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)

The activities of the lysosomal acid hydrolases-cathespin D, acid phosphatase, beta-N-acetylglucosaminidase, and beta-glucuronidase-were measured in rat myometrium under the following hormonal conditions: during the estrus stage of the estrous cycle (NE); at 1,2, and 3 wk after ovariectomy; and in 3-wk postovariectomized females after hormone replacement therapy with 17 beta-estradiol (E2), progesterone (P), or E2 + P. Activities per milligram protein and per milligram DNA of the enzymes were significantly decreased after ovariectomy and were restored to the NE level or above after injecting E2 or E2 + P. Lysosomal enzyme activities did not change with hormonal state in hypophysectomized rats, suggesting that other hormones are required for mediation of enzyme activity. Acid hydrolase activities in other tissues and nonlysosomal enzyme activites in the myometrium did not fluctuate with hormonal state. Studies of lysosomal membrane integrity suggested that one population of lysosomes richer in cathepsin D and acid phosphatase and another rich in beta-N-acetylglucosaminidase and beta-glucuronidase may be present in rat myometrium. Estrogen seemed to labilize the lysosomal membrane of at least the latter of the two proposed populations of myometrial lysosomes.
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PMID:Effect of ovarian hormones on lysosomal acid hydrolase activities in rat myometrium. 55 4

Pro-cathepsin D is overexpressed in breast cancer cells compared to normal mammary epithelial cells. Moreover, its processing and maturation are altered resulting in increased secretion. In estrogen-responsive breast cancer cell lines such as MCF7 cells and ZR75-1 cells, the 2.2-kb cathepsin D mRNA is accumulated specifically by estrogens and growth factors. Estrogen regulation is mostly transcriptional, while growth factors stabilize the mRNA and act indirectly. In estrogen-receptor-negative cell lines, there is a constitutive high production of cathepsin D mRNA. Moreover in uterine cells, progesterone is the inducer rather than estrogen, indicating the complexity of regulation by steroids, depending on the tissue. The increased production of cathepsin D appears to be correlated with the aggressiveness of the tumour, as shown by retrospective clinical studies, suggesting a role in mammary carcinogenesis.
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PMID:Overexpression and hormonal regulation of pro-cathepsin D in mammary and endometrial cancer. 262 16

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

We evaluated the intra- and inter-observer reproducibility of quantitative immunohistochemical (IHC) analyses using the Cell Analysis Systems (CAS) 200/486 image analyzer of Estrogen Receptor (ER), Progesterone Receptor (PR), proliferation-associated nuclear protein (Ki67), HER-2/neu (c-erbB-2) protein over-expression and cathepsin D (CD) in 20 randomly-selected invasive breast carcinomas. Qualitative analysis of IHC Epidermal Growth Factor Receptor (EGF-R) was also assessed in this study for comparative purposes. Duplicate blind assessments by the same observer showed excellent correlations for all quantitative IHC features (P < 0.001; P = 0.004 for neu). However, the immuno-quantitative analyses results between the 3 different operators showed lower correlation coefficient values, thus being less reproducible. This resulted in systematic differences and bias between the observers. This was also clear from the overall agreement between the 3 observers which was 70% for ER, 70% for PR, 56% for Ki67, 79% for c-erbB-2 and 75% for CD. The qualitative visual assessments of EGF-R, expressed as either positive or negative, showed a 75% agreement between observers and 85% intra-observer agreement (comparable to quantitative digital image processing results). The same results were obtained with kappa statistics. A further analysis of the factors causing the lack of reproducibility was performed. For quantitative IHC, segmentation of stored and retrieved digitized images was quite reproducible between and within well-trained observers. However, variation between different fields of vision of one and the same section showed large variations for most cases. Therefore, differences in sampling of fields within a section appeared to be the major cause of lack of reproducibility between observers, although segmentation differences still added slightly to the inter-observer variations. Accordingly, a strict sampling protocol of fields of vision is mandatory to obtain reproducible quantitative IHC results. It is clear from the present study that so-called random (but in fact, at convenience) selection of fields of vision for measurement is not a sufficient guarantee of adequacy of the sampling.
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PMID:Quantitative immunohistochemistry using the CAS 200/486 image analysis system in invasive breast carcinoma: a reproducibility study. 754 96

Estrogen receptors (ERs) have recently been reported to be present in carcinomas of stomach, an organ that has so far been considered as nontarget for sex hormones. Cathepsin D is an estrogen-regulated lysosomal protease that has been overexpressed in breast cancer. ER and cathepsin D immunohistochemical expression were studied in this research in order to estimate their association to known histopathological and clinical parameters and their possible prognostic significance as well. Sixty-two patients with gastric adenocarcinomas were included in this study. The cancers were studied immunohistochemically concerning ER positivity in tumor cell nuclei and cathepsin D cytoplasmic expression. Nuclear ER staining was detected in tumor cells of 25% of male and 27% of female patients. ER positivity was demonstrated mainly in the well and moderately differentiated carcinomas; 87.5% of ER(+) tumors were also characterized as cathepsin D positive and a significant correlation between ER and cathepsin D positive expression was demonstrated (P < 0.05). Cytoplasmic cathepsin D expression was observed in carcinomatous cells of 70.9% of gastric tumors. Early tumor stage and good differentiation were significantly associated with increased cathepsin D expression (P < 0.05, P < 0.001). Histologic type, degree of differentiation and tumor stage were significantly correlated to survival (P < 0.05, P < 0.001 and P < 0.001). The patients who were cathepsin D(+) had a significant prognostic advantage over the cathepsin D(-) patients (P < 0.001). The presence of ER and estrogen-regulated cathepsin D indicates the involvement of sex hormonal factors in these tumors and cathepsin D positive expression in tumor cells seems to be related to better prognosis. Their biological, clinical, and prognostic roles remain to be further elucidated.
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PMID:Significance of estrogen receptors and cathepsin D tissue detection in gastric adenocarcinoma. 789 14

At this time the initial prognostic assessment of breast cancer patients is still most powerfully driven by basic histopathologic information, axillary nodal involvement, and tumor size. Estrogen and progesterone receptor status are important initial pieces of information for many patients, but this information is more important in deciding the most appropriate type of treatment, rather than the prognosis of the patient. Histologic and nuclear grading can provide important prognostic information, but broader application of this information awaits better methods to ensure accuracy and decrease intraobserver variability. Whether flow cytometry-derived information can be used to select patient subsets at very low risk of relapse awaits prospective validation in cooperative group trials. A number of new prognostic tests such as cathepsin D that have shown promise in some studies await definitive prospective validation. Further development of techniques to integrate prognostic factor information and the use of this information in individualized prognostic factor decisions is needed.
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PMID:A practical view of prognostic factors for staging, adjuvant treatment planning, and as baseline studies for possible future therapy. 815 Jul 80

The overexpression of c-erbB-2 protein (ErbB2), epidermal growth factor receptor (EGFR), and/or cathepsin D (CD) in breast cancer is known to be a poor prognostic factor. Eighty frozen breast cancer specimens obtained at the initial operation were examined for ErbB2, EGFR, and CD by immunohistochemical assay (ICA) and enzyme immunoassay (EIA). Estrogen and progesterone receptors (ER and PgR) were measured simultaneously by EIA. The mean values +/- 1SD for ErbB2, EGFR and CD were 141 +/- 400 U/mg membrane protein (range: 0-3385), 4.88 +/- 4.33 fmol/mg membrane protein (range: 0-21.1), and 47.1 +/- 32.8 pmol/mg cytosol protein (range: 4.7-182), respectively. The percentage of specimens positive for ErbB2, EGFR, and CD was 12.5, 38.8, and 35%, when the tentative cutoff value were used as 200 U/mg protein, 5 fmol/mg protein, and 50 pmol/mg protein, respectively. These E1A results were correlated with ICA, EGFR and ER were negatively correlated. Although the prognostic value of ErbB2 and EGFR was superior to hormone receptors, ErbB2 and EGFR were interior as predictors compared with lymph node involvement and tumor size. Quantitation of ErbB2, EGFR, and CD can be performed readily using the same specimen in which hormone receptors are measured.
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PMID:Simultaneous quantitative analyses of c-erbB-2 protein, epidermal growth factor receptor, cathepsin D, and hormone receptors in breast cancer. 904 60

The estrogenic activity of dieldrin, toxaphene, and an equimolar mixture of both compounds (dieldrin/toxaphene) was investigated in the 21-day-old B6C3F1 mouse uterus, MCF-7 human breast cancer cells, and in yeast-based reporter gene assays. Treatment of the animals with 17beta-estradiol (E2) (0.0053 kg/day x3) resulted in a 3.1-, 4.8-, and 7.8-fold increase in uterine wet weight, peroxidase activity, and progesterone receptor binding, respectively. In contrast, treatment with 2.5, 15 and 60 micromol/kg (x3) doses of toxaphene, dieldrin, or dieldrin/toxaphene (equimolar) did not significantly induce a dose-dependent increase in any of the E2-induced responses. The organochlorine pesticides alone and the binary mixture did not bind to the mouse uterine estrogen receptor (ER) in a competitive binding assay using [3H]E2 as the radioligand. In parallel studies, estrogenic activities were determined in MCF-7 cells by using a cell proliferation assay and by determining induction of chloramphenicol acetyl transferase (CAT) activity in MCF-7 cells transiently transfected with plasmids containing estrogen-responsive 5'-promoter regions from the rat creatine kinase B and human cathepsin D genes. E2 caused a 24-fold increase in CAT activity in MCF-7 cells transiently transfected with creatine kinase B and a 3.8-fold increase in cells transiently transfected with the human cathepsin D construct. Treatment of MCF-7 cells with dieldrin, toxaphene, or an equimolar mixture of dieldrin plus toxaphene (10(-8)-10(-5) M) did not significantly induce cell proliferation or CAT activity in the transient transfection experiment with both plasmids. The relative competitive binding of the organochlorine pesticides was determined by incubating MCF-7 cells with 10(-9) M [3H]E2 in the presence or absence of 2 x 10(-7) M unlabeled E2 (to determine nonspecific binding), toxaphene (10(-5) M), dieldrin (10(-5) M), and equimolar concentrations of the dieldrin plus toxaphene mixture (10(-5) M). The binding observed for [3H]E2 in the whole cell extracts was displaced by unlabeled E2, whereas the organochlorine pesticides and binary mixture exhibited minimal to nondetectable competitive binding activity. E2 caused a 5000-fold induction of beta-galactosidase (beta-gal) activity in yeast transformed with the human ER and a double estrogen responsive element upstream of the beta-gal reporter gene. Treatment with 10(-6)-10(-4) M chlordane, dieldrin, toxaphene, or an equimolar mixture of dieldrin/toxaphene did not induce activity, whereas 10(-4) M endosulfan caused a 2000-fold increase in beta-gal activity. Diethylstilbestrol caused a 20-fold increase in activity in yeast transformed with the mouse ER and a single estrogen responsive element upstream of the beta-gal reporter gene. Dieldrin, chlordane, toxaphene, and endosulfan induced a 1.5- to 4-fold increase in activity at a concentration of 2.5 x 10(-5) M. Synergistic transactivation was not observed for any equimolar binary mixture of the pesticides at concentrations of either 2.5 x 10(-5) M or 2.5 x 10(-4) M. The results of this study demonstrate that for several estrogen-responsive assays in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based reporter gene assays, the activities of both dieldrin and toxaphene were minimal, and no synergistic interactions were observed with a binary mixture of the two compounds.
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PMID:Estrogenic activity of a dieldrin/toxaphene mixture in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based estrogen receptor assays: no apparent synergism. 907 11

We have proposed that an early step in estrogen carcinogenesis in the hamster kidney is tubular damage followed by reparative cell proliferation. This tubular injury is progressive and increases in severity with continued estrogen treatment; one pertinent feature is a marked rise in the number of both secondary and tertiary lysosomes. Data presented herein indicate that cathepsin D, an estrogen-responsive lysosomal proteolytic enzyme, is increased in the kidney following estrogen treatment in the hamster. Three isoforms of cathepsin D were detected in estrogen-treated kidneys, 52, 31, and 27 kDa, the major being 52 kDa. At 1 and 3 months of estrogen treatment, 52-kDa cathepsin D content increased 1.4- to 1.6-fold. These changes coincided with a rise in renal estrogen receptor levels during the same estrogen treatment periods. More pronounced rises in cathepsin D levels, 2.7- and 3.5-fold, were seen after 4 and 5 months of estrogen treatment, respectively. A concomitant, 3.0- to 4.0-fold rise in estrogen receptor content was also observed. At 5 months of estradiol or DES treatment, both 27- and 31-kDa isoforms were present in hamster kidneys, in addition to the 52-kDa form. Neither progesterone nor DHT treatment affected the untreated levels of cathepsin D. Interestingly, either concomitant tamoxifen or DHT and estrogen treatment prevented the rise in cathepsin D and estrogen receptor content observed after estrogen treatment alone. Primary estrogen-induced renal tumors and their metastases exhibited markedly elevated levels of all three isoforms of cathepsin D. Immunohistochemical analysis of cathepsin D in kidney sections confirmed the Western blot findings. These data suggest a novel role for estrogen-induced cathepsin D in the hamster kidney during tumorigenesis; that is, mediating renal tubular damage as a prelude to reparative cell proliferation, thus initiating a multi-step estrogen-driven process which leads to renal tumor formation.
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PMID:Induction of cathepsin D protein during estrogen carcinogenesis: possible role in estrogen-mediated kidney tubular cell damage. 923 Feb 83

Overexpression of cathepsin D (CD), a ubiquitous lysosomal protease, is closely associated with a poor clinical outcome for patients with breast cancer. Estrogen greatly induces transcription of the CD gene in estrogen receptor (ER)-positive breast cancer cells. In this report, we transiently introduced a human CD promoter/chloramphenicol acetyltransferase reporter gene into human MCF-7 breast cancer cells to study the mechanisms by which the ER activates the promoter. Using an in vivo Exonuclease III footprinting assay, we found that estrogen stimulation of MCF-7 cells induced loading of a transcription factor(s) to a portion of the promoter (-124 to -104) that is homologous to the adenovirus major late promoter element. Subsequent gel mobility shift assays with a 21-bp CD -124/-104 probe and nuclear extracts prepared from naive and estrogen-stimulated cells detected a single sequence-specific protein-DNA complex. Southwestern and UV cross-linking experiments detected two proteins of 44 kDa and 43 kDa that were specifically bound to the 21-bp fragment of the promoter. Gel super-shift assays with upstream stimulatory factor 1 (USF-1) and USF-2 antibodies demonstrated that USF-1 and USF-2 bound to the E box probe. Sequence specific binding was abolished by a 2-bp change shown previously to prevent the binding of USF to the E box. Incorporation of a mutant E box into the wild-type CD promoter/chloramphenicol acetyltransferase gene abolished USF binding and reduced the levels of both basal and estrogen-stimulated transcription. These results suggest that the ER targeting of USF-1 and USF-2 is a critical step in hormone activation of CD gene transcription in human breast cancer cells.
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PMID:Upstream stimulatory factors mediate estrogen receptor activation of the cathepsin D promoter. 973


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