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)

The IGFBP proteases were first described in pregnancy serum as a proteolytic activity against IGFBP-3. Since then, IGFBP proteases have been described in many other clinical situations, in various body fluids, and have been shown to cleave IGFBP-2 to -6 with varying specificity. The molecular nature of some of these proteases is being unraveled and three classes of IGFBP proteases have been recognized. These include kallikreins, cathepsins and matrix metalloproteinases (MMPs). We utilized two cellular systems to demonstrate the significance of IGFBP proteases in cellular growth regulation. In primary cultures of prostatic cells, we have shown that prostate-specific antigen (PSA) has the ability to enhance IGF mitogenic action by reducing the effects of IGFBPs. Similar kallikreins such as gamma nerve growth factor (NGF) share this activity. Within the prostatic milieu, we have also demonstrated epithelial production of the acid-activated IGFBP protease, cathepsin D, and its secretion into seminal plasma, as well as the serum of patients with prostate malignancy. We have also identified MMPs in prostatic cells and fluids. Using cultured airway smooth muscle (ASM) cells, we have demonstrated the synergism between IGFs and inflammatory agents in mediating ASM cell proliferation. Examination of this phenomenon revealed that these agents (e.g. leukotriene D4 and interleukin1-beta) induce the secretion of an IGFBP protease which cleaves the IGFBPs secreted by ASM cells, allowing IGFs to stimulate proliferation. Using several methods, including immunoblotting and immunodepletion techniques, we have identified this protease as MMP-1. These two pathophysiological systems demonstrate the importance of IGFBP proteases as autocrine paracrine growth regulators. Furthermore, IGFBP proteases may be critical elements in malignant and benign proliferative diseases, including prostate cancer and the ASM hyperplasia of long-standing asthma.
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PMID:Insulin-like growth factor binding protein (IGFBP) proteases: functional regulators of cell growth. 881 70

A specialized subset of invasive embryonic cytotrophoblast cells gains access to maternal uterine arteries early in the gestation of higher primates. These cells continue to migrate extensively within the lumina of spiral arteries, converting them to the highly modified uteroplacental arteries of pregnancy. Although trophoblast cell-mediated modifications are considered critical to the progress of normal pregnancy, few studies have addressed the cellular interactions between maternal arteries and embryonic cells in situ. Macaque placentas and endometrial tissues were collected from 12 animals from day 14 of gestation (blastocyst implantation begins on day 9) to day 49. Standard indirect immunoperoxidase methods were used to identify matrix metalloproteinases (MMP-1, MMP-3, MMP-9), cathepsin B, cathepsin D, platelet-endothelial cell adhesion molecule, cytokeratins, smooth muscle actin, CD68, and factor VIII-related antigen. Cytotrophoblast cells were located deep within spiral arteries in each of the specimens examined. In some examples tightly packed clusters of cytotrophoblast occluded the lumina of invaded arteries. Initial penetration of arterial tunica intima was revealed by discontinuities in the staining pattern for factor VIII and cytotrophoblast intrusion was indicated by cytokeratin staining of the trophoblast cells. Continued cytotrophoblast intrusion into the tunica media was apparent by gaps in the smooth muscle. MMP-1, MMP-3, and MMP-9 were localized within intraluminal and intramural cytotrophoblast. By contrast, neither cathepsin B nor cathepsin D were present, although both were seen in uterine macrophages and stromal cells. Upon reaching the surrounding uterine stroma the cytotrophoblast cells ceased migration. As cytotrophoblast accumulated in the arterial wall the vascular lumen expanded. Evidence of cell death was rarely encountered in associated maternal or embryonic tissues. We conclude that intra-arterial cytotrophoblast cells express several proteinases with substrate specificities sufficient to permit independent remodeling of the extracellular matrix comprising uterine artery walls. The remodeling of the arteries, which involves extensive displacement of maternal endothelium and smooth muscle, in addition to degradation and synthesis of extracellular matrix, is accomplished with little evidence of cell death or loss of the integrity of the arteries. This process provides an interesting example of cooperation between different types of interacting tissues from genetically distinct individuals.
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PMID:Trophoblast cell-mediated modifications to uterine spiral arteries during early gestation in the macaque. 941 53

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

Regional periprosthetic bone resorption plays an important role of prosthesis loosening. In order to study the possible mechanisms of loosening, we investigated the presence of matrix proteolytic enzymes in the periprosthetic tissue by immunohistochemical technique in 72 patients undergoing revision operation of loosened joint prosthesis, including 22 males and 50 females and aged from 19 to 88 years (mean, 61.7 years). Thirty-nine patients had a loosened hip prosthesis (18 males and 21 females) whereas 33 patients had a loosened knee prosthesis (4 males and 29 females). Tissue specimens collected during revision surgery underwent thin slide sections and H & E staining, and were observed under light microscopy and polarized-light microscopy. The results showed many macrophages, histiocytes, fibroblasts, as well as many phagocytosed metal debris and polyethylene debris in the periprosthetic tissues, suggesting an active bone resorption. Furthermore, we used immunohistochemical techniques to detect the distribution of matrix proteolytic enzymes in periprosthetic tissue, including lysosome enzymes (cathepsin B, cathepsin D and cathepsin G), and matrix metalloproteinase (MMPs, MMP-1, MMP-2, MMP-3). The immunostaining were classified as strong positivity, > 70% positive cells; moderate positivity, 20-70% positive cells; weak/negative, < 20% positive cells. The results showed that cathepsin B, cathepsin D and cathepsin G were found in most fibroblasts and macrophage-like cells, including multinuclear giant cells and epithelioid cells. MMPs were found in most fibroblasts and macrophage-like cells, as well as a scant amount in the extracellular matrix. These enzymes were also found in or around blood vessels, the endothelial cells in the richly vascularized tissue. All negative controls showed no staining. The results of immunoreactive staining ranged from 61.1% to 68.1% of strong to moderate positivity. Since these enzymes were related to the degradation of matrix protein, they may be related to the periprosthetic bone resorption. The further clinical significance needs further investigation.
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PMID:Immunohistochemical analysis of matrix proteolytic enzymes in the periprosthetic tissue in the patients with loosening prostheses. 960 17

Some proteolytic enzymes, trypsin, cathepsin B, cathepsin D, collagenase, elastase and their inhibitors, API and AMG, in serum of patients with colorectal carcinoma have been evaluated. Twenty patients belonged to stage B of colorectal carcinoma, twenty two patients to stage D (Astler and Coller classification) and a control group of thirty healthy volunteers were evaluated. Except in cathepsin D, patients exhibit higher enzymatic activities than healthy subjects, and both groups have all the proteolytic activities assayed in serum. Patients with disseminated disease have increased cathepsin B and collagenase levels, with a decrease of trypsin activity, showing an increment in API and AMG in sera. However, only the API values were significantly higher in patients with metastases. The coexistence of proteolytic activities in human sera together with their inhibitors is considered as well as the origin of these, tumoral and/or reactive, increments. Cathepsin B levels are raised in colorectal neoplasms and contribute to the destruction of the extracellular matrix and the proliferation of tumoral cells. There is evidence that a relation between collagenase like activity and tumor invasiveness exists. Cathepsin B and collagenase increases agree with the tumoral mass. On the other hand, trypsin decrease in metastatic carcinoma is probably related to the increment of their inhibitors, API and AMG, acute phase reactant proteins.
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PMID:Serum proteolytic activities and antiproteases in human colorectal carcinoma. 973 3

Leukocyte enzymatic activities are important in non-specific protection against bacterial infections, but traditional methods for the detection of intracellular enzymatic activities rely on cumbersome and complex assays. The development of specific substrates, which become fluorescent upon degradation of the biomolecule after its passive entry into intact cells, permits a simplified evaluation of leukocyte enzymatic activities. We have used this method to assess intracellular elastase, collagenase and cathepsin D activities of peripheral blood leukocytes using flow cytometry in a series of HIV patients and healthy controls. Monocytes displayed the highest enzymatic activities for the three proteases tested. In HIV-infected patients, the collagenase and cathepsin D activities of monocytes were significantly lower, whereas the elastase and cathepsin D activities of polymorphonuclear cells were elevated. Slightly higher elastase activity was detected in the lymphocytes of patients. This study demonstrates the feasibility of this new method for the study of intracytoplasmic enzymatic activities. Significant variations were observed in the peripheral blood of HIV-infected patients and different patterns were especially evident in monocytes and polymorphonuclear cells.
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PMID:Assessment by flow cytometry of peripheral blood leukocyte enzymatic activities in HIV patients. 1133 73

Activities of acid and alkaline phosphatases, collagenase, cathepsin D, trypsin-like proteinases, alpha(1)-proteinase inhibitor (alpha(1)-PI), alpha(2)-macroglobulin (alpha(2)-MG) were measured in blood plasma and tumor tissue of patients with giant-cell tumor of the bone (GCTB) and bone chondrosarcoma. These tumors differed by enzymatic activities. GCTB is characterized by increased activity of alkaline phosphatase, while in chondrosarcoma tissue the activities of collagenase and cathepsin D were the highest. Activities of acid phosphatase, collagenase, trypsin-like proteinases were increased in the plasma of patients with both tumors; alpha(1)-PI/alpha(2)-MG ratio was increased. Bone resorption parameters correlated with proteolysis inhibitors. Activities of collagenase and acid phosphatase were increased in tumor tissue and plasma in the presence of low activities of alpha(2)-MG and increased alpha(1)-PI/alpha(2)-MG index, which seems to require special attention during the postoperative period.
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PMID:[Indices of proteolysis in evaluation of resorption in bone tumors]. 1148 42

Recently, we demonstrated that boron modulates the turnover of the extracellular matrix and increases TNFalpha release. In the present study, we used an in vitro test to investigate the direct effect of boron on specific enzymes (elastase, trypsin-like enzymes, collagenase and alkaline phosphatase) implicated in extracellular matrix turnover. Boron decreased the elastase and alkaline phosphatase activity, but had no effect on trypsin and collagenase activities. The effect of boron on the enzyme activities was also tested in fibroblasts considered as an in vivo test. In contrast to the results obtained in vitro, boron enhanced the trypsin-like, collagenase, and cathepsin D activities in fibroblasts. Boron did not modify the generation of free radicals compared to the control and did not seem to act on the intracellular alkaline phosphatase activity, However, as it did enhance phosphorylation, it can be hypothesized that boron may affect living cells via a mediator, which could be TNFalpha whose transduction signal involves a cascade of phosphorylations.
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PMID:Mechanisms implicated in the effects of boron on wound healing. 1253 May 86

Tumor cell invasion requires expression of degradative enzymes such as plasminogen activator, collagenase, and cathepsins. Cathepsin D, a lysosomal aspartic protease produced constitutively in human breast cancer cell lines, also has mitogenic activity in breast cancer cells. Additionally, high cathepsin D expression is associated with increased risk of metastasis in patients with node-negative breast cancer. Recently, a novel aspartic protease gene, ALP56 (aspartic-like protease 56kDa), has been identified. To examine possible interrelationships we quantitated ALP56 mRNA and cathepsin D mRNA in breast cancers using reverse transcription polymerase chain reaction. ALP56 mRNA expression was greater in cancers than in noncancerous tissues (p < 0.0001), as was expression of cathepsin D mRNA. ALP56 gene expression was dose-dependently down-regulated in T-47D breast cancer cells treated with estradiol, while cathepsin D was up-regulated. Expression of ALP56 mRNA in estrogen receptor (ER)-positive breast cancers was less than that in ER-negative cancers, and mRNA expression for ALP56 and cathepsin D did not correlate with one another. Thus ALP56 as well as cathepsin D may be a useful target molecule in breast cancer treatment.
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PMID:A novel aspartic protease gene, ALP56, is up-regulated in human breast cancer independently from the cathepsin D gene. 1261 55

Cancer invasion and metastasis develop through a sequence of processes involving loss of cell-cell and cell-matrix adhesions, proteolysis and induction of angiogenesis. We reviewed the current literature on the molecules that have been shown to play a significant role in these three steps of metastatisation in bladder cancer (BC) cells and their host microenvironment. Particular emphasis was given to markers that are assessable through immunohistochemistry and for which an additional prognostic value over the TNM variables has been recognized, in order to identify a subset of tumour markers readily available for application in daily clinical practice. We conclude that markers such as E-cadherin, Sialosyl-LeX, laminin, collagen IV, TSP-1 and MVD are useful prognostic markers, alpha, beta, and gamma catenin, MMP-2 and -9, uPAR, PD-ECGF and Bfgf can be considered potentially useful, while research on CD44, MMP-1 and -3, uPA, cathepsin D and VEGF has proved inconclusive. Further research in this field should concentrate on the molecules listed in the first group.
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PMID:Metastasis markers in bladder cancer: a review of the literature and clinical considerations. 1530 99


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