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)

Isolated hearts of fetal mice in organ culture maintain active protein synthesis and protein degradation. Rates of degradation exceed rates of synthesis and as a result, the hearts are in state of negative protein balance as evidenced by net loss of protein and release of amino acids. Several hormones can alter amino acid metabolism and protein balance by altering synthesis or degradation, or both. In cultured fetal mouse hearts, insulin, the most extensively studies of the hormones increases the rate of protein synthesis by 13 +/- 3.7% and decreases the rate of protein degradation by 22 +/- 4.1% (p less than 0.01 for both). Together, these changes account for a 30-40% reduction in the loss of cardiac protein and in the release of phenylalanine from the heart. These changes are accompanied by a decrease of 21 +/- 2.7% in the total activity of the lysosomal proteinase cathepsin D. and by a reduction in the proportion of the enzyme that is present in the nonsedimentable fraction of the issue homogenate. This suggests that the possibility that insulin may function in part by altering lysosomal enzyme activity or availability, or both. The effects of insulin on protein degradation, amion acid release, and cathepsin D activity persist even when protein synthesis has been inhibited by cycloheximide. These results suggest that insulin plays an important role in the control of cardiac protein synthesis and degradation.
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PMID:Hormonal control of cardiac protein and amino acid balance. 126 89

A number of growth factors have been implicated in the control of the proliferation of breast cancer cells and some have been reported to mediate the proliferative effects of oestradiol. MCF-7 cells were treated with growth factors in the presence and absence of oestradiol. Oestradiol increased the response of cells to the proliferative effects of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and basic fibroblast growth factor (bFGF). Platelet derived growth factor (PDGF) and cathepsin D had no effect in the presence or absence of oestradiol while TGF-beta slightly reduced the stimulation by oestradiol. In the absence of oestradiol, there was little effect of combinations of growth factors although the effects of bFGF and IGF-I were additive. In the presence of oestradiol, the effects of bFGF and TGF-alpha were additive whereas bFGF acted as an IGF-I antagonist. Overall, bFGF had the greatest effect on cell proliferation although this was less marked than the previously described effect of the IGFs and insulin. The effects of oestradiol on the sensitivity of cells to the proliferative effects of bFGF did not appear to result from regulation of bFGF receptor expression.
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PMID:Modulation of the proliferative response of breast cancer cells to growth factors by oestrogen. 141

In this study, the polyanionic compound suramin was shown to be a potent in vitro growth inhibitor of both hormone-insensitive, estrogen receptor-negative human breast cancer cells (MDA MB231 and SK-BR-3) and hormone-responsive, estrogen receptor-positive human breast cancer cells (ZR 75-1, T47D, and MCF7). The inhibitory effect of suramin was dose dependent, with a median effective dose varying from 7 microM for MDA MB231 cells to 50 microM for MCF7 cells. This result indicated that estrogen receptor-negative cells were more sensitive to the drug. In MCF7 cells, not only did suramin block the mitogenic action of growth factors such as epidermal growth factor (EGF) and insulin-like growth factors I and II (IGF-I and IGF-II, respectively), but it also totally abolished the increase in cell proliferation induced by the steroid hormone 17 beta-estradiol (E2). Maximal inhibition was obtained after 5 days of suramin treatment, and inhibition either was partially reversed by E2, IGF-I, and IGF-II or was not reversible by EGF following removal of drug. In addition, suramin significantly decreased synthesis and secretion of the lysosomal enzyme cathepsin D, which was shown to be associated with a high risk of breast tumor metastasis. These results therefore suggest that, because of its effects on growth and cathepsin D secretion, suramin might be a helpful additional therapeutic tool for breast cancer patients, especially for patients with estrogen receptor-negative tumors which are insensitive to antihormonal strategies.
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PMID:Inhibition of breast cancer growth by suramin. 173 71

Antibodies specific for the insulin-regulatable glucose transporter (GLUT 4) were used to immunolocalize this protein in brown adipose tissue from basal- and insulin-treated rats. Cryosections of fixed tissue were incubated with antibodies, which were subsequently labeled with Protein A/gold and examined by EM. Antibodies against albumin and cathepsin D were also used with gold particles of different sizes to identify early and late endosomes, respectively. Under basal conditions 99% of the GLUT 4 labeling was located within the cell. Labeling was predominantly in the trans-Golgi reticulum and tubulo-vesicular structures elsewhere in the cytoplasm. In insulin-stimulated cells approximately 40% of the GLUT 4 labeling was at the cell surface, where it was randomly distributed, except for occasional clustering in coated pits. Moreover, after insulin treatment, GLUT 4 was also enriched in early endosomes. We conclude that translocation of GLUT 4 to the cell surface is the major mechanism by which insulin increases glucose transport. In addition, these results suggest that in the presence of insulin GLUT 4 recycles from the cell surface, probably via the coated pit-endosome pathway that has been characterized for cell surface receptors, and also that insulin causes the redistribution of GLUT 4 by stimulating exocytosis from GLUT 4-containing tubulo-vesicular structures, rather than by slowing endocytosis of GLUT 4.
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PMID:Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. 200 17

Cathepsin D was highly purified from the skeletal muscle of Japanese monkey (Macaca fuscata fuscata) by a procedure including affinity chromatography on concanavalin A-Sepharose and pepstatin-Sepharose, and then resolved into ten isozymes (A through J) by isoelectric focusing. When examined for specificity toward oxidized insulin B chain, isozyme A was highly specific and cleaved exclusively the Leu15-Tyr16 bond, whereas isozyme F was less specific, cleaving the Leu15-Tyr16 and Glu13-Ala14 bonds, with slower cleavages at several other bonds. These results demonstrate for the first time the occurrence of isozymes with different specificities among cathepsin D isozymes obtained from a single source.
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PMID:Occurrence of cathepsin D isozymes with different specificities in monkey skeletal muscle. 202 92

The subcellular site where insulin is degraded by rat hepatocytes in vivo is controversial. While several potential insulin-degrading enzyme systems, each with its own characteristic cellular location, are known to exist in the liver, questions remain about which of them participates in the degradation of physiologic doses of insulin. These studies examine the proteases that degrade physiologic doses of [125I]-insulin in vivo to determine (1) when and where initial degradation occurs, and (2) which of the potential degradative enzymes is active. Following injection into the mesenteric veins of male rats, intact [125I]-insulin and its labeled degradation products were analysed by reverse-phase high-performance liquid chromatography (RP-HPLC) of biopsy homogenates. [125I]-insulin was rapidly degraded in vivo; the t 1/2 of degradation was approximately 2.7 minutes. To test for extracellular protease activity, an isolated perfused liver system was employed. [125I]-insulin (or [125I]-glucagon) uptake was controlled by changing the temperature of the perfusion medium. Five minutes after [125I]-insulin injection, surface-bound label was recovered in an acidic (pH 3.5) wash. In perfusion at 15 degrees C, both the internalization and degradation of [125I]-insulin were inhibited; 7.2% of unbound hormone was degraded and 5.1% of surface-bound insulin was degraded. Only 11.4% of unbound insulin and 17.4% of surface-bound insulin were degraded at 35 degrees C. In contrast, 95.5% of unbound glucagon and 89.9% of surface-bound glucagon were degraded at 35 degrees C. Thus, although glucagon degradation occurs at the sinusoidal plasmalemma of perfused livers, the same membrane does not mediate the rapid degradation of insulin observed in vivo. Analysis of the RP-HPLC [125I]-insulin elution profiles from liver biopsy homogenates, and comparison of them to profiles produced by purified proteases, suggested that insulin protease is responsible for most hepatic degradation of physiologic doses of insulin. Some cathepsin D-like activity was also observed in vivo, confirming that two pathways exist for insulin metabolism. The time course over which insulin was degraded was more rapid than previous studies in vitro would have predicted. This suggests that more insulin was receptor-bound at the time of its initial degradation, and that the active protease was soluble and was introduced into endocytic peripheral endosomes within seconds after their formation.
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PMID:[125I]-insulin metabolism by the rat liver in vivo: evidence that a neutral thiol-protease mediates rapid intracellular insulin degradation. 240 25

1. The volume fraction of autophagic vacuoles in liver parenchymal and exocrine pancreatic cells was smallest and the serum insulin level highest in the 24 hr prestarved mouse immediately after 3 hr feeding period. 2. The size of the autophagic vacuole and lysosome (dense body) compartments increased in both types of cells during 2-72 hr fasting parallel with decreasing serum insulin levels. 3. The protein content of the cells decreased and the DNA-based activity of acid phosphatase showed little change throughout fasting. The activity of cathepsin D increased during days 2 and 3 of food deprivation. 4. Vinblastine (50 mg/kg body wt) applied for the last 2 hr of different periods (2, 12, 24, 48 and 72 hr) of fasting decreased serum insulin level and increased the fractional cytoplasmic volume of autophagic vacuoles and dense bodies. This increase was smaller when the drug was applied shortly after feeding and much larger after prolonged fasting. The increase was more pronounced in the pancreatic than in the liver cells. 5. Our data show that the effect of vinblastine on the size of the autophagic-lysosomal compartment depends on the feeding status of the animals.
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PMID:Combined effects of fasting and vinblastine treatment on serum insulin level, the size of autophagic-lysosomal compartment, protein content and lysosomal enzyme activities of liver and exocrine pancreatic cells of the mouse. 269 84

The estrogen-induced 52K protein secreted by human breast cancer cells is a lysosomal protease recently identified as a pro-cathepsin D by sequencing several cDNA clones isolated from MCF7 cells (Augereau et al., Mol. Endocr.). Using one of these clones, we detected, in MCF7 cells, a 2.2 kb mRNA whose level was rapidly increased 4- to 10-fold by estradiol, but not by other classes of steroids. Other mitogens, such as epidermal growth factor and insulin, also induced the 2.2 kb mRNA in a dose-dependent manner. Induction with epidermal growth factor was as rapid but was 2- to 3-fold lower than with estradiol. Antiestrogens had no effect on the 52K-cathepsin-D mRNA in MCF7 cells, but became estrogen agonists in two antiestrogen-resistant sublines R27 and LY2. The use of transcription and translation inhibitors and nuclear run-on experiments indicate that estradiol enhances transcription of the 52K-cathepsin-D gene in MCF7 cells.
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PMID:Estrogens and growth factors induce the mRNA of the 52K-pro-cathepsin-D secreted by breast cancer cells. 328 24

Streptozotocin-induced diabetes resulted in a decrease in the cathepsin D activity (free and total) in rat liver, kidney, brain and heart with a concomitant increase in tissue protein content and amino acids pool size. Treatment with insulin brought about the restoration of the cathepsin D activity to normal or greater than normal levels; tissue protein content and amino acids pool size also returned to normal values.
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PMID:Insulin-dependent changes in lysosomal cathepsin D activity in rat liver, kidney, brain and heart. 328 52

An extract of rat neutrophils was found to contain a high hemoglobin-hydrolyzing activity at pH 3.2, about 70% of which does not cross-react with anti-rat liver cathepsin D antibody. A neutrophil non-cathepsin D acid proteinase was successfully isolated from cathepsin D and characterized in comparison with the properties of rat liver cathepsin D. The neutrophil enzyme differed from cathepsin D in chromatographic and electrophoretic behaviors as well as immunological cross-reactivity, and its molecular weight was estimated to be 98,000 by gel filtration on Toyopearl HW 55. These findings strongly suggest that the neutrophil enzyme could be classified as cathepsin E. The enzyme, now designated rat cathepsin E, had an optimal pH at 3.0-3.2, preferred hemoglobin to albumin as substrate, and was markedly resistant to urea denaturation. Rat cathepsins D and E cleaved the insulin B-chain at six and eight sites, respectively; five sites were common for both enzymes. Possible relations among cathepsin E and cathepsin D-like or E-like acid proteinases reported so far were discussed.
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PMID:Cathepsin E from rat neutrophils: its properties and possible relations to cathepsin D-like and cathepsin E-like acid proteinases. 330 66


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