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)

Proteolytic modification of circulating insulin-like growth factor binding protein-3 (IGFBP-3) has been described in a number of conditions. Using Western ligand blotting and SDS-PAGE analysis of fragmentation patterns of 125I-labelled IGFBP-3 and 125-labelled IGFBP-1, we have examined conditioned media from cultured human cell lines for the presence of proteolytic activity and compared this with the action of circulating proteases and with characterized enzymes including cathepsin D, kallikrein, plasmin and tissue plasminogen activator. 125I-Labelled IGFBP-3 was incubated with serum from pregnant women, patients following heart surgery and patients with cancer of the breast, lung or head/neck. Following separation of the preincubated samples by SDS-PAGE, a distinct pattern of degradation fragments was observed which was similar in all cases. This proteolytic activity was inhibited in the presence of EDTA, phenanthroline and 4(-2-aminoethyl)-benzenesulphonylfluoride, HCl. These proteases had no detectable effect on IGFBP-1. Serum-free conditioned medium from a human dermal fibroblast cell line, a rabdomyosarcoma, a cervical, a bladder, a chorio- and two-tongue squamous cell carcinoma cell lines all contained proteolytic activity which fragmented IGFBP-3. The pattern of fragments was similar in all cell lines but different from that produced by the circulating proteases. Six out of nine cell lines produced protease(s) which degraded IGFBP-1 in addition to IGFBP-3. Whilst all the characterized enzymes tested also fragmented IGFBP-3 and plasmin cleaved IGFBP-1, none of these acted in the same way as either circulating or cell line-derived proteolytic activity. The activity associated with the characterized enzymes and cell lines was inhibited in the presence of serum from normal healthy subjects. These results demonstrate that the serum of pregnant women, post-operative patients and patients with cancer contain circulating proteases which cause fragmentation of IGFBP-3 but have little effect on IGFBP-1. Cell-derived proteases were shown to act on IGFBP-3 and IGFBP-1 in a number of instances but are not active in the presence of circulating inhibitors. These proteases may play an important role in regulating the availability of IGFs to normal and neoplastic tissues.
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PMID:Proteolytic modification of insulin-like growth factor-binding proteins: comparison of conditioned media from human cell lines, circulating proteases and characterized enzymes. 750 92

Affinity-purified lysosomal protease cathepsin D cleaved recombinant human IGFBP-1 to -5 in fragments of defined sizes, while IGFBP-6 was not degraded. To assess the role of cathepsin D for proteolytic processing of IGFBP in vivo, serum from cathepsin D-deficient mice and conditioned media from cathepsin D-deficient fibroblasts and organ explants were analyzed. No differences for the pattern and level of IGFBPs were detected. When conditioned media from fibroblasts were incubated at acid pH, proteolysis of IGFBP-1 and -4 was observed only in media derived from cathepsin D-expressing cells. Additional experiments showed that the proteolysis of IGFBP-4 is mediated by cathepsin D and not by a protease activated by cathepsin D. The IGFBP-4 degrading activities in media from organ explants from cathepsin D-deficient mice were found to be sensitive to inhibitors of aspartyl and cysteine proteases. The data indicate that different classes of acid pH-dependent proteases can contribute to the regulation of IGFBP-4 abundance.
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PMID:Proteolysis of IGFBPs by cathepsin D in vitro and in cathepsin D-deficient mice. 881 69

Various proteinases have been postulated to function in limited proteolysis of insulin-like growth factor binding proteins (IGFBPs) contributing to the regulation of IGF bioavailability. In this study, we report on the in vitro degradation of IGFs and IGFBPs by the purified acidic aspartylprotease cathepsin D that has been shown to proteolyze IGFBP-3. Recombinant human [125I] IGFBP-1 to -5 were processed by cathepsin D to fragments of defined sizes in a concentration dependent manner, whereas IGFBP-6 was not degraded. Ligand blotting revealed that none of the IGFBP-1 or -3 fragments formed by cathepsin D retain their ability to bind IGF. By N-terminal sequence analysis of nonglycosylated IGFBP-3 fragments produced by cathepsin D, at least four different cleavage sites were identified. Some of these cleavage sites were identical or differed by one amino acid from sites used by other IGFBP proteases described. The IGFBP-3 and -4 cleavage sites produced by cathepsin D are located in the nonconserved central region. IGF-I and -II, but not the unrelated platelet-derived growth factor BB, were degraded by cathepsin D in a time and concentration-dependent manner. We speculate that the major functional site of cathepsin D is intracellular and may be involved 1) in the selected clearance either of IGFBP or IGFs via different endocytic pathways or 2) in the general lysosomal inactivation of the IGF system.
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PMID:Proteolysis of insulin-like growth factors (IGF) and IGF binding proteins by cathepsin D. 927 67

The insulin-like growth factors (IGF-I and -II) are structurally related peptides participating in the regulation of metabolism, growth and cellular differentiation. In the present study, the human hepatoma cell line PLC was studied for the expression of individual components of the IGF axis. Northern blot analysis using IGF-I and -II coding cDNAs failed to detect IGF-I- or -II-specific transcripts in total RNA from PLC cells. Biosynthesis of type I and II IGF receptors was demonstrated by northern blotting and binding studies as well as cross-linking of the respective radiolabeled ligand. Both IGF-I and -II stimulated [3H]-thymidine incorporation dose-dependently. The mitogenic activity of exogenously added IGFs was reduced by the presence of IGF-binding proteins of 24, 30, 34, 41 and 45 kDa in supernatants of PLC cells identified as IGFBP-4, -1, -2 and -3, respectively, by [125I]IGF-I ligand-, immuno- and northern blotting. Biosynthesis of IGFBP-3 was stimulated dose-dependently by IGF-I and -II, while IGFBP-1, -2 and -4 were not affected. The increase of IGFBP-3 in response to IGF-I and -II was due to a stimulation of IGFBP-3 specific mRNA as well as to an inhibition of IGFBP-3 endocytosis. Proteolytic activity for rhIGFBP-3 was detected in media from PLC cells at acidic pH that was inhibited by the aspartyl protease inhibitor pepstatin A as well as after immunodepletion of cathepsin D from media of PLC cells. Thus, a role of cathepsin D for the regulation of IGFBP-3 bioavailability via endocytosis in acidic prelysosomal compartments was suggested. The susceptibility of PLC for IGF-I and -II was restricted by their ability to increase the abundance of inhibitory IGFBPs and to decrease the level of IGF-I receptor expression. The present data point to the IGF axis as a complex regulatory system that self limits the mitogenic activity of exogenous IGFs.
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PMID:Characterization of the insulin-like growth factor axis in a human hepatoma cell line (PLC). 988 66

Differential techniques have revealed several novel genes and peptides involved in trophoblast development including PL74/gdf15/MIC-1, a TGFbeta family cytokine that controls apoptosis and differentiation, PL48, a new serine-threonine protein kinase, serum and glucocorticoid-induced kinase, PBK-1, a tunicamycin-responsive gene, a cathepsin D-like gene (DAP-1) and hypoxia- regulated genes HRF-1,2,6,8 and HIF-1alpha, HIF-1beta, and hEPAS-1. Syncytin, a cell fusion- inducing gene, has been cloned from placenta where it regulates cell fusion. ERV-3 has also been demonstrated to promote cell fusion. These two genes represent the first demonstrated functions of endogenous retroviral sequences in human tissues. Endoglin, PlGF, TGFbeta3, IGF-II, IGFBP-1, and a placental IGFBP protease have found new roles in regulating cytotrophoblast proliferation and invasiveness. A specific placental p105 rasGAP protein has been identified. The homeobox genes DLX4, HB24, MSX2 and MOX2 also likely play a role in development at the epithelial-mesenchymal boundary. Transcription factors such as TEF-5, Hand1, HEB, HASH-2 and two genes represented by ESTs may have regulatory roles in placental development. Evidence suggests that the placenta has an unusual two-cell system for apoptosis regulation in which the cytotrophoblast may direct later apoptotic events in the syncytium, and with syncytialization possibly triggered by the "phosphatidylserine flip". Thus, the placenta is both a rich source of new growth-regulatory substances, and a model system for originating new paradigms of developmental biology.
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PMID:Life and death in the placenta: new peptides and genes regulating human syncytiotrophoblast and extravillous cytotrophoblast lineage formation and renewal. 1236 35