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)

Insulin-like growth factor-binding protein-3 (IG-FBP-3) is an important member of a family of proteins which binds IGF peptides and modulates their biological actions. In this study, we describe an acid-activated IGFBP-3 protease in media derived from a variety of human cell lines. Radiolabeled IGFBP-3 remained intact during incubation (pH 5.5-8) in media conditioned by normal and transformed human fibroblasts, MG-63 osteoblastic cells, and breast cancer cell lines MCF-7 and Hs578T. However, acidification of the conditioned medium samples (pH < 5.5) resulted in 125I-IGFBP-3 hydrolysis and the appearance of specific radiolabeled fragments. No proteolysis of 125I-IGFBP-3 occurred during incubation in unconditioned medium at neutral or acid pH. Estrogen treatment of estrogen receptor-positive MCF-7 cells enhanced acid-activatable IGFBP-3 proteolysis in the cell-conditioned medium but had no effect on proteolytic activity in estrogen receptor-negative Hs578T cells. The cell-derived IGFBP-3 protease was identified as the aspartic proteinase cathepsin D, based on acidic pH optimum, inhibition by pepstatin, distinctive proteolytic fragment pattern, and immunoreactivity with cathepsin D antisera. Furthermore, immuno-depletion of cathepsin D effectively attenuated acid-activated IGFBP-3 proteolysis. These data suggest a role for cathepsin D in the regulation of cellular IGF action by virtue of its potential to alter the structure/function of IGFBP-3.
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PMID:Acid-activated insulin-like growth factor-binding protein-3 proteolysis in normal and transformed cells. Role of cathepsin D. 751 Feb 81

Insulin-like growth factor I (IGF-I) seems to play an important role in prostate cell growth and its actions may be modified by IGF-binding proteins (IGFBPs) secreted by prostate epithelial cells. The IGFBP system was studied in two human prostate carcinoma cell lines, PC3 and LNCaP. Androgen receptor-negative PC3 cells secrete IGFBP-3, IGFBP-4, and IGFBP-5, as determined by immunoprecipitation of the serum-free conditioned medium with specific IGFBP antibodies. Androgen receptor-positive LNCaP cells secrete IGFBP-2 and IGFBP-3. At neutral pH, there was little or no effect of a 24-h, 37 C cell-free incubation of PC3 and LNCaP conditioned media on IGFBP. On the other hand, when media was incubated at pH 3 for 24 h, [125I]IGFBP-3 hydrolysis and the virtual elimination of endogenous IGFBP detected by Western ligand blotting were observed. This loss was not due to the acid treatment, per se, since IGFBPs remained intact if the incubation at pH 3 was carried out at 4 C. The acid-activated IGFBP protease in LNCaP and PC3 cell-conditioned media was identified as cathepsin D based on acidic pH optimum and immunoblotting. Furthermore, immunoadsorption of cathepsin D from the media attenuated the acid-activated IGFBP hydrolysis [125I]IGF-I binding to prostate cancer cells was reduced in the presence of LNCaP conditioned media that had been incubated at neutral pH for 24 h (i.e. containing intact IGFBP) but not by acid-incubated conditioned media (i.e. cathepsin D-mediated hydrolyzed IGFBP). These data indicate that prostate carcinoma cells secrete specific IGFBPs, as well as a general IGFBP protease, cathepsin D. In the proper environment, cathepsin D is capable of hydrolyzing all endogenous IGFBP and, thus, modifying IGF-I action in prostatic cells.
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PMID:Endogenous cathepsin D-mediated hydrolysis of insulin-like growth factor-binding proteins in cultured human prostatic carcinoma cells. 753 76

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

In this study, we demonstrate insulin-like growth factor binding protein (IGFBP) acid proteolysis in conditioned media (CM) from normal and malignant primary cultures of prostatic epithelial cells, prostatic cell lines, and in seminal plasma. We further demonstrate the absence of such activity in CM from prostatic stromal cells. Radio-labeled IGFBPs (1-6) were incubated with various acidified CM and seminal plasma. None of these media showed IGFBP proteolytic activity at neutral pH, but all CM from prostatic epithelial cells (PC-E) demonstrated strong IGFBP proteolysis at acidic pH. No acid-activated proteolysis was observed in the CM from stromal cell cultures. In order to ascertain the role of cathepsin D, anti-cathepsin antibodies were used to immunodeplete the media of the selected enzymes prior to incubation with IGFBPs. Depletion of cathepsin D greatly reduced the proteolytic activity of the PC-E CM. Additionally, purified cathepsin D yielded a digestion pattern identical to that produced by prostatic cell CM and seminal plasma, following acidic incubation with IGFBP-3. Remarkably, the proteolytic pattern generated by seminal plasma, when incubated with IGFBP-3 at neutral pH, corresponded to that produced by prostate-specific antigen (PSA), demonstrating the interpolation of both neutral and acid proteases from prostate cells into seminal plasma. In conclusion, prostatic epithelial cells secrete acid-specific IGFBP protease(s) related to cathepsin D. Although no significant statistical difference was observed in the degree of acid-specific proteolysis in the media from normal versus malignant primary epithelial cell cultures, physiological characteristics of the malignant state might facilitate increased cathepsin D activity. We suspect this proteolysis may play a role in prostatic cell proliferation and invasive tumor growth.
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PMID:Acid-activated insulin-like growth factor binding protein protease activity of cathepsin D in normal and malignant prostatic epithelial cells and seminal plasma. 913 Apr 67

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

The Type-2 insulin-like growth factor receptor (IGF2R) mediates the transport of lysosomal hydrolases to lysosomes and the clearance of insulin-like growth factor II (IGF-II). Mutant mice lacking IGF2R usually die perinatally, but are completely rescued from lethality in the absence of IGF-II. IGF2R/IGF-II-deficient mice have elevated levels of circulating IGF binding protein (IGFBP)-3 and show a strong IGFBP-6 immunoreactivity in all pancreatic islet cells and in secretory granules of different size in acinar cells and interlobular connective tissue of exocrine pancreas. Fibroblasts derived from double mutant mice missort the lysosomal protease cathepsin D, and are able to degrade endocytosed (125I)IGFBP-3 intracellularly, however, with lower efficiency than in control cells. These results show that the deficiency of IGF2R and IGF-II affects the expression and metabolism of IGFBPs in a tissue- and cell type-specific manner.
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PMID:Alteration in pancreatic immunoreactivity of insulin-like growth factor (IGF)-binding protein (IGFBP)-6 and in intracellular degradation of IGFBP-3 in fibroblasts of IGF-II receptor/IGF-II-deficient mice. 1022 7

Perturbations of the insulin-like growth factor (IGF) axis, including the autocrine production of IGFs, IGF binding proteins (IGFBPs) and IGFBP proteases such as prostate specific antigen (PSA), and cathepsin D have been identified in prostate, lung and breast cancer cells and tissues. Serum IGFBP-3 levels have been found to be negatively correlated to the risk of cancer. Interestingly, IGFBP-3 is a potent inhibitor of IGF action and also mediates apoptosis via an IGF-independent mechanism. Recent case-control studies have found an approximately 10% increase in the serum levels of IGF-I in patients with prostate, breast and lung cancers, which are among the most frequently diagnosed cancers. While the studies indicate an association between serum IGF-I levels and cancer risk, causality has not been established. Thus, serum IGF-I level may actually be a confounding variable, serving as a marker for autocrine tissue IGF-I production. Growth hormone (GH) therapy raises both IGF-I and IGFBP-3 levels in serum. However, the role of GH in controlling prostate, breast and lung growth and carcinogenesis remains unclear from animal studies. Increased GH levels as seen in acromegaly have been associated with benign prostatic hyperplasia but not with prostate, breast or lung cancers, although colon cancer mortality may be increased. Should serum IGF-I levels be proven to play a causal role in the pathogenesis of cancer, interpreting the risk associated with therapies such as GH replacement must take into account both the duration of exposure and the risk magnitude associated with the degree of serum IGF-I elevation. Since GH-deficient patients often have a subnormal IGF-I serum level, which normalizes on therapy, their cancer risk on GH therapy probably does not increase substantially above that of the normal population. Until further research in the area dictates otherwise, ongoing surveillance and routine monitoring of IGF-I levels in GH recipients should become standard of care.
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PMID:IGFs and human cancer: implications regarding the risk of growth hormone therapy. 1059 43

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