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)

We have studied the cellular content and the extracellular release of cathepsins B and D, and of plasminogen activator, in 2 different tumor cell populations before confluence and after late confluence: the HT-29 colon carcinoma cell line, which contains primarily undifferentiated cells, and a subpopulation derived from this cell line, which contains cells committed to differentiation into mucus-secreting goblet cells after confluence. In both populations, cellular cathepsin-B activity increased after confluence, and latent cathepsin B was found in all culture media. In the parental cell line, cellular cathepsin D activity decreased after confluence; however, cathepsin D was secreted at high levels into the extracellular medium. In contrast, in the subpopulation of cells committed to differentiation, cellular cathepsin D activity increased after confluence, and cathepsin D was not secreted into the extracellular medium, but was immunolocalized in the apical brush border of the differentiated cells. Plasminogen activator of urokinase type was identified by immunocytochemistry. Both subconfluent cell populations, and the post-confluent undifferentiated cell population, produced plasminogen activator activity at similar levels. In contrast, in the differentiated postconfluent cells, the production of plasminogen activator activity was markedly lower. Our data show that the differentiation of HT-29 colon carcinoma cells into mucus-secreting cells impairs the secretion of plasminogen activator and cathepsin D, but does not affect cathepsin B.
Int J Cancer 1994 Jun 15
PMID:The state of differentiation of HT-29 colon carcinoma cells alters the secretion of cathepsin D and of plasminogen activator. 791 58

In the natural history of post-menopausal patients with primary breast cancer, high estrogen receptor levels (ER) have been associated with a poor recurrence-free survival. The purpose of this study was to investigate whether there are any biological intratumoral characteristics to support this puzzling clinical observation. In a population of 542 post-menopausal, primary-breast-cancer patients, 3 normal distributions fitted into the frequency distribution curve of the logarithmically transformed ER-EIA values. The biological profiles of the low ER group, and of the intermediate and high ER groups identified in the ER-positive population were compared. Parameters correlated with ER functional aspect (progesterone receptors and PS2), receptors of epidermal growth factor (EGFR), protease cathepsin D and tumor proliferation (deduced from thymidine kinase activity) were analyzed. As previously reported, the levels of progesterone receptors and PS2 increased significantly from the low to the high ER groups. The highest levels of cathepsin D and thymidine kinase which have been previously related to a poor prognosis in breast cancer were found in the low ER group, but high levels were, surprisingly, also found in the high ER group. This study indicates that the ER-positive post-menopausal population is biologically heterogeneous. The high levels of thymidine kinase found in the high ER group suggest that overexpression of ER may be associated with proliferation enhancement, partly explaining the poor spontaneous prognosis related to this subset.
Int J Cancer 1994 Oct 01
PMID:Biological heterogeneity of ER-positive breast cancers in the post-menopausal population. 792 97

Cathepsin D, a lysosomal proteinase, is induced by estrogens in mammary cancer cells where its concentration is correlated with a higher risk of metastasis. Its gene expression is stimulated by estrogens in MCF7 cells, and we have shown that a short proximal promoter fragment from -365 to -122 is required for this induction. We now characterize, at -261, a nonconsensus estrogen-responsive element (ERE) (E2) with two differences in the distal half of its palindrome, which confers estradiol responsiveness to the heterologous Herpes simplex virus thymidine kinase promoter in transient transfection experiments. This ERE is located in a 21-base pair sequence: 5'GGGCCGGGCTGACCCCGC GGG3', containing a GC-rich region in its 3'-part, which is almost perfectly repeated at -362 (the E1 site). The E2 site was necessary but not sufficient to mediate an estrogen response and required cooperation with the homologous E1 element and/or with general transcription sites located downstream. In vitro, the E2 site but not the E1 site was protected by estrogen receptor (ER) against DNAse I digestion, and gel shift experiments suggested an interaction with the ER as a dimer. Moreover, we showed in vivo that ER DNA binding domain was required to mediate estrogen induction from the cathepsin D ERE. We conclude that estradiol induction of cathepsin D is mediated by interaction of the ER with a nonconsensus ERE that requires synergy with other elements located upstream and/or downstream of this central ERE.
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PMID:Characterization of the proximal estrogen-responsive element of human cathepsin D gene. 793 85

The secretion of pro-cathepsin D (pro-cath-D) in some human metastatic breast cancer cells (MCF7, MDA/MB231), contrary to normal mammary cells, is not increased by ammonium chloride treatment, indicating a mannose-6-phosphate-independent sorting to lysosomes. By studying a variety of cell lines and lysosomal enzymes, we show that secretion of newly synthesized pro-cath-D was not mediated by the 46-kDa mannose-6-phosphate receptor (MPR) and that its resistance to NH4Cl for secretion was specific to cath-D and not to other lysosomal enzymes. This resistance appeared to be correlated with the basal hypersecretion of pro-cath-D, but not with its overexpression. By contrast, pro-cath-D secretion was increased by NH4Cl in fibroblasts and nontumoral epithelial mammary cells, suggesting a specificity for cancer cells. Immunofluorescence staining showed that pro-cath-D, but neither cathepsin B nor beta-hexosaminidase, accumulated in intracytoplasmic vesicles of cells treated with ammonium chloride. In pulse--chase experiments and by subcellular fractionation on Percoll gradient, cath-D was found to be sorted into dense lysosomes whether cells were treated or not by NH4Cl. Treatment of cells with NH4Cl, however, inhibited processing and maturation of pro-cath-D, which was also observed in light vesicles in the absence of NH4Cl. Part of pro-cath-D, but not processed enzyme, was also found to be membrane associated in saponin-permeabilized cells. We conclude that in breast cancer cells, the MPR-independent pathway of pro-cath-D to lysosome is predominant compared to normal cells and other lysosomal enzymes. This alternative pathway should therefore be considered, in addition to MPR, to explain pro-cath-D sorting and activation in breast cancer cells.
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PMID:Specific mannose-6-phosphate receptor-independent sorting of pro-cathepsin D in breast cancer cells. 795 63

Bcl-2 gene product functions to prevent apoptosis in a variety of in vitro and in vivo experiments. The prognostic significance of Bcl-2 protein expression was investigated by immunocytochemistry from paraffin-embedded tissue in a series of 174 women with breast cancer, treated with radical surgery with or without regional radiotherapy, and who had been followed up for the median of 31 years or until death. A minority (25%) of cancers were entirely negative for Bcl-2 protein. Moderate to strong Bcl-2 protein expression (present in 46%) was strongly associated with several favorable prognostic features, such as a low mitotic count, high histological grade of differentiation, and lack of p53 protein expression (P < 0.0001 for each). It was also significantly associated with lack of tumor necrosis, a low S-phase fraction size, low cathepsin D expression, DNA diploidy, and the lobular histological type, but not with the primary tumor size or the axillary nodal status. Women with cancer with moderate to strong Bcl-2 protein expression had more favorable short-term (69% versus 46% alive at 5 years) but similar long-term (29% versus 33% alive at 30 years) disease-specific survival as those with cancer with weak or lacking expression. Bcl-2 protein expression did not have independent prognostic value in a multivariate survival analysis. We conclude that Bcl-2 protein is frequently expressed in breast cancer, and its expression is associated with favorable clinicopathological features.
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PMID:Bcl-2 protein expression and long-term survival in breast cancer. 797 49

The proform of cathepsin D is secreted by some human breast-cancer cell lines upon stimulation with oestrogen. In these cell lines, procathepsin D was described to act as an autocrine mitogen, and a correlation between the cathepsin D concentration in tumour tissues and poor prognosis for the patient was demonstrated in several independent investigations. In the present study, we focused on the mechanism of procathepsin D mitogenic activity. Procathepsin D isolated from secretions of ZR-75-1 breast-cancer cell line was used to test for mitogenic activity on a set of seven human cell lines. For nanomolar procathepsin D concentrations, we found a stronger dose-responsive cellular reaction in the case of several different human breast-cancer-derived cell lines. The mitogenic activity was not blocked by the inhibition of proteolytic activity nor by the inhibition of the interaction of procathepsin D with mannose-6-phosphate receptors. On the other hand, the addition of antibodies raised against the propeptide impaired the mitogenic activity of procathepsin D, and a synthetic peptide alone corresponding to the propeptide of procathepsin D produced similar effects, as did the zymogen molecule. The synthetic propeptide was shown to block partially the interaction of procathepsin D with the cellular surface. Our results indicate that the mitogenic function involves the propeptide of cathepsin D, which appears to be recognized by a surface receptor.
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PMID:Mitogenic function of human procathepsin D: the role of the propeptide. 798 Apr 46

Aspartic proteinases have recently been shown to be implicated in antigen processing. We explored the expression of two aspartic proteinases, cathepsins E and D, and of human leukocyte antigen-DR (HLA-DR) molecules in a consecutive series of 80 transbronchial biopsies from transplanted lungs. For controls, we studied five normal donor lungs (not suitable for transplantation on account of thoracic trauma) and macroscopically normal areas of three cancer-affected lungs. Two of the five unsuitable donor lungs showed minimal inflammatory changes. Macroscopically normal samples from the three cancerous lungs showed mild and focal inflammatory infiltrates. In histologically normal lungs, HLA-DR expression was limited to professional antigen-presenting cells. Macroscopically normal lung samples with minimal inflammatory changes from both donor and cancer lungs showed variable HLA-DR expression by alveolar and bronchial epithelial cells and by endothelial cells. All transplanted lung biopsies showed HLA-DR expression by epithelial (alveolar and bronchial) and endothelial cells, with a trend for increased positivity in acute rejection. Cathepsin E was restricted to Clara and to rare bronchus-associated lymphoid tissue-related epithelial cells in histologically normal lung samples, whereas minimal de novo cathepsin E expression by rare alveolar pneumocytes was noted in control lung samples exhibiting minimal inflammatory changes. In all transplanted lung biopsies, cathepsin E was diffusely expressed de novo by hyperplastic alveolar epithelial cells, regardless of the presence or degree of rejection. Cathepsin D was expressed only by alveolar macrophages and by ciliated bronchial cells of normal, minimally inflamed, and transplanted lungs. In transplanted lung, Clara cells and several hyperplastic alveolar pneumocytes coexpressed HLA-DR and cathepsin E, whereas all alveolar macrophages and a few ciliated cells coexpressed cathepsin D and HLA-DR. The present investigation suggests that the de novo expression of cathepsin E and HLA-DR by hyperplastic alveolar pneumocytes of transplanted lung may be crucial for antigen processing and presentation to recipient competent T cells, and thus for the triggering of the immune-inflammatory cascade that leads to rejection.
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PMID:Coexpression of aspartic proteinases and human leukocyte antigen-DR in human transplanted lung. 805 91

Activity of lysosomal proteinases cathepsin B, L and D was studied in tissues of malignant tumors, cancer and normal lymph nodes and mucosal membrane obtained from 18 patients with gastric cancer. The enzymatic activity was distinctly higher in cancer tissues as compared with controls. Activity of cathepsin D was increased in tissues with diminished rate of the tumor differentiation, with pronounced cancer invasion and metastases to regional lymph nodes--the group of highly negative prognosis. At the same time, activity of cathepsin B was increased in tissues of patients with positive prognosis of gastric cancer; negative correlation of cathepsin B activity was observed in both groups of patients. This correlation may be considered as an additional prognostic factor.
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PMID:[Proteolytic enzyme activity in stomach cancer patients with various prognoses]. 807 38

High cathepsin D (cath-D) concentration in breast cancer cytosol is associated with increased risk of metastasis. To specify the relative contribution of the different cells types responsible for cath-D level in cytosol, we validated semiquantitative cath-D immunoperoxidase staining on formalin-fixed, paraffin-embedded sections, using the M1G8 monoclonal antibody, one of the two antibodies of the cytosolic assay. Using computer-aided image analysis, cath-D level in cancer cells was estimated by integrating both staining intensity in each cell and proportion of stained cells. We confirmed on 41 primary breast cancers a higher expression of cath-D in cancer cells compared with peritumoral mammary glands. Cancer cell staining was mostly in lysosomes and for some invasive ductal carcinomas in large vesicles corresponding to phagosomes. Lymphocytes and fibroblasts were not or were only weakly stained. Macrophages also were stained for cath-D, generally on the periphery of the tumor area. The cytosolic cath-D level was correlated with cath-D expression in cancer cells (r = .76; P = 1 x 10(-4)) rather than with the number of macrophages in the tumor (r = .29; P = .09), as determined by use of the specific anti-CD68 antibody. There was a significant increase in the tissue cath-D level in tumors containing large vesicles compared with tumors without large vesicles. This approach provides a means to separately estimate the prognostic significance of cath-D expression in cancer cells and macrophages when evaluating risk of metastasis.
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PMID:Cathepsin D immunostaining in paraffin-embedded breast cancer cells and macrophages: correlation with cytosolic assay. 808 57

Commercially available immunoradiometric assays were used for pS2 and total cathepsin D determination in the cytosol fraction obtained from 266 primary breast cancers. We show that pS2 and cathepsin D values were significantly associated (Spearman's rank correlation: P < 0.0001) in tumours from lymph node-positive patients (N+), while such association did not reach significance in tumours taken from patients with negative lymph nodes (N-). Moreover, cathepsin D concentrations in pS2-rich tumours (pS2 above the median value, 5 ng mg-1 protein) were significantly higher (Mann-Whitney-Wilcoxon's rank-sum test: P = 0.00001) than those obtained in the samples expressing less than 5 ng of pS2 per mg of protein. pS2 was also correlated to both the oestrogen receptor (ER) (Spearman's rank correlation: P < 0.0001) and the progesterone receptor (PR) (Spearman's rank correlation: P = 0.022). No significant differences in the expression of pS2 and cathepsin D taken from N+ and N- patients were found. Furthermore, no significant differences in pS2 and cathepsin D expression were obtained by stratifying tumours on the basis of their size (T). pS2 and cathepsin D values obtained in ER-positive/PR-positive tumours did not significantly differ from the values obtained in ER-positive/PR-negative and in ER-negative/PR-positive tumours. We conclude that pS2 could have a role in cathepsin D expression, and that it can be used in the assessment of a functioning oestrogen response machinery in those tumours that express only ER.
Br J Cancer 1994 Mar
PMID:Immunoradiometric detection of pS2 and total cathepsin D in primary breast cancer biopsies: their correlation with steroid receptors. 812 86


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