and a sensitivity of 50% in predicting malignancy.
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PMID:Prognostic markers in pheochromocytoma. 1020 74


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