Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of gonadotropins to act on and regulate normal ovarian surface epithelial (OSE) cells and ovarian cancer cells was investigated. Bovine OSE was used as a model to study normal OSE. Results demonstrate that follicle stimulating hormone (FSH) and the luteinizing hormone (LH) like molecule, human chorionic gonadotropin (hCG), can both stimulate (3H)-thymidine incorporation into DNA in normal OSE cells. Similar results were obtained using either purified hormones or recombinant human hormones. A human ovarian cancer cell-line OCC1 was also stimulated to grow in response to FSH and hCG, but the growth of a different human ovarian cancer cell-line SKOV3 was not affected. In addition to effects on cell growth, gonadotropins also stimulated growth factor expression. Both FSH and hCG stimulated steady state levels of keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and kit ligand (KL) mRNA in OSE cells. Previously, KGF, HGF, and KL have been shown to stimulate OSE growth. Both follicle stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) were observed in OSE cells by Northern blot analysis. Reverse transcription polymerase chain reaction (RT-PCR) analysis was performed on fresh and cultured OSE cells. Normal OSE was found to express FSHR and LHR both in vivo and in vitro. The PCR reaction products were sequenced and found to provide a 100% homology with the bovine gonadotropin receptor sequences previously reported. FSHR and LHR transcripts were also detected in gonadotropin responsive OCC1 cells, but not in the gonadotropin insensitive SKOV3 cells. Observations support the hypothesis that gonadotropins may influence some ovarian cancers. In summary, the current study demonstrates the novel observation that both the FSHR and LHR are expressed by bovine OSE and selected ovarian cancers. Interestingly, the actions of FSH and LH to promote OSE growth may in part be mediated indirectly through an elevation in the expression of autocrine growth factors (KGF, HGF, and KL). Ovarian cancer is more common in conditions with elevated gonadotropins such as post-menopausal women. Therefore, gonadotropin actions on the OSE are postulated to be a potential factor in the onset and progression of some ovarian cancers.
Mol Cell Endocrinol 2001 Feb 14
PMID:Expression and actions of both the follicle stimulating hormone receptor and the luteinizing hormone receptor in normal ovarian surface epithelium and ovarian cancer. 1116 55

A novel approach to mutation screening in the large exon 11 (comprising 3427 bp) of the human BRCA1 gene is presented. Restriction endonuclease fingerprinting single-strand conformation polymorphism (REF-SSCP) is based on repeated detection of DNA sequence variants in different restriction endonuclease fragments, and we evaluated the method using blood samples from 25 Norwegian patients with hereditary breast/ovarian cancer. We compared REF-SSCP to constant denaturant gel electrophoresis (CDGE) and to the protein truncation test (PTT). REF-SSCP detected 12 different DNA variants. Four of these were not detected by CDGE, and only one variant detected by CDGE was missed by REF-SSCP. PTT detected 4 of these 13 variants. REF-SSCP was subsequently applied to a second patient series (Swedish, n=20). A total of 14 different DNA variants were detected by REF-SSCP, 6 of which were truncating mutations (PTT detected only 4). Nonsense and frameshift mutations that are putative breast/ovarian cancer mutations, were detected in 7 of the 25 Norwegian and 9 of the 20 Swedish patients.
J Mol Med (Berl) 2000
PMID:Enhanced detection of mutations in BRCA1 exon 11 using restriction endonuclease fingerprinting-single-strand conformation polymorphism. 1119 32

The U6 expression system was explored for efficient expression of a ribozyme against the human proto-oncogene c-neu. A hammerhead ribozyme (neuRz) and the control mutant ribozyme (MRz) were targeted to cleave c-neu mRNA at the tyrosine kinase domain. In vitro cleavage showed that neuRz was very active while MRz was not. Near-maximal target cleavage observed at a low ribozyme:target ratio (0.1) suggests that neuRz has good activity and turnover capability under physiological conditions, i.e., <5 mM MgCl(2) and 37 degrees C. Chimeric U6 ribozyme was expressed at about 5 x 10(6) copies/cell at 48 h in the ovarian carcinoma cell line SKOV-3.ip1. Partial down-regulation of c-neu mRNA and protein was observed in a dose-dependent manner in cells transiently transfected with U6neuRz- but not with MRz-containing plasmid. Sorted transient transfectants demonstrated dramatic growth inhibition with the neuRz-expressing cells. Our results demonstrate that the U6 expression system is very efficient and suitable for the expression of a hammerhead ribozyme. Moreover, nonviral delivery of the neuRz-expressing plasmid resulted in specific down-regulation of c-neu and, subsequently, growth inhibition of ovarian cancer cells overexpressing c-neu.
Mol Ther 2001 Feb
PMID:Specific down-regulation of HER-2/neu mediated by a chimeric U6 hammerhead ribozyme results in growth inhibition of human ovarian carcinoma. 1123 73

Cantab is developing its DISC technology as a potential gene therapy product for cancer (DISC-Onc) and neurological and blood disorders (DISC-GT). Clinical trials are expected to commence in early 1999 [296831]. The DISC technology utilizes a herpes virus that has had a gene removed to prevent it from replicating [250526]. Phase I trials in leukemia were scheduled to commence in 1998 [250526], however, it was decided that although DISC-Onc is capable of carrying genes into leukemic cells, the levels of immunomodulator genes did not meet the target initially set for the commencement of trials. Hence, Cantab turned its attention to other cancers, and hoped to identify an alternative target for phase I trials in the first half of 1998 [279798]. Additional preclinical work using a murine version of the lead construct produced a significant therapeutic effect in animal tumor models [289716]. DISC-Onc is envisaged to deliver immunogenic genes such as cytokine or stimulatory protein genes [275129]. Cantab, in collaboration with Nottingham Trent University and Birmingham University, has shown that the DISC-Onc has delivered genes effectively to human colorectal, gastric and ovarian cancer tumors. Transfection rates have been shown to be favorable and have been proven to be at least as good as, if not better than, other vectors [279798]. Also, DISC-Onc carrying a functional GM-CSF, has antitumor activity in mouse models of renal cancer and leukemia [250526], [261768]. The DISC Neurology technology (DISC-GT), for gene therapy of neurological disease, is being developed in collaboration with Cambridge University, and enables HSV-driven long-term gene expression in nerve cells [279798].
Curr Opin Mol Ther 1999 Feb
PMID:Technology evaluation: DISC. 1124 75

The current delineation of the molecular basis of cancer provides a strong rationale to consider gene therapy approaches for cancer as a complement to other cancer therapies. Phase III trials focused on adenoviral vector-mediated delivery of wild-type p53 to compliment p53 mutations were recently initiated for head and neck cancer and ovarian cancer. Clinical testing of the tumor inhibitory gene E1A, delivered by synthetic vectors is ongoing. Positive clinical data from these clinical studies will establish the use of gene therapy as a component of the multimodal treatment for certain cancers.
Curr Opin Mol Ther 2000 Aug
PMID:Gene therapy: a molecular approach to cancer treatment. 1124 73

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.
Curr Opin Mol Ther 2000 Aug
PMID:Technology evaluation: Valspodar, Novartis AG. 1124 78

Functional significance has been demonstrated in vitro for the exon 3 T-->C Tyr113His amino acid substitution polymorphism of the microsomal epoxide hydrolase (EPHX) gene. The higher activity or fast TT genotype was previously reported to be associated with an increased risk of ovarian cancer, and this association may reflect enhanced activation of endogenous or exogenous substrates to more reactive and mutagenic derivatives. Components of cigarette smoke are examples of exogenous substrates subject to such bioactivation, and smoking exposure may thus modify the risk associated with the EPHX polymorphism. We examined 545 cases of epithelial ovarian cancer and 287 unaffected controls for this EPHX T-C genetic variant to investigate whether, in the Australian population, the TT genotype was associated with (i) specific ovarian tumor characteristics; (ii) risk of ovarian cancer, overall or for specific subgroups; and (iii) risk of ovarian cancer in smokers specifically. Genotyping was carried out using the Perkin-Elmer ABI Prism 7700 Sequence Detection System for fluorogenic polymerase chain reaction allelic discrimination. Stratification of the ovarian cancer cases according to tumor behavior (low malignant potential or invasive), grade, stage, and p53 immunohistochemical status failed to show any heterogeneity with respect to the genotype defined by the EPHX polymorphism. There was a suggestion of heterogeneity with respect to histologic subtype (P=0.03), largely due to a decreased frequency of the TT genotype in endometrioid tumors. EPHX genotype distribution did not differ significantly between unaffected controls and ovarian cancer cases (overall, low malignant potential, or invasive) either overall or after stratification by smoking status. However, the TT genotype was associated with a decreased risk of invasive ovarian cancer of the endometrioid subtype specifically (age-adjusted odds ratio=0.38, 95% confidence interval=0.17-0.87). The results suggest that the proposed EPHX-mediated bioactivation of components of cigarette smoke to mutagenic forms is unlikely to be involved in the etiology of ovarian cancer in general but that a greater rate of EPHX-mediated detoxification may decrease the risk of endometrioid ovarian cancer. Mol. Carcinog. 30:71-78, 2001.
Mol Carcinog 2001 Jan
PMID:The microsomal epoxide hydrolase Tyr113His polymorphism: association with risk of ovarian cancer. 1125 66

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.
Hum Mol Genet 2001 Apr
PMID:BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. 1125 3

While germline mutations in BRCA1 and BRCA2 account for most, if not all families with autosomal dominant transmission of susceptibility to both breast and ovarian cancer, it has become clear that together these genes only account for a small proportion of hereditary site-specific breast cancer susceptibility. However, difficulties due to genetic heterogeneity, reduced penetrance and perhaps gene mutation frequency complicate ongoing efforts to identify additional susceptibility genes. Therefore, multiple approaches are being used to identify additional high and low penetrance genes. Families with three or more breast cancer cases are being used in traditional linkage studies, which are expected to yield only moderate or high penetrance susceptibility genes. Breast cancer case-control studies are being used to look for genetic variants or polymorphisms that confer an increased risk of breast cancer in a wide variety of cellular pathways, ranging from the detoxification of environmental carcinogens to steroid hormone metabolism, DNA damage repair and immune surveillance, an approach useful primarily to identify low penetrance susceptibililty genes. However, neither approach has yielded convincing results to date. A third approach, using BRCA1 and BRCA2 mutation carriers to identify genes that are associated with modification of breast cancer risk has met with some limited success, perhaps because effects on breast cancer risk in BRCA1 and BRCA2 mutation carriers are more readily detected in smaller studies, given the much higher number of events in these cohorts at very high risk of breast cancer. Clearly, hereditary breast cancer susceptibility is a complex phenomenon, in which multiple genes may play a role. It will be necessary to use all of these approaches, as well as more comprehensive genomic studies, to identify additional breast cancer-related genes.
Hum Mol Genet 2001 Apr
PMID:"Other" breast cancer susceptibility genes: searching for more holy grail. 1125 4

Ovarian surface epithelium (OSE) is the tissue of origin for the majority of ovarian cancers. The mechanism underlying the neoplastic transformation of OSE to ovarian cancer is poorly understood. Activin, a member of the transforming growth factor-beta superfamily, has been shown to increase cell proliferation in ovarian cancer cells. The present study was carried out to investigate the expression and regulation of activin/inhibin subunits and activin receptors in normal and neoplastic OSE. Using reverse transcriptase-polymerase chain reaction and Southern blot analysis, the mRNA levels of alpha, betaA and betaB subunits and activin receptor type IIA and IIB were analyzed in normal OSE and the ovarian cancer cell line, OVCAR-3 cells. The alpha and betaA subunits were highly expressed in normal OSE when compared to OVCAR-3 cells. By contrast, betaB subunit was highly expressed in OVCAR-3 cells, when compared to normal OSE cells. Interestingly, activin receptor IIB mRNA levels were significantly higher in OVCAR-3 when compared to normal OSE cells, whereas activin receptor IIA mRNA levels were the same in both cell types. To characterize the growth modulatory role of activin during neoplastic progression, normal OSE and OVCAR-3 cells were treated with recombinant human activin A (rh-activin A). At concentrations of 1,10 and 100 ng/ml, rh-activin A stimulated the growth of OVCAR-3 cells, but not of normal OSE. Treatment with follistatin, binding protein of activin, attenuates the stimulatory effect of activin. To determine whether the growth stimulatory action of activin in the neoplastic OSE is mediated via an autocrine regulatory mechanism, OVCAR-3 cells were treated with rh-activin A in a dose- and time-dependent manner and the expression levels of activin/inhibin subunits and activin receptors were investigated. Treatments with activin increased the alpha and betaA subunit mRNA levels in a dose- and time-dependent manner. However, no difference was observed in levels of betaB subunit, or in activin receptor type IIA and IIB mRNAs following activin treatments in OVCAR-3 cells. Taken together, these results suggest that different levels of activin/inhibin and activin receptor isoforms are expressed in normal and neoplastic OSE cells. In addition, the altered expression of the activin/inhibin subunits, as well as the cell proliferative effect of activin observed in OVCAR-3 but not in normal OSE cells, indicate that activin may act as an autocrine regulator of neoplastic OSE progression.
Mol Cell Endocrinol 2001 Mar 28
PMID:Differential expression of activin/inhibin subunit and activin receptor mRNAs in normal and neoplastic ovarian surface epithelium (OSE). 1130 76


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