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)

We have earlier described a monoclonal antibody (323/A3) against a Mr 43,000 surface glycoprotein of MCF-7 human breast cancer cells which shows considerable specificity for primary and metastatic breast tumors (Cancer Res., 46: 1306-1317, 1986). Here we report the occurrence of the 323/A3 antigen in a large cohort of primary breast tumors (m = 384) and its interrelationship with several clinically important variables. Frozen, stored tumor tissues were examined by a Western blot procedure, and the level of 323/A3 protein in individual tumors was calculated in arbitrary units based on the integrated Mr 43,000 signal in tumors compared with an MCF-7 internal standard. Thirty-six % (139 of 384) of tumors were found to be positive for 323/A3. Higher frequencies of 323/A3 protein were found in tumors larger than 2 cm (P = 0.03), tumors with infiltrated lymph nodes (P = 0.01), and tumors without estrogen receptor (P = 0.006). No significant relationship was found with patient age, menopausal status, or progesterone receptor status. Of the newer clinical determinants proliferative rate (% S phase), DNA ploidy, and the lysosomal protease cathepsin D, but not the HER-2/neu oncogene protein, were significantly correlated with 323/A3. The presence of 323/A3 protein was also related to increased recurrence (P = 0.003) and mortality (P = 0.036) after primary treatment. As an exposed surface antigen, this glycoprotein might be a useful target in radioimaging and immunotherapy of some human breast tumors, especially those having large size, infiltrated lymph nodes, deficient estrogen receptor, high proliferative rate, abnormal DNA content, and high levels of cathepsin D, all of which are ominous indicators of tumor behavior.
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PMID:Association of the 323/A3 surface glycoprotein with tumor characteristics and behavior in human breast cancer. 233 24

The mechanism of release of Gal beta 1-4GlcNAc alpha-2,6-sialyltransferase (CMP-N-acetylneuraminate: beta-galactoside alpha-2,6-sialytransferase, EC 2.4.99.1) from rat liver during the acute-phase response is due to the action of a cathepsin D-like proteinase that cleaves the trans-Golgi membrane-bound enzyme from a membrane anchor; this allows a major portion of the enzyme containing the catalytic site to escape into the extracellular space [Lammers & Jamieson (1988) Biochem. J. 256, 623-631]. The release of sialytransferase was most effective at pH 5.6, suggesting that release of sialyltransferase from the Golgi in whole cells is dependent on maintaining an acidic environment in the trans-Golgi compartment of the hepatocyte. Golgi membranes contain a proton pump that maintains the acidic pH in these compartments [Glickman, Croen, Kelly & Al-Awquati (1983) J. Cell Biol. 97, 1303-1308; Yamashiro, Tycko & Maxfield (1984) Cell (Cambridge, Mass.) 37, 789-800; Zhang & Schneider (1983) Biochem. Biophys. Res. Commun. 114, 620-625; Anderson & Pathak (1985) Cell (Cambridge, Mass.) 40, 635-643]. Lysosomotropic agents, such as NH4Cl, chloroquine and methylamine can penetrate acidic compartments of the cell, such as the Golgi complex, raise the pH, and thus affect proteolytic cleavage events. The present paper describes the effect of lysosomotropic agents on the release of sialyltransferase from the hepatocyte using liver slices as a whole-cell system. Slices were prepared from control rats and rats suffering from the acute-phase response, where release of sialyltransferase is increased substantially [Lammers & Jamieson (1988) Biochem. J. 256, 623-631; Kaplan, Woloski, Hellman & Jamieson (1983) J. Biol. Chem. 258, 11505-11509]. Release of sialyltransferase was almost abolished in presence of 50 mM-NH4Cl, 50 mM-methylamine or 1 mM-chloroquine. Inhibition of release of sialyltransferase was reversed when the lysosomotropic agents were removed from the medium, showing that these agents are not cytotoxic to the cells under the conditions used. The secretion of rat alpha 1-acid glycoprotein, which is not subject to proteolytic processing in the Golgi complex, was not found to be substantially affected by the presence of lysosomotropic agents. The results suggest that proteolytic cleavage of the catalytic site of sialyltransferase is a process that is significantly affected by the intra-Golgi pH.
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PMID:Studies on the effect of lysosomotropic agents on the release of Gal beta 1-4GlcNAc alpha-2,6-sialytransferase from rat liver slices during the acute-phase response. 250 60

Eight liver biopsy specimens from five patients with PAS-negative intracisternal hyalin were investigated by immunofluorescence for: (1) immunoglobulins (Ig) G, A, M, D, E; (2) light chains (kappa and lambda); (3) complement components C1q, C4, C3c, C5, C9; (4) C1-inactivator; (5) C3-activator; (6) alpha 1-antitrypsin; (7) alpha 1-antichymotrypsin; (8) plasminogen; (9) fibrinogen; (10) fibrinogen breakdown products D and E; (11) fibronectin; (12) prealbumin; (13) albumin; (14) betalipoprotein; (15) apolipoprotein; (16) alpha 1- and alpha 2-glycoprotein; (17) cholinesterase; (18) ceruloplasmin; (19) haemopexin; (20) myoglobin; (21) placenta lactogen; (22) transferrin; (23) actin; (24) myosin; (25) cathepsin D; and (26) hepatitis B surface and core antigens (HBsAg and HBcAg). The globules reacted significantly with antisera against C3c (three patients), C4 (three patients), C3-activator (one patient) and fibrinogen (two patients). The cause of the protein accumulation is not clear. Serial studies indicate the possibility of a disturbance of protein secretion and an as yet unidentified immune complex disorder.
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PMID:Immunohistological investigations of PAS-negative globular intracisternal hyalin in human liver biopsy specimens. 285 88

UDP-N-acetylglucosamine:glycoprotein N-acetylglucosamine-1-phosphotransferase activity has been identified in both Acanthamoeba castellani and Dictyostelium discoideum. Each of these activities exhibits a different in vitro specificity toward various purified glycoproteins. The N-acetylglucosaminyl-phosphotransferase of A. castellani is very similar to the mammalian enzyme in that it phosphorylates the lysosomal enzymes cathepsin D and uteroferrin much more efficiently than nonlysosomal glycoproteins and appears to recognize a determinant on the protein portion of these good acceptors. In contrast the D. discoideum enzyme cannot utilize cathepsin D as a good substrate and, although it phosphorylates uteroferrin efficiently, it does not recognize the protein portion of this acceptor. The oligosaccharide of uteroferrin appears to assume a different conformation than the oligosaccharides of other glycoproteins and glycopeptides, as evidenced by its enhanced sensitivity to mannosidase digestion. This conformation, presumably induced by some interaction with the underlying protein, may be responsible for the specific phosphorylation of uteroferrin by the N-acetylglucosaminylphosphotransferase of D. discoideum.
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PMID:Glycoprotein phosphorylation in simple eucaryotic organisms. Identification of UDP-GlcNAc:glycoprotein N-acetylglucosamine-1-phosphotransferase activity and analysis of substrate specificity. 293 74

In contrast to liver, adipose tissue, and muscle, in which the diabetic state is associated with a "catabolic response," some tissues, typically the kidney and perhaps the intestinal mucosa and some vascular cell types, show an "anabolic response" to diabetes, with enhanced activity of the anabolic pathways and diminished activity of the catabolic ones. The kidney of alloxan or streptozotocin diabetic rats is hypertrophied, and shows enrichment in intracellular glycogen and abundant accumulation of glycoprotein material at the basement membrane level. Accordingly, protein synthesis and the enzymes of glucose utilization as well as those engaged in UDP sugar formation or in the hydroxylation and glycosylation processes (required for glycoprotein synthesis) show increased activity in the diabetic kidney, while the catabolic, lysosomal enzymes (cathepsin D and several glycosidases) are depressed. We observed a reduction of -24% in the activity of cathepsin D and -23% in that of galactosidase in the kidney of streptozotocin diabetic mice, as opposed to increases of +135 and +32%, respectively, found in liver. It is not known which factor(s) may be responsible for such an anabolic response of some tissues to diabetes, but persistent hyperglycemia and/or some hormonal abnormalities may be involved. The above data refer to changes in tissue enzyme content caused by induction-repression mechanisms, but rapid (activation-inhibition) effects may also occur. We observed that preincubation of slices of mouse kidney cortex for 10 min with 20.8 mmole/liter glucose resulted in a 80% activation of phosphofructokinase, as assayed in the tissue homogenate at physiological (50 mumole/liter) concentration of the substrate fructose-6-P, suggesting that hyperglycemia may be responsible for some of the metabolic changes occurring in the diabetic kidney.
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PMID:Anabolic response of some tissues to diabetes. 293 59

Readily detectable levels of renin activity were demonstrated in the human brain. This activity was inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific action of proteases such as cathepsin D. The pineal gland was found to be the richest source of renin followed by the pituitary, hypothalamus and hippocampus. The substantia nigra, caudate nucleus, putamen and thalamus contained moderately high concentrations of renin. The brain renins from pineal and pituitary glands shared some biochemical features with well-known kidney renin, such as molecular weight (46,000 daltons for pineal renin; 37,000-45,000 daltons for pituitary renin), optimum pH (6.0-7.0), the presence of trypsin activatable inactive renin, and a glycoprotein nature. However, the electrofocusing pattern of renin from pituitary tissue (pI = 4.43, 5.77) differed from that of plasma and kidney enzymes heretofore reported, a discrepancy which could be interpreted as evidence for the endogeneous synthesis of renin in the brain tissue. Furthermore, a high activity of immunoreactive renin was found in human neuroblastoma tissue. The biochemical characteristics of the neuroblastomal renin were generally similar to the known properties of kidney renin in many respects, providing evidence of the presence of the renin-angiotensin system within human neuronal cells.
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PMID:Immunoreactive renin in human brain: distribution and properties. 299 58

A high activity of renin was demonstrated in human pheochromocytoma tissue. This activity was inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific actions of proteases such as cathepsin D. The specific renin shared some biochemical features with well-known kidney renin, such as molecular weight (47,000 daltons), optimum pH (6.0), the presence of trypsin-activatable inactive renin, and glycoprotein nature. However, the isoelectrofocusing pattern of renin from the pheochromocytoma differed from that of kidney and plasma renins hitherto reported, a discrepancy which could be interpreted as evidence for endogenous synthesis of the enzyme. Furthermore, angiotensin converting enzyme activity was found in the tissue. Since pheochromocytoma is considered to be of neural crest origin, these results provide biochemical and immunological evidence for the presence of the renin-angiotensin cycle within human neuronal cells.
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PMID:Biochemical identification of renin in human pheochromocytoma. 300 87

Human hepatoma cell (HepG2) or rabbit hepatocyte monolayers were incubated with [35S]methionine in presence or absence of tunicamycin, a potent inhibitor of asparagine-linked glycosylation. The 35S-labeled nonglycosylated and control fibrinogens purified from the media were used to evaluate the influence of the oligosaccharide on the catabolic properties of this glycoprotein. Plasmin, pronase, cathepsin D or cathepsin B each degraded the nonglycosylated and control fibrinogens similarly, as evidenced by the release of trichloroacetic acid-soluble radioactivity and by SDS-polyacrylamide gel electrophoresis and autoradiography of plasmic digests. Nonglycosylated and control fibrin clots also showed no differences in susceptibility to plasmic digestion. The two forms of fibrinogen demonstrated the same plasma half-life in rabbits. These data indicate that the oligosaccharide does not influence the proteolytic stability or the in vivo plasma survival of fibrinogen, and suggest that other biochemical determinants may influence the catabolic properties of this molecule.
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PMID:Catabolic properties of aglycofibrinogen synthesized by tunicamycin-treated human hepatoma (HepG2) cells and rabbit hepatocytes. 301 19

Cathepsin D was assessed in C6 glioma cells grown in medium with an intermediate- or low-percent composition of serum. The amount, form, and subcellular location of cathepsin D differed after treatment with cyanate or monensin in cells grown in a low-serum, growth-factor-supplemented medium. Immunoblotting showed that cathepsin D in the lysosomal fraction of the C6 cell line had a molecular weight (Mr) of 42 kD, whereas that in the microsomal fraction had Mr's of 42, 47, and 78 kD. After treatment for 1 to 16 hr with 4 mmol/L cyanate and subcellular fractionation, the molecular weight of lysosomal cathepsin D was the same in treated and untreated cells, but more enzyme was found in lysosomes of treated cells at 8 and 16 hr. In the microsomal fraction, the amounts of both the 42 and 47 kD forms were increased after 1 to 16 hr of treatment. When exposed to 20 mmol/L cyanate, C6 cells remained viable, but compared with untreated cells, they showed 25% less lysosomal cathepsin D, with increased amounts found in the microsomal fraction. The 78 kD protein detected by immunoblotting was present in both the lysosomal and microsomal fractions but was predominant in the latter. The apparent molecular weight of this protein was the same after cyanate but differed with monensin, where Mr's of 39, 42, and 73 kD were found. Monensin-treated cells had less lysosomal cathepsin D and relatively more microsomal enzyme. The differing molecular weights of cathepsin D from cyanate- and monensin-treated cells suggest that their inhibitions occur at different processing loci in distal elements of the Golgi stacks. The differences in the pI of cathepsin D and the number of its forms from cyanate- and monensin-treated cells are also consistent with interference in the late stages of glycoprotein maturation. In this paper we show that the amount, molecular form, and consequent intracellular location of cathepsin D in cells of the C6 line can be affected by agents that selectively disrupt stages in Golgi-related protein modification and transport.
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PMID:Alterations of the posttranslational processing of a lysosomal enzyme in C6 glioma cells. 304 14

The plasma levels of the opsonic glycoprotein fibronectin are decreased in patients with fulminant hepatic failure, which may be an important factor in their impaired host-defense. Twenty-nine patients in fulminant hepatic failure were studied on admission, and the mean fibronectin level in Grade 0-2 encephalopathy was 82 micrograms per ml (range = 0 to 150) and in Grade 3-4 encephalopathy 61 micrograms per ml (range = 5 to 158) as compared to normal controls (268 micrograms per ml, range = 178 to 380, n = 62). No fibronectin degradation products could be detected in fulminant hepatic failure plasma by sodium dodecyl sulfate-gel electrophoresis on a polyacrylamide gradient (5 to 15%) followed by immunoblotting onto nitrocellulose with detection using a rabbit antihuman fibronectin antiserum visualized with a peroxidase conjugate. The plasma levels of the marker proteolytic enzyme cathepsin D were significantly elevated in fulminant hepatic failure (120 +/- 31 mU per ml per hr) as compared to the normal controls (18 +/- 2.1 mU per ml per hr, n = 10, p less than 0.01). Cross-immunoelectrophoresis of fulminant hepatic failure plasma for fibronectin on agarose plates gave an additional slower migrating peak in 15 of the 29 patients, as well as that of fibronectin, which corresponded to the fibronectin complex reported by other workers in leukemia. An intermediate gel containing antihuman fibrinogen demonstrated fibrinogen to be one component of this complex. Binding of other substances to fibronectin will reduce its apparent biological activity and may be the result of their lack of clearance by the damaged liver.
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PMID:Characterization of the molecular forms of fibronectin in fulminant hepatic failure. 309 66


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