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)

In 87 breast cancer patients, the immunohistochemical expression of the basement membrane (BM)-degrading enzyme cathepsin D (CD) was correlated with the expression of extracellular matrix components, with growth fraction, steroid receptor content and with the other conventional prognostic variables in breast cancer. Only 6.25% of tumours had laminin-defined BM, while 86.8% showed staining for fibronectin. CD was also identified in carcinoma cells (cancer cell CD; CCCD) and in stromal cells (stromal cell CD; SCCD). Forty-five percent of tumours showed CCCD and 47.5%, SCCD expression. CCCD expression was significantly correlated with positive oestrogen receptor content, with low Ki-67 and high PCNA score and with SCCD expression. There was no correlation with collagen type IV, laminin or fibronectin. SCCD expression was positively correlated with collagen type IV, laminin expression and tumour grade. The data suggest that the CD of tumour cells and the CD of tumour-associated macrophages have different roles in breast cancer. CCCD correlates with cell proliferation and is regulated by oestrogens, while SCCD relates to cell differentiation, is oestrogen-independent, and has a proteolytic role in the breakdown of BM components.
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PMID:Immunohistochemical expression of cathepsin D in correlation with extracellular matrix component, steroid receptor status and proliferative indices in breast cancer. 946 71

Matrix metalloproteinases (MMPs) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development. The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 (MMP-3, stromelysin-1) in correlation with the expression of Basement Membrane (BM) antigen (type IV collagen, laminin), fibronectin, cathepsin D, p53, c-erbB-2, proliferative activity (Ki-67, PCNA), steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer. This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP-3 (Ab-1). Stromelysin-1 (ST1) was observed in about 10% of epithelial cells in the control groups (cases of fibrocystic and benign proliferative breast disease), while expression (> 10% of expression) was detected in 89.7% of tumours. The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma (p < 0.001). A significantly positive correlation was found between ST1 expression, and p53 tumour suppressor gene product (p = 0.004), and a relationship with c-erbB-2 protein and progesterone receptor status was also indicated. These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component, the proteolytic enzyme cathepsin D and the growth fraction of the tumour, and that it could be a potential new prognostic marker in breast cancer.
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PMID:Matrix metalloproteinase expression in human breast cancer: an immunohistochemical study including correlation with cathepsin D, type IV collagen, laminin, fibronectin, EGFR, c-erbB-2 oncoprotein, p53, steroid receptors status and proliferative indices. 967 87

A case of an aggressive desmoid tumor in a patient with familial adenomatous polyposis is described. The lesion rapidlyenlarged with compression of adjacent structures including the ureter and small bowel, and the patient died because of small bowel perforation and hydronephrosis 3 years after detection of small desmoid tumors at the time of a prophylactic coloproctectomy for a colon carcinoma. Immunohistochemically, proliferating cell nuclear antigen (PCNA), p21WAF1/CIP1 and cathepsin D indices, but not the bcl-2 index, which were defined as the numbers of immunoreactive tumor cells per 1000 tumor cells, increased in line with tumor progression. The tumor did not show staining for collagen IV, but was characterized by intense staining for basic fibroblast growth factor (bFGF). Accordingly, tumor aggression was related to increases in both cell proliferation and protease activity, as well as an enhanced expression of bFGF. In addition, the desmoid tumor showed deregulation between PCNA and p21WAF1/CIP1 because the normal inverse relation between these two was not apparent.
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PMID:An aggressive desmoid tumor in a patient with familial adenomatous polyposis: immunohistochemical findings. 1002 64

CD44 has diverse functions in cell-cell and cell-matrix interactions and may be a determinant of metastatic and invasive behaviour in carcinomas. The immunohistochemical expression of CD44 in a series of 110 colorectal carcinomas and 25 adenomas was examined using the monoclonal mouse anti-human phagocytic glycoprotein-1, CD44 (clone DF 1485) in correlation with the expression of basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, p53, Rb, bcl-2, c-erbB-2, EGFR, proliferation indices (Ki-67, PCNA) and with other conventional clinicopathological variables. In adenomas, low CD44 expression (<10% of neoplastic cells) was present in 16%, moderate (10-50% of neoplastic cells) in 52% and extensive (>50% of neoplastic cells) in 32% of cases. In carcinomas, low CD44 expression was found in 14.5%, moderate in 28.2% and extensive in 57.30%. Although the CD44 expression was higher in carcinomas than in adenomas, we found no statistically significant difference between these two groups. CD44 expression in carcinomas was positively correlated with tumour size (P=0.018), tumour cells cathepsin D (P=0.022), stromal cell cathepsin D (P=0.003) and Rb protein (P=0.021). An inverse correlation was observed between CD44 and the anti-apoptotic protein expression bcl-2 in adenocarcinomas (P=0.039) and in adenomas (P=0.021). These data suggest that CD44 may be involved in the process of invasion and metastasis, probably with the cooperation of cathepsin D. Its expression may be an indicator of poor prognosis in colorectal adenocarcinomas.
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PMID:Glycoprotein CD44 expression in colorectal neoplasms. An immuno-histochemical study including correlation with cathepsin D, extracellular matrix components, p53, Rb, bcl-2, c-erbB-2, EGFR and proliferation indices. 1007 Dec 34

Metallothionein (MT) is a low molecular weight, cysteine-rich, zinc-binding protein that may have a function in cellular repair processes, growth and differentiation. Using a monoclonal antibody (E9) to metallothionein, we investigated the immunohistochemical expression of MT in routinely fixed and paraffin-embedded tissue from 98 cases of female breast carcinomas. The MT expression was studied in comparison with the expression of the basement membrane (BM) antigens (type IV collagen, laminin), fibronectin, cathepsin D, adhesion molecule CD44, p53 protein, the pRb, c-erbB-2 oncoprotein, EGFR, stromelysin-1, proliferation indices (Ki-67, PCNA), steroid receptor content as well as with other conventional clinicopathological parameters of breast cancer. Strong MT expression was observed in the majority of tumour cells in 18.4% of tumours, focal MT positivity in 13.3% and almost complete lack of MT expression in 68.4% of cases (mean value 33.36 +/- 26.36). The MT expression in carcinoma cells was strongly associated with the DCIS component of the tumour (p < 0.0001). High values of MT were correlated with low steroid receptor status (p = 0.08 for ER receptor and p = 0.019 for PgR receptor content). MT positive cases were correlated with stromelysin-1 expression (p = 0.059) and cathepsin D (p = 0.058). These findings suggest that MT expression is characteristic of the early phase of breast carcinogenesis, possibly regulated by hormones, and could be a new potential prognostic marker in breast cancer.
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PMID:Immunohistochemical localization of metallothionein in human breast cancer in comparison with cathepsin D, stromelysin-1, CD44, extracellular matrix components, P53, Rb, C-erbB-2, EGFR, steroid receptor content and proliferation. 1047 Jan 61

In tumor tissue specimens of 27 primary and 17 secondary glioblastomas and the precursor lesions, the immunohistochemical expression patterns of the membrane protein CD44s, the basal lamina proteins laminin, collagen IV, and fibronectin, the lectin galectin-3 recognizing tenascin and N-CAM as well as of the matrix-degrading enzymes matrix metalloproteinase MMP-2 and MMP-9, and cathepsin D were studied. Besides expression of basal lamina proteins in vessels, all glioblastomas and the precursor lesions showed strong immunoreactivity of CD44s, tenascin, galectin-3, and N-CAM which were restricted to solid tumor masses. Present in solid tumor areas, MMP-2, MMP-9 and cathepsin D were also strongly expressed by single tumors cells invading adjacent brain tissue at the infiltrative margin. Neither the expression pattern in primary and secondary glioblastomas nor in the precursor tumors revealed significant differences. There was also no intraindividual constant expression pattern during glioma progression or correlation with malignancy. Restricted expression of CD44s, galectin-3, tenascin and N-CAM in solid tumor masses seems to contribute to homotypic tumor cell adhesion while single tumor cells abolish this expression profile and acquire invasive activities by expression of cathepsin D, MMP-2 and MMP-9.
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PMID:Expression of adhesion factors and degrading proteins in primary and secondary glioblastomas and their precursor tumors. 1072 72

Hydroxylation of lysyl residues is crucial for the unique glycosylation pattern found in collagens and for the mechanical strength of fully assembled extracellular collagen fibers. Hydroxylation is catalyzed in the lumen of the endoplasmic reticulum (ER) by a specific enzyme, lysyl hydroxylase (LH). The absence of the known ER-specific retrieval motifs in its primary structure and its association with the ER membranes in vivo have suggested that the enzyme is localized in the ER via a novel retention/retrieval mechanism. We have identified here a 40-amino acid C-terminal peptide segment of LH that is able to convert cathepsin D, normally a soluble lysosomal protease, into a membrane-associated protein. The same segment also markedly slows down the transport of the reporter protein from the ER into post-ER compartments, as assessed by our pulse-chase experiments. The retardation efficiency mediated by this C-terminal peptide segment is comparable with that of the intact LH but lower than that of the KDEL receptor-based retrieval mechanism. Within this 40-amino acid segment, the first 25 amino acids appear to be the most crucial ones in terms of membrane association and ER localization, because the last 15 C-terminal amino acids did not possess substantial retardation activity alone. Our findings thus define a short peptide segment very close to the extreme C terminus of LH as the only necessary determinant both for its membrane association and localization in the ER.
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PMID:A single C-terminal peptide segment mediates both membrane association and localization of lysyl hydroxylase in the endoplasmic reticulum. 1074 89

This study aims at the in situ identification of factors mediating glioma cell invasion requiring adhesion, extracellular matrix degradation, and migration. Forty-five gliomas (astrocytomas, glioblastomas, oligodendrogliomas, and mixed gliomas) were investigated for the immunohistochemical expression of the membrane protein CD44s, the basal lamina proteins laminin, collagen IV, and fibronectin, the lectin galectin-3 recognizing tenascin and N-CAM, as well as for the matrix-degrading enzymes metalloproteinases MMP-2, MMP-9, and cathepsin D. Besides vessels expressing basal lamina proteins, tenascin, MMP-2, MMP-9, and galectin-3, tumor cells revealed strong immunoreactivity for CD44s, tenascin, galectin-3, and N-CAM, which was restricted to solid tumor masses. Single invading cells displayed distinct expression of MMP-2 and MMP-9, also found in solid tumor areas, as well as of cathepsin D. Restricted expression of CD44s, galectin-3, tenascin, and N-CAM in solid tumor masses seems to contribute to homotypical tumor cell adhesion. However, switching to an invasive phenotype, single tumor cells lack this expression pattern and acquire degrading and phagocytic activities by expressing cathepsin D, MMP-2, and MMP-9, which are also expressed by solid tumor masses facilitating the loosening and invasion of single neoplastic cells. The blocking of these factors may be of potential benefit in anti-invasive therapy.
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PMID:Adhesive and invasive features in gliomas. 1108 57

The substrate specificity of porcine pepsin has been altered by site-directed mutagenesis in an attempt to selectively cleave bovine hide collagen at only a few sites, similar to cathepsin D, for the production of high quality gelatin. Kinetic parameters were determined using chromogenic peptide substrates based on the sequence Lys-Pro-Xaa-Yaa-Phe*Nph-Arg-Leu (where Xaa is Ile or Pro, Yaa is Glu. Leu, Gln or Lys, Nph is p-nitrophenylalanine, and * is the site of cleavage). Substitution of Thr222 and Glu287 within the S2 subsite of pepsin by Val and Met, respectively, produced a double mutant with a two- to fourfold higher kcat/Km, compared with wild-type pepsin, for the chromogenic peptides with residues Leu, Gln, and Glu at position P2 (Yaa). The results suggest that the functional group of the P2 side chain may be exposed to solvent, while the aliphatic portion interacts with hydrophobic residues comprising S2. Wild-type pepsin cleaved a peptide corresponding to the carboxy-terminal telopeptide region of bovine type I collagen alpha1 chain, SGGYDLSFLPQPPQE, predominantly at three sites (Asp-Leu, Leu-Ser, and Phe-Leu) and at a significantly lower rate at Ser-Phe. However, Thr222Val/Glu287Met cleaved site Ser-Phe at a rate 20-fold higher than the wild-type. Significantly, enzymes containing the double substitution Phe111Thr/Leu112Phe cleaved this peptide predominantly at one site Leu-Ser (similar to cathepsin D) and at a rate 23-fold higher than the wild-type. These mutants can potentially enhance the rate of solubilization of bovine hide collagen under conditions mild enough to maintain the triple helix structure and hence minimize the rate of subsequent denaturation and proteolytic cleavage.
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PMID:Modification of the substrate specificity of porcine pepsin for the enzymatic production of bovine hide gelatin. 1110 68

Human plasma fibronectin (pFN) contains a cryptic metalloprotease present in the collagen-binding domain. The enzyme could be generated and activated in the presence of Ca2+ from the purified 70-kDa pFN fragment produced by cathepsin D digestion. In this work we cloned and expressed the metalloprotease, designated FN type IV collagenase (FnColA), and a truncated variant (FnColB) in E. coli. The recombinant pFN protein fragment was isolated from inclusion bodies, and subjected to folding and autocatalytic degradation in the presence of Ca2+, and yielded an active enzyme capable of digesting gelatin, helical type II and type IV collagen, alpha- and beta-casein, insulin b-chain, and a synthetic Mca-peptide. In contrast, isolated plasma fibronectin, type I collagen, and the DNP-peptide were no substrates. Both catalytically active recombinant pFN fragments were efficiently inhibited by EDTA, and batimastat, and, in contrast to the glycosylated enzyme isolated from plasma fibronectin, were also inhibited by TIMP-2.
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PMID:The proteolytic activity of the recombinant cryptic human fibronectin type IV collagenase from E. coli expression. 1130 53


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