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Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF- 1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high-penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low-penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.
J Cell Mol Med
PMID:Understanding breast cancer risk -- where do we stand in 2005? 1578 78

P450 aromatase (P450arom, CYP19), a CYP19 gene product, is a member of the cytochrome P450 superfamily that catalyzes the formation of aromatic C(18) estrogen from C(19) androgen. To begin to understand the molecular mechanisms of P450 aromatase action in the protogynous wrasse, we isolated two cDNAs: one encoding CYP19a from ovary and the other encoding CYP19b from brain. The full-length cDNA of wrasse CYP19a, isolated from ovary cDNA library, is 2020 bp long and encodes 519 amino acids. The amino acid sequence of CYP19a has 62-83% identity with ovary-type aromatases of other teleosts. The full-length cDNA of wrasse CYP19b obtained using 5' and 3' RACE consists of 2666 bp, and its open reading frame encodes 496 amino acids. The deduced amino acid sequence has 62-83% identity with brain-type aromatases of other teleosts. Northern blot analysis identified a single 2.2-kb transcript in the ovary (CYP19a), and a single 2.6-kb transcript in the brain (CYP19b), suggesting that there are single forms of CYP19a and CYP19b, respectively, in the wrasse. RT-PCR assay showed that two CYP19 genes were expressed ubiquitously in various tissues, although each CYP19 subtype was expressed at highest level in the ovary and brain of the wrasse. These results suggest that CYP19 genes act in diverse tissue types, in addition to their effects on the physiological and reproductive functions of estrogen.
Comp Biochem Physiol B Biochem Mol Biol 2005 May
PMID:Molecular cloning of cytochrome P450 aromatases in the protogynous wrasse, Halichoeres tenuispinis. 1582 Jan 34

We report the occurrence of two CYP19b genes, namely CYP19b-I and CYP19b-II, encoding forms I and II of cytochrome P450aromB, the prevalently cerebral variant of aromatase in fish, in the nuclear genome of the rainbow trout. The CYP19b-I gene is 7.6 kbp-long, more than double the size of the known fish CYP19a and b genes, owing to the presence of three introns (1, 4 and 5) that enclose repeated sequences and are longer than 1 kbp. Unlike the CYP19a genes, but similarly to the CYP19b gene of the Nile tilapia, it contains 10, and not 9, exons, including an untranslated exon 1 (83 bp), as found also in the 5' non-coding region of mammalian CYP19 genes. The 5'-UTR is composed by exon 1 and the first 41 bp of exon 2 (150 bp), whose coding region covers the first 36 amino acid residues that incorporate the transmembrane domain. The CYP19b-II gene is only 2.5 kbp-long, because it contains only one intron, corresponding to the third intron of CYP19b-I, and lacks also its first two exons. Thus, it encodes for a presumably soluble protein. Apart from this difference, the rest of the coding region is virtually the same as that of the CYP19b-I gene. The 5'-UTR corresponds in part to the 3'-end (132 bp) of the second intron of the CYP19b-I gene, while the remaining portion (208 bp) bears no homology. CYP19b-II could be regarded as a pseudogene of the CYP19b-I gene, though it is unclear whether it is a processed or a duplicated pseudogene. Moreover, since it is transcriptionally active, it may retain a functional role for the overall brain aromatase activity in the rainbow trout.
J Steroid Biochem Mol Biol 2005 Feb
PMID:Genomic organization of the CYP19b genes in the rainbow trout (Oncorhynchus mykiss Walbaum). 1586 49

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R(s)=+0.63, p=0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p=0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.
J Steroid Biochem Mol Biol 2005 May
PMID:Aromatase and comparative response to its inhibitors in two types of endometrial cancer. 1593 86

Our goal is to define the cellular and molecular mechanisms for tissue- and cell-specific, developmental and hormonal regulation of the human CYP19 (aromatase P450/P450arom) gene in estrogen-producing cells. In this article, we review studies using transgenic mice and transfected cells to identify genomic regions and response elements that mediate CYP19 expression in placenta and ovary, as well as to define the molecular mechanisms for O2 regulation of differentiation and CYP19 gene expression in human trophoblast cells in culture. We also highlight recent findings regarding LRH-1 versus SF-1 mRNA expression and cellular localization in the mouse ovary during the estrous cycle and various stages of pregnancy. Spatial and temporal expression patterns of mRNAs encoding these orphan nuclear receptors in comparison to those of P450arom and 17alpha-hydroxylase/17,20-lyase mRNAs, suggest an important role of LRH-1 together with SF-1 in ovarian steroidogenesis.
J Steroid Biochem Mol Biol 2005 May
PMID:Transcriptional regulation of aromatase in placenta and ovary. 1596 5

Aromatase expression and enzyme activity in breast cancer patients is greater in or near the tumor tissue compared with the normal breast tissue. Regulation of aromatase expression in human tissues is quite complex, involving alternative promoter sites that provide tissue-specific control. Previous studies in our laboratories suggested a strong association between aromatase (CYP19) gene expression and the expression of cyclooxygenase (COX) genes. Our hypothesis is that higher levels of COX expression result in higher levels of prostaglandin E2 (PGE2), which in turn increases CYP19 expression through increases in intracellular cyclic AMP levels. This biochemical mechanism may explain the beneficial effects of non-steroidal anti-inflammatory drugs (NSAIDs) on reducing the risks of breast cancer. The effects of NSAIDs (ibuprofen, piroxicam, and indomethacin), a COX-1 selective inhibitor (SC-560), and COX-2 selective inhibitors (celecoxib, niflumic acid, nimesulide, NS-398, and SC-58125) on aromatase activity and CYP19 expression were investigated in breast cancer cell culture systems. Dose-dependent decreases in aromatase activity were observed following treatment with an NSAID or COX inhibitor, with the most effective agents being COX selective inhibitors. Real time PCR analysis of aromatase gene expression showed a significant decrease in mRNA levels in treated cells when compared to vehicle control. These results suggest that the effect of COX inhibitors on aromatase occurs at the transcriptional level. To further probe these interactions, short interfering RNAs (siRNA) were designed against either human CYP19 mRNA or human COX-2 mRNA. Treatment of breast cancer cells with aromatase siRNAs suppressed CYP19 mRNA and aromatase enzyme activity. Finally, treatment with COX-2 siRNAs downregulated the expression of COX-2 mRNA; furthermore, the siCOX-2-mediated suppression of COX-2 also resulted in suppression of aromatase mRNA. In summary, pharmacological regulation of aromatase and cyclooxygenases can act locally in an autocrine fashion to decrease the biosynthesis of estrogen and may provide additional therapy options for patients with hormone-dependent breast cancer.
J Steroid Biochem Mol Biol 2005 May
PMID:Translational studies on aromatase, cyclooxygenases, and enzyme inhibitors in breast cancer. 1596 85

Aldosterone plays a key role in salt and water homeostasis but is also involved in the development and progression of congestive heart failure and myocardial fibrosis. As a new pharmacological strategy for the treatment of these diseases, we propose the inhibition of the key enzyme of mineralcorticoid formation, CYP11B2 (aldosterone synthase). For studies of the effects of CYP11B2 inhibitors on the adrenal cortex, we selected the NCI-H295R cell line which expresses most of the key enzymes necessary for steroidogenesis. To evaluate this cell line as a test system for effects and side effects of CYP inhibitors, we established assays using radiolabeled substrates of CYP11B2 and CYP11B1 and subsequently tested a series of CYP11B2 inhibitors including the CYP19 inhibitor fadrozole. Fadrozole and compounds 6, 9 and 10 were more potent towards CYP11B2 compared to CYP11B1 with IC(50) values in the nanomolar range. To analyze their overall effect, the formation of steroids in the cell culture supernatant was monitored. All compounds led to a concentration-dependent reduction of the aldosterone secretion but also reduced the formation of cortisol and androgens. In conclusion, the H295R cell line is a suitable tool for the prediction of overall side effects of CYP11B2 inhibitors on steroidogenesis.
J Steroid Biochem Mol Biol 2005 Aug
PMID:The adrenocortical tumor cell line NCI-H295R as an in vitro screening system for the evaluation of CYP11B2 (aldosterone synthase) and CYP11B1 (steroid-11beta-hydroxylase) inhibitors. 1598 65

We investigated integrin-linked kinase (ILK), a focal adhesion serine-threonine protein kinase, as a new molecular target for treating anaplastic thyroid cancer. ILK mediates cell growth and survival signals and is overexpressed in a number of cancers. Therefore, we hypothesized that inhibition of ILK leads to growth arrest and apoptosis of thyroid cancer cells. According to Western blotting, the level of ILK protein was highly expressed in one papillary (NPA187) and four of five (Hth74, DRO, ARO, KAT4, and K4) anaplastic thyroid cancer cell lines. Immunohistochemical analysis of a human tissue microarray revealed that ILK was highly expressed in anaplastic thyroid cancer but not in normal human thyroid tissue. Treating thyroid cancer cell lines with a new ILK inhibitor, QLT0267, inhibited epidermal growth factor-induced phosphorylation of AKT, inhibited cell growth, and induced apoptosis in the NPA187, DRO, and K4 cell lines. QLT0267 also inhibited the kinase activity of immunoprecipitated ILK in four of five cell lines. Tumor volumes in mice treated with QLT0267 were significantly reduced compared with those in untreated mice. In immunohistochemical studies, QLT0267 suppressed phosphorylated p-AKT and angiogenesis (i.e., reduced mean vascular density) and induced apoptosis in both tumor cells and tumor-associated endothelial cells of the thyroid DRO xenografts. In summary, we found that ILK expression and activity were elevated in human anaplastic thyroid cancer and ILK inhibition led to growth arrest and apoptosis in vitro and in vivo. Our results provide preliminary evidence that ILK is a potential therapeutic target for treating anaplastic thyroid cancer.
Mol Cancer Ther 2005 Aug
PMID:Integrin-linked kinase is a potential therapeutic target for anaplastic thyroid cancer. 1609 30

P450aromatase (CYP19) is an essential part of the enzyme complex catalyzing the conversion of androgens into estrogens, which is a key reaction in the sex differentiation in vertebrates. Two full-length cDNAs encoding the genetic distinct CYP19A and CYP19B isozymes were isolated from Atlantic halibut (Hippoglossus hippoglossus) by RT-PCR of ovarian and brain RNA, respectively. The deduced enzymes CYP19A and CYP19B of 523 and 508 residues, respectively, showed less sequence homology with each other than with their orthologs in other teleost species. This indicates an ancient duplication of the common cyp19 gene that was supported by the constructed phylogenetic tree. Whereas cyp19b mRNA was ubiquitously expressed in the adult male and female, the cyp19a expression was more restricted and showed sex specificity in the gonads as verified by RT-PCR. The detection of transcripts encoding both CYP19A and CYP19B in the embryo clearly preceding any morphological gonadal sex differentiation provides evidence that these genes play important roles in early developmental stages in teleosts. The distinct temporal and spatial expression of the two cyp19 genes in larvae and adults, respectively, together with their low sequence similarity strongly indicate that the genes are differently regulated and that the encoding isozymes have adopted distinct functional roles in Atlantic halibut.
Mol Reprod Dev 2005 Dec
PMID:Molecular characterization and expression of two cyp19 (P450 aromatase) genes in embryos, larvae, and adults of Atlantic halibut (Hippoglossus hippoglossus). 1615 60

This chapter focuses on technology for construction of recombinant adenoviruses containing reporter genes under the control of putative regulatory regions of the human (h)CYP19 (aromatase) gene, as well as expression vectors. These recombinant adenoviruses have been used in primary cultures of human placental cells to characterize regulatory regions of the hCYP19 gene and to analyze the function of transcription factors on hCYP19 expression and on trophoblast differentiation.
Methods Mol Med 2006
PMID:Adenoviral-mediated gene delivery to trophoblast cells. 1625 60


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