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)

17 beta-Estradiol (E2) induces cathepsin D mRNA levels and intracellular levels of immunoreactive protein in MCF-7 human breast cancer cells. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) alone does not affect cathepsin D gene expression in this cell line; however, in cells cotreated with TCDD and E2, TCDD inhibited E2-induced cathepsin D mRNA levels, the rate of gene transcription, and levels of immunoreactive protein. The inhibitory responses were observed within 30 to 120 min after the cells were treated with TCDD. TCDD also inhibited E2-induced secreted alkaline phosphatase activity in aryl hydrocarbon (Ah)-responsive MCF-7 and wild-type mouse Hepa 1c1c7 cells cotransfected with the human estrogen receptor (hER) and the pBC12/S1/pac plasmid, which contains the 5' promoter region (-296/+57) of the cathepsin D gene and an alkaline phosphatase reporter gene. The E2-responsive ER/Sp1 sequence (-199 to -165) in the cathepsin D 5' region contains an imperfect GTGCGTG (-175/-181) xenobiotic responsive element (XRE); the role of this sequence in Ah responsiveness was investigated in gel electrophoretic mobility shift assays and with plasmid constructs containing a wild-type ER/Sp1 oligonucleotide or a mutant ER/Sp1-"XRE" oligonucleotide containing two C-->A mutations in the XRE sequence (antisense strand). In plasmid constructs which contained a chloramphenicol acetyltransferase reporter gene and the wild-type ER/Sp1 promoter sequence, E2-induced chloramphenicol acetyltransferase activity and mRNA levels were inhibited by TCDD whereas no inhibition was observed with the mutant ER/Sp1-"XRE" plasmids. Electrophoretic mobility shift assays showed that the nuclear or transformed cytosolic Ah receptor complex blocked formation of the ER-Sp1 complex with the wild-type but not the ER/Sp1 mutant oligonucleotide. Moreover, incubation of the wild-type bromodeoxyuridine-substituted ER/Sp1 oligonucleotide with the nuclear Ah receptor complex gave a specifically bound cross-linked 200-kDa band. These data demonstrate that Ah receptor-mediated inhibition of E2-induced cathepsin D gene expression is due to disruption of the ER-Sp1 complex by targeted interaction with an overlapping XRE.
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PMID:Molecular mechanism of inhibition of estrogen-induced cathepsin D gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in MCF-7 cells. 852 36

Estrogen receptor positive ovarian cancer is often refractile to antiestrogen therapy. Here we describe the SKOV3 human ovarian carcinoma cell line as an in vitro model for estrogen and antiestrogen resistant ovarian cancer. While SKOV3 cells expressed estrogen receptor (ER) mRNA and protein at a similar level as the estrogen responsive T47D breast carcinoma cell line, their growth was not responsive to estradiol (E2) and was not inhibited by the antiestrogens OH-tamoxifen and ICI 164,384. The ER in SKOV3 cells was normal with respect to apparent Kd for binding with E2, E2 regulation of a transiently transfected ERE driven reporter gene, and E2 stimulation of expression of the early growth response genes c-myc and c-fos. However, the SKOV3 cells exhibited no expression of the progesterone receptor gene (PR) even after addition of E2, and the protein products of the estrogen responsive genes HER-2/neu and cathepsin D were expressed at constitutive levels that were not regulated by E2. Therefore, estrogen resistance in these cells may be a result of constitutive expression and loss of E2 regulation of selected growth regulatory gene products rather than a defect in estrogen activation of ER as a transcriptional regulator.
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PMID:SKOV3 ovarian carcinoma cells have functional estrogen receptor but are growth-resistant to estrogen and antiestrogens. 854 Dec 24

Cathepsin D was assayed in 74 primary breast cancer specimens by enzyme immunoassay (EIA) and immunohistochemical assay (ICA). Of the 74 specimens, 38 (51.4%) were scored positive by ICA, and 25 (33.8%) were scored positive by EIA. The coincidence rate between ICA and EIA was 71.6% (53/74). There was no significant correlation between cathepsin D and menopausal status, tumor size, number size, number of metastatic lymph nodes, histological type of the tumor, or steroid receptor status. Cathepsin D status designated by EIA or ICA predicted neither disease-free survival (DFS) nor overall survival (OAS). Subject analysis with estrogen receptor, menopausal, and lymph node status revealed no association between cathepsin D and DFS or OAS. Therefore, cathepsin D is not an independent prognostic factor in breast cancer.
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PMID:Clinical significance of cathepsin D assay in breast cancer tissues. 855 29

The study of several human breast cancer cell lines containing oestrogen receptors has allowed characterization of a number of oestrogen-induced proteins (e.g. progesterone receptor, cathepsin D, pS2, Hsp27, c-Myc). In primary tumours these markers have different prognostic significance for predicting whether the tumour will be hormone responsive (e.g. pS2, progesterone receptor) and whether it will metastasize (e.g. cathepsin D). The mechanism of regulation of gene expression by oestrogens and anti-oestrogens in breast cancer is complex and varies according to the nature of both the gene and the cell in which it is transcribed. Our laboratory has identified the sequences mediating oestrogen activity in the proximal region of cathepsin D, including a non-consensus oestrogen-responsive element located at -260 which acts in synergy with other regulatory elements. In addition to the classical effect of oestrogen receptor in stimulating transcription of genes controlled by the oestrogen-responsive element, we found that estrogen receptor is able to modulate transcription of AP-1-responsive genes without interacting directly with DNA. Cross-talk between oestrogen receptor and members of the Fos/Jun family via protein-protein interactions may explain how anti-oestrogens inhibit the mitogenic effect of growth factors in the apparent absence of oestrogens and why tamoxifen is able to stimulate cathepsin D gene expression and induce apoptosis in certain oestrogen receptor-positive breast cancer cells. The nature and degree of this cross-talk appears to vary according to the gene, the cell type and the type of oestrogen receptor ligand involved. Studies of oestrogen-regulated genes are not only useful for classifying breast cancers according to their ability to metastasize and respond to therapies, but also should lead to new therapeutic approaches for hormone-dependent and hormone-resistant cancers.
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PMID:Oestrogen- and anti-oestrogen-regulated genes in human breast cancer. 858 2

Although the physiological role of the immunophilins cyclophilin-40 and FKBP52 is unknown, their identification as components of the unactivated estrogen receptor has raised the possibility that they might influence receptor activity in response to the binding of immunosuppressants cyclosporin A and FK506, respectively. We have used Northern analysis to determine the influence of cyclosporin A on the expression of the estrogen-inducible cathepsin D gene in human MCF7 breast cancer cells. We report that 1-3 microM cyclosporin A can potentiate cathepsin D mRNA expression by up to 2-fold in cells treated with 10(-12) to 10(-10) M estradiol. A decreased potentiation effect was noted at higher hormone concentrations. Cyclosporin A alone was unable to induce cathepsin D expression and the increased gene activation observed with combined estradiol/cyclosporin A treatment was negated by the antiestrogen ICI 164,384. Our results suggest that the increased potency of estradiol in the presence of cyclosporin A is associated with an enhanced transcriptional activity of the estrogen receptor and support a role for receptor-associated cyclophilin-40 in the activation process.
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PMID:Cyclosporin A potentiates estradiol-induced expression of the cathepsin D gene in MCF7 breast cancer cells. 860 46

Aryl hydrocarbon receptor (AhR) ligands have diverse biological effects including striking antiestrogenic activity. We have investigated at the molecular level the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We show that the previously documented TCDD-mediated decrease in estradiol-inducible gene products such as cathepsin D (cat D) is due to a sharp decline in mRNA accumulation despite any change in estrogen receptor (ER) mRNA levels. The decline in cat D mRNA level is most likely due to a decrease in transcription of the cat D gene since TCDD blocks the ability of ER to transactivate from an estrogen response element. AhR is required for this activity as TCDD is no longer antiestrogenic in a mutant cell line that is deficient in functional AhR. We provide evidence that the loss of transactivation potential by ER in the presence of TCDD is due to a sharp decrease in its ability to bind to an estrogen response element. Reciprocally, estradiol treatment blocked TCDD-induced accumulation of CYP1A1 mRNA and AhR-mediated activation of the CYP1A1 promoter. This is due to the ability of liganded ER to interfere with the binding of AhR to the xenobiotic response element. These results provide a molecular mechanism for the antiestrogenic effects of TCDD and demonstrate the presence of a two-way crosstalk between the intracellular signaling pathways involving estrogens and aryl hydrocarbons.
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PMID:Antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin are mediated by direct transcriptional interference with the liganded estrogen receptor. Cross-talk between aryl hydrocarbon- and estrogen-mediated signaling. 863 52

Tamoxifen, although widely used in the treatment of estrogen-dependent tumors, is a partial estrogen agonist producing undesirable effects in breast cancer patients. ICI 182,780 a steroidal antiestrogen displays pure antagonist activity which is due to its ability to prevent dimerization of the estrogen receptor (ER). Our previous studies have shown that 1,1-dichloro-cis-2,3-diaryl cyclopropane (Analog II), a diarylcyclopropyl compound is devoid of estrogenic activity, has a weak binding affinity for the estrogen receptor in the mouse uterine tissue and inhibits the growth of breast cancer cells in culture. These findings suggest that Analog II may not inhibit tumor cell growth at the cellular level by an ER-mediated mechanism of action. Since these three antiestrogens appear to have different mechanisms of antiestrogenic activity, the purpose of this study was to compare the influence of the three antiestrogens on estradiol-induced expression of pS2 and cathepsin D (cath-D). These genes are known to be primarily under the influence of estrogen in ER positive MCF-7 human breast cancer cells. The results of this study demonstrate different mechanisms of regulation of the cath-D and pS2 genes by antiestrogens in MCF-7 cells. This study indicates that ICI 182,780 is a pure antagonist at the levels of gene regulation and cell proliferation. The relative order of inhibitory action was found to be ICI 182,780 > tamoxifen > Analog II.
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PMID:The influence of antiestrogens on pS2 and cathepsin D mRNA induction in MCF-7 breast cancer cells. 868 38

Estrogens play an important role in breast cancer and the effect of estrogen on growth of breast cancer cells has been extensively studied. However, only little information is available about the response of normal breast epithelial cells to estrogen, mainly due to the difficulties in establishing estrogen receptor (ER)-positive human breast epithelial cells in culture. We have stably transfected the human estrogen receptor (hER) wt cDNA into the ER-negative, spontaneously immortalized human breast epithelial cell line, HMT-3522S1, in order to develop a model for studying the effect of estrogen on nonmalignant human breast epithelial cells. Characterization of the transfected clone F9 confirmed incorporation of the estrogen receptor gene in the genome, expression of hER mRNA and hER protein. However, proliferation of F9 cells was inhibited by both estradiol (E2) and tamoxifen, whereas the pure antiestrogen ICI 182,780 had no effect on cell proliferation. This seems paradoxical since E2 stimulated the expression of the endogenous genes, TGF-alpha, cathepsin D, and alpha1-antitrypsin. In breast cancer cell lines, high expression of these genes is correlated to estrogen-stimulated cell proliferation. The spontaneously immortalized HMT-3522S1 cells transfected with wt ER cDNA behave similarly to cell lines from nonmalignant breast tissue immortalized by carcinogens and transfected with mutated ER cDNA as described by others. The discrepancy between growth inhibition and induction of positive growth factors by E2 indicates that either ER-positive nonmalignant breast epithelial cells are growth-inhibited by E2 in contrast to malignant cells or that introduction of the ER into ER-negative cells is not sufficient for restoring "normal' estrogen responsiveness.
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PMID:Characterization of a nontumorigenic human breast epithelial cell line stably transfected with the human estrogen receptor (ER) cDNA. 879 53

The mts1 (S100A4) gene, encoding a Ca(2+)-binding protein of the S-100 subfamily, is involved in the control of tumor metastasis in some murine tumor cell lines. To further analyze its role, we transfected hormone-responsive human breast cancer MCF-7 cells with the mts1 gene under the control of a strong constitutive promoter. All of the 3 tested clones (MCF-7/mts1) producing Mts1 protein acquired an ability for hormone-independent growth in nude mice. Tumors derived from mts1 transfectants revealed local invasiveness into surrounding muscle and adipose tissues and metastasized to regional lymph nodes and lungs, characteristics which are rarely observed with parental MCF-7 cells. Electron-microscopic analysis of MCF-7/mts1 cells demonstrated structural changes in anchoring junctions, particularly in intermediate filament attachment site (desmosomes). The mts1-transfected clones expressed estrogen receptor, and their growth in tissue culture was both estrogen- and anti-estrogen responsive. Changes in regulation of the estrogen-dependent proteins progesterone receptor and cathepsin D were observed in some of the transfected clones. Our results indicate that mts1 expression in human breast cancer cells induces several changes characteristic of malignant phenotype and tumor progression.
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PMID:Effect of mts1 (S100A4) expression on the progression of human breast cancer cells. 882 56

There has been increasing evidence which suggests that abnormal expression of the estrogen receptor (ER) protein in nonmalignant breast tissue may be important in the carcinogenic process. To examine the effects of ER expression in immortalized nonmalignant mammary epithelial cells, an expression vector containing human ER cDNA was transfected into the ER negative human breast cells, MCF10A. Characterization of a clone stably expressing ER, 139B6, provided evidence for the regulated synthesis of a functional ER capable of binding estradiol-17 beta (E2) and undergoing processing. Expression of the ER gene did not enable E2 to stimulate endogenous genes [progesterone receptor (PgR), pS2, cathepsin D and TGF alpha] which normally respond to estrogens in breast cancer cells. The ER in 139B6 cells was, however, capable of inducing expression of an ERE-regulated reporter gene, indicating its ability to interact with transcriptional machinery. Furthermore, cultures in log growth displayed a slight increase in doubling time in the presence of E2. These results indicate that ER expression alone is not sufficient to induce a transformed phenotype. Thus, the 139B6 cell line should provide a new model for determining what additional changes lead to increased growth potential in response to E2 and for exploring how E2 itself may help bring about changes leading to progression of preneoplastic breast epithelial cells.
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PMID:Characterization of the estrogen receptor transfected MCF10A breast cell line 139B6. 882 37


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