Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We analyzed 53 specimens from primary squamous cell carcinomas of the skin for the expression of collagenase IV, cathepsin D and metallothionein by means of immunohistochemistry along with histological data. We compared tumors that metastasized (30) with tumors that did not (23) during a follow-up period of at least 5 years. The expression of the two proteolytic enzymes cathepsin D and collagenase IV was also assessed at the invading front of the tumors. Statistical analyses revealed significant differences for the overall expression of cathepsin D (P < 0.05), expression of cathepsin at the invading front (P < 0.05) and the tumor thickness (P < 0.01). The results showed that cathepsin D may be a prognostic factor for squamous cell carcinomas of the skin. We then combined the results of parameters with statistically significant differences by multiplication. The prognostic value of such a combined risk-factor score showed higher confidence than any of the single parameters alone: a sensitivity of 63.3%, a specificity of 87.0% and an efficiency of 73.6%. This kind of combined risk-factor score might be used to more accurately detect patients at high risk of metastasis.
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PMID:The prognostic value of the expression of collagenase IV, cathepsin D and metallothionein in squamous cell carcinomas of the skin determined by immunohistochemistry. 1135 24

A 19-residue antimicrobial peptide parasin I is generated from histone H2A in the skin mucus of catfish by the action of cathepsin D activated by a procathepsin D-processing enzyme induced upon epidermal injury. Here we report the isolation and characterization of the procathepsin D-processing enzyme in the mucus of wounded catfish. Sequence analysis of the cDNA identified the purified procathepsin D-processing enzyme as matrix metalloproteinase 2 (MMP 2). By acting as a procathepsin D convertase upon epidermal injury, MMP 2 is involved in the regulation of parasin I production in catfish skin mucosa.
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PMID:Matrix metalloproteinase 2 is involved in the regulation of the antimicrobial peptide parasin I production in catfish skin mucosa. 1243 93

Hypoxia-inducible factor 1 (HIF-1) transactivates genes the products of which mediate tumor angiogenesis and glycolytic metabolism. Overexpression of the HIF-1 alpha subunit, resulting from intratumoral hypoxia and genetic alterations, has been demonstrated in common human cancers and is correlated with tumor angiogenesis and patient mortality. Here we demonstrate that hypoxia or HIF-1 alpha overexpression stimulates Matrigel invasion by HCT116 human colon carcinoma cells, whereas this process is inhibited by a small interfering RNA directed against HIF-1 alpha. We show that HIF-1 regulates the expression of genes encoding cathepsin D; matrix metalloproteinase 2; urokinase plasminogen activator receptor (uPAR); fibronectin 1; keratins 14, 18, and 19; vimentin; transforming growth factor alpha; and autocrine motility factor, which are proteins that play established roles in the pathophysiology of invasion. Neutralizing antibodies against uPAR block tumor cell invasion induced by hypoxia or HIF-1 alpha overexpression. These results provide a molecular basis for promotion of the invasive cancer phenotype by hypoxia and/or HIF-1 alpha overexpression.
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PMID:Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. 1261 33

Phagocytosis of photoreceptor outer segments (OS) by retinal pigment epithelium (RPE) is essential for OS renewal and survival of photoreceptors. Internalized, oxidatively modified macromolecules perturb the lysosomal function of the RPE and can lead to impaired processing of photoreceptor outer segments. In this study, we sought to investigate the impact of intracellular accumulation of oxidatively damaged lipid-protein complexes on maturation and distribution of cathepsin D, the major lysosomal protease in the RPE. Primary cultures of human RPE cells were treated with copper-oxidized low density lipoprotein (LDL) and then challenged with serum-coated latex beads to stimulate phagocytosis. Three observations were noted to occur in this experimental system. First, immature forms of cathepsin D (52 and 46 kDa) were exclusively associated with latex-containing phagosomes. Second, maturation of cathepsin D was severely impaired in RPE cells loaded with oxidized LDL (oxLDL) prior to the phagocytic challenge. Third, pre-treatment with oxLDL caused sustained secretion of pro-cathepsin D and the latent form of gelatinase A into the extracellular space in a dose-dependent manner. These data stimulate the hypothesis that intracellular accumulation of poorly degradable, oxidized lipid-protein cross-links, may alter the turnover of cathepsin D, causing its mistargeting into the extracellular space together with the enhanced secretion of a gelatinase.
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PMID:Products of lipid peroxidation induce missorting of the principal lysosomal protease in retinal pigment epithelium. 1515 11

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) and poly(ethylene glycol) (PEG)-grafted PHEG conjugates of N,N-di(2-chloroethyl)-4-phenylenediamine mustard (PDM) were synthetised. A collagenase-sensitive oligopeptide spacer was selected to link the cytotoxic agent PDM onto the polymeric carrier. First, the oligopeptide-drug conjugate, L-pro-L-leu-gly-L-pro-gly-PDM, was prepared. In a second step, the low molecular weight PDM derivative and PEG-NH(2) were coupled to a N,N-disuccinimidylcarbonate activated PHEG. Dynamic laser light scattering measurements indicated the formation of aggregates. The presence of human serum albumin had no significant effect on the diameter of the conjugates. The hydrolytic stability of the conjugates was investigated in buffer solutions. The conjugates showed an improved stability compared to the parent nitrogen mustard. The enzymatic degradation studies of the polymeric conjugates were performed in the presence of collagenase type IV (Clostridiopeptidase A; EC 3.4.24.3), cathepsin B (EC 3.4.22.1), cathepsin D (EC 3.4.23.5) and tritosomes. Only the bacterial collagenase type IV was able to cleave the spacer releasing free PDM and its peptidyl derivative, gly-L-pro-gly-PDM. The in vitro cytotoxicity of the conjugates was evaluated against HT1080 fibrosarcoma cells and MDA adenocarcinoma cells. All conjugates showed low toxicity towards these cell lines.
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PMID:Synthesis and in vitro evaluation of macromolecular antitumour derivatives based on phenylenediamine mustard. 1566 87

To better understand the biochemical mechanisms necessary for prostate cancer invasion and metastases, we studied the expression and interaction of proteolytic enzymes cathepsin D, cathepsin B, urokinase and collagenase IV in human prostate cell lines LNCAP (hormone sensitive) and DU145 (hormone refractory). Cellular fractionation and immunoblotting revealed that both cell lines expressed similar amounts of the 34 kD form of cathepsin D, 72 kD form of collagenase IV and the 55 kD form of urokinase. However, DU145 expressed an increased amount of the 28 kD form of cathepsin B. When E64, a cysteine protease inhibitor was added, a decreased amount of the active cathepsin D was expressed. Furthermore, when cathepsin B was added to concentrated plasma membrane homogenates, urokinase was processed to its active form at 33 kD. E64 inhibited the ability of both cell lines to degrade fibronectin. An in vitro Boyden chamber demonstrated that DU145 was more motile than LNCAP and that preincubation with E64 could decrease motility of both cell lines. We suggest that cathepsin B may promote tumor invasion not only by proteolysis of basement membrane components, but also by activating other proteases.
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PMID:Characterization of protease expression in human prostate-cancer cell-lines. 2155 69


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