Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aromatase (CYP19) mRNA is induced by follicle-stimulating hormone (FSH) in granulosa cells of preovulatory follicles and subsequently is rapidly diminished as a consequence of the luteinizing hormone (LH) surge. Primary cultures of rat granulosa cells were used to identify some of the cellular mechanisms by which FSH increases and LH decreases steady-state levels of aromatase mRNA. Induction of aromatase mRNA by FSH was increased by cycloheximide but was blocked by alpha-amanitin and the C-kinase activators gonadotropin-releasing hormone (GnRH) and phorbol 12-myristate 13-acetate (PMA). In contrast, the decrease in steady-state levels of aromatase mRNA by LH was mimicked by A-kinase (forskolin) and C-kinase (PMA or GnRH) activators. The decrease in aromatase mRNA was associated with decreased amounts of mRNA and protein for steroidogenic factor-1 (SF-1), a nuclear orphan receptor that binds and trans-activates the aromatase promoter, and with the A-kinase subunit type II (RII beta), which is required for mediating cAMP action in these cells. The down-regulation of aromatase, SF-1, and RII beta by each kinase activator and alpha-amanitin was prevented by cycloheximide when the drug was added in combination with the activator. If, however, cycloheximide was added 2 h after PMA (or LH), the drug did not prevent the rapid loss of mRNA. When granulosa cells were transfected with an aromatase CAT transgene, CAT activity was stimulated 10- to 20-fold by FSH and forskolin but not by PMA. Taken together, these results indicate that the A-kinase but not the C-kinase pathway can trans-activate the aromatase gene in immature granulosa cells, whereas the C-kinase, as well as A-kinase pathways, mimic the LH surge to decrease aromatase mRNA in preovulatory cells. By increasing degradation of aromatase mRNA and by inhibiting transcription, the LH surge rapidly terminates the granulosa cell pattern of gene expression while reprogramming the cells to express genes associated with ovulation and luteinization.
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PMID:Expression of aromatase in the ovary: down-regulation of mRNA by the ovulatory luteinizing hormone surge. 902 37

The inhibitory actions of prolactin on gonadal steroidogenesis have been reported in different species and under a variety of experimental approaches. In this study, the mechanisms of the in-vitro effects of human prolactin (hPRL) on human follicle stimulating hormone (hFSH)-induced aromatase activity were determined using cultured granulosa cells from diethylstilboestrol (DES)-primed immature rats. Human PRL caused a dose-dependent decrease in hFSH-induced 17 beta-oestradiol production, even when cells were cultured in the presence of a cAMP analogue (8-Br-cAMP). These effects of hPRL appeared to be specific, since addition of an anti-rat PRL receptor monoclonal antibody (mAb) mimicked the hPRL inhibitory effect upon steroidogenesis in rat granulosa cells. In order to assess the importance of tyrosine kinase and protein kinase-C activation in the hPRL inhibitory effects upon oestrogen biosynthesis, cells were cultured in the presence of kinase inhibitors. The results showed that addition of genistein or staurosporine (a tyrosine kinase and protein kinase-C antagonist respectively) to cultured granulosa cells resulted in potent inhibition of hPRL actions upon hFSH-induced aromatization in a dose-dependent manner. These observations suggest that tyrosine kinase and protein kinase-C activation are involved in the biochemical events leading to hPRL inhibitory effects at the gonadal level.
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PMID:The prolactin inhibition of follicle-stimulating hormone-induced aromatase activity in cultured rat granulosa cells is in part tyrosine kinase and protein kinase-C dependent. 923 89

Estrogen biosynthesis in adipose tissue increases with age and obesity, and has been implicated in the development of endometrial cancer and breast cancer. In normal human adipose tissue, expression of the CYP19 gene which encodes aromatase P450, the enzyme responsible for estrogen biosynthesis, is regulated by a distal promoter, namely promoter I.4. Stimulation of expression in adipose stromal cells by members of the type 1 cytokine family, i.e. interleukin (IL)-6, IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), is mediated via a Jak-STAT3 signaling pathway and a GAS element upstream of promoter I.4. In contrast, aromatase expression in breast adipose tissue proximal to tumor is increased three- to four-fold to the utilization of another promoter, namely promoter II, proximal to the translation initiation site. In the present report, we show that prostaglandin (PG) E2 is the most potent factor which stimulates aromatase expression via cyclic AMP and promoter II. PGE2 acts via EP1 and EP2 receptor subtypes to stimulate both the PKC and PKA pathways. The combined stimulation of both of these pathways results in the maximal expression of promoter II-specific CYP19 transcripts. Because PGE2 is a major secretory product both of breast tumor epithelial cells and fibroblasts, as well as of macrophages infiltrating the tumor site, then this could be the mechanism whereby estrogen biosynthesis is stimulated in breast sites adjacent to a tumor, leading in turn to increased growth and development of the tumor itself.
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PMID:Transcriptional regulation of CYP19 gene (aromatase) expression in adipose stromal cells in primary culture. 936 91

The aim of the present study was to explore the mechanisms by which nitric oxide (NO) may inhibit aromatase activity of human granulosa cells. Ovarian granulosa-luteal cells, obtained from patients undergoing in-vitro fertilization (IVF) were cultured in the presence of NO-related substances. After 24 h of culture, aromatase activity of the cells was significantly inhibited by treatment with the NO donors, SNAP or NOC12 at > or =10(-4) M in a dose-dependent manner. Treatment with NO catabolites or a peroxynitrite-releasing compound, SIN1, had no significant influence. Treatment with SNAP at 10(-3) M decreased relative aromatase mRNA values by 72% (P<0.05) and intracellular cyclic AMP concentrations by 53% (P<0.01). However, treatment with H89, an inhibitor of protein kinase A, did not inhibit aromatase activity. Since there were no significant effects of NO catabolites or peroxinitrite, the inhibitory action of NO donors on aromatase must be related to NO release. The action of NO is, in part, attributable to the down-regulation of aromatase gene transcription. Although NO decreased intracellular cAMP values, down-regulation of aromatase gene transcription may not be mediated by protein kinase A-dependent mechanisms.
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PMID:Inhibitory effects of nitric oxide on the expression and activity of aromatase in human granulosa cells. 1033 61

The atheroprotective effects of estrogen are well established and the presence of an estrogen receptor in vascular tissues has recently been reported. Therefore, we investigated the localization of the estrogen-producing enzyme aromatase in vascular tissues to assess the possible contribution of endocrine, paracrine, and autocrine modes of action. Aromatase was found in human vascular smooth muscle cells (SMCs) but not in endothelial cells on in situ hybridization. These observations were further supported by quantitative analysis of aromatase mRNA and the activity in 15 human vascular specimens. Only trace levels of expression were detected in the 3 infants examined, whereas 0.0088 to 0.0806 amol/ microg RNA of aromatase mRNA and 12.9 to 122.3 fmol. h-1. mg-1 protein of the activity were detected in 12 of the adult individuals. The switching of tissue-specific exon 1 of the human aromatase gene was also observed in some cases. Aromatase was found to be expressed only in cultured SMCs and not in cultured endothelial cells of human aorta and pulmonary artery and to be regulated through dexamethasone and the signaling pathways of protein kinase A and C. Study results revealed the localized expression of aromatase in vascular SMCs, which indicated a possible direct action of locally produced estrogen in an autocrine or paracrine manner, with possible cross talk between smooth muscle and endothelial cells.
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PMID:Localized expression of aromatase in human vascular tissues. 1036 66

The objective of the present study was to determine whether dehydroepiandrosterone (DHEA) modifies growth factor-induced mitogen-activated protein kinase (MAPK) activation, based on our previous study demonstrating that DHEA attenuates fetal calf serum-induced proliferation in human male aortic smooth muscle cells (human male aortic SMCs). Human male aortic SMCs were used for this study. Platelet-derived growth factor-BB (PDGF-BB), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), but not insulin-like growth factor-1 (IGF-1), stimulated MAPK activity. Only MAPK activation induced by PDGF-BB was reduced by pretreatment with DHEA, although DHEA did not affect the MAPK activation induced by EGF or bFGF. The basal and PDGF-stimulated MAPK activity were decreased by two types of cyclic AMP (cAMP) elevating agents and increased by cAMP-dependent protein kinase (PKA) inhibitor in human male aortic SMCs, suggesting that cAMP regulates MAPK negatively. The intracellular cAMP was increased by PDGF-BB. The increase of cAMP by PDGF-BB was augmented by pretreatment with DHEA, although DHEA alone did not affect cAMP. Neither EGF nor bFGF affected cAMP with and without DHEA pretreatment. Secretion of PGE2 induced by PDGF was augmented by pretreatment with DHEA. Stimulatory effects of DHEA on the production of PGE2 and cAMP were partially canceled by aromatase inhibitor and completely canceled by indomethacin or selective inhibitor of cyclooxygenase-2. These results suggest that DHEA inhibited MAPK activation induced by PDGF-BB via PGE2 overproduction and subsequent cAMP-dependent pathway in human male aortic SMCs.
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PMID:Effects of dehydroepiandrosterone on mitogen-activated protein kinase in human aortic smooth muscle cells. 1042 29

The responsiveness of granulosa cells to FSH (cAMP) changes as these cells switch from the proliferative stage in growing follicles to the terminally differentiated, nonproliferating stage after LH-induced luteinization. To analyze this transition, two well characterized culture systems were used. 1) Granulosa cells isolated from immature rats were cultured in serum-free medium, a system that permits analysis of dynamic, short-term responses to hormones/cAMP. 2) Granulosa cells from preovulatory (PO) follicles that have been exposed in vivo to surge concentrations of hCG (PO/ hCG) were cultured in medium containing 1% FBS, a system that permits analyses of cells that have undergo irreversible, long-term changes associated with luteinization. To analyze the biochemical basis for the switch in cAMP responsiveness, the localization of A-kinase pathway components was related to the expression of two cAMP target genes, aromatase (CYP19) and serum-and glucocorticoid-induced kinase (Sgk). Components of the A-kinase pathway were analyzed by Western blotting and indirect immunofluorescence using specific antibodies to the C subunit, RIIalpha/beta subunits, CREB (cAMP-regulatory element binding protein), phospho-CREB, CBP (CREB binding protein), and Sgk. Cellular levels of C subunit and CREB were similar in all cell types and hormone treatments. CREB and CBP were nuclear; RIIalpha/beta was restricted to a cytoplasmic basket-like structure. Addition of FSH to immature granulosa cells caused rapid nuclear import of C subunit within 1 h. Nuclear C subunit decreased by 6 h after FSH but could be rapidly reimported to the nucleus by the addition of forskolin at 6, 24, or 48 h. Nuclear C subunit was associated with the rapid but transient increases in phospho-CREB. FSH induced Sgk in a biphasic manner in which the protein was nuclear at 1 h and cytoplasmic at 48 h. Aromatase mRNA was only expressed at 24-48 h after FSH, a pattern that was not altered by phosphodiesterases or phosphatases. In the luteinized (PO/hCG) granulosa cells, immunoreactive C subunit was localized in a punctate pattern in the nucleus as well as to a cytoplasmic basket-like structure, a distribution pattern not altered by forskolin. Aromatase, Sgk, and phospho-CREB were expressed at elevated levels in a non-forskolin-responsive manner. Most notable, both phospho-CREB and Sgk were preferentially localized in a punctate pattern within the cytoplasm and not altered by forskolin. Collectively, these data indicate that when granulosa cells differentiate to luteal cells the subcellular localization (nuclear vs. cytoplasmic) of A-kinase pathway components changes markedly. Thus, either the mechanisms of nuclear import and export or the presence of distinct docking sites (and functions ?) dictate where A-kinase, phospho-CREB and Sgk are localized in granulosa cells compared with the terminally differentiated luteal cells.
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PMID:Functional and subcellular changes in the A-kinase-signaling pathway: relation to aromatase and Sgk expression during the transition of granulosa cells to luteal cells. 1044 6

There is increasing concern that certain chemicals in the environment can cause endocrine disruption in exposed humans and wildlife. Investigations of potential effects on endocrine function have been limited mainly to interactions with hormone receptors. A need exists for the development of alternate in vitro methods to evaluate chemicals for their potential to disturb various endocrine functions via other mechanisms. Our laboratory is using the human H295R adrenocortical carcinoma cell line to examine chemicals for their potential to interfere with the activity and/or expression of several key cytochrome P450 (CYP) enzymes involved in the biosynthesis of steroid hormones. In this report we demonstrated that the commonly used 2-chloro-s-triazine herbicides atrazine, simazine, and propazine dose-dependently (0-30 microM) induced aromatase (CYP19) activity to an apparent maximum of about 2.5-fold in H295R cells. Basal- and triazine-induced aromatase activity was completely inhibited by the irreversible aromatase inhibitor 4-hydroxyandrostenedione (100 microM). The triazines increased levels of CYP19 messenger ribonucleic acid (mRNA) between 1.5- and 2-fold. The time-response profile of the induction of aromatase activity and CYP19 mRNA by the triazines was similar to that by 8-bromo-cyclic adenosine monophosphate, a known stimulant of the protein kinase-A pathway that mediates the induction of aromatase in these cells. The observed induction of aromatase, the rate-limiting enzyme in the conversion of androgens to estrogens, may be an underlying explanation for some of the reported hormonal disrupting and tumor promoting properties of these herbicides in vivo.
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PMID:2-Chloro-s-triazine herbicides induce aromatase (CYP19) activity in H295R human adrenocortical carcinoma cells: a novel mechanism for estrogenicity? 1074 39

Ovarian cancer originates mainly from surface epithelial cells, which are potential targets of estrogen action. Using immunohistochemistry and RT-PCR analysis, aromatase (estrogen synthetase) can be detected in human ovarian surface epithelial tumors. In this study, we functionally characterized the aromatase expressed in a primary cell culture, normal human ovarian surface epithelial (HOSE) 17. The apparent K(m) and V(max) values were determined to be 5.8 +/- 0.5 nM, and 0.3 +/- 0.0 pmol/mg.h, respectively. The aromatase activity in HOSE 17 cells can be induced effectively by phorbol esters and forskolin, suggesting that estrogen biosynthesis in HOSE 17 cells is mainly regulated through protein kinase C- and protein kinase A-mediated mechanisms. Exon I-specific RT-PCR revealed that phorbol esters predominantly up-regulated promoter II. Whereas forskolin treatment increased exon I.3A-containing messenger RNA, the aromatase activity remained low in the cells treated with this agent. In vitro transcription/translation analysis using plasmids containing T7 promoter and the human snail gene (SnaH) as a reporter capped with different untranslated exon Is revealed that exon PII-containing transcripts were translated more effectively than exon I. 3-containing transcripts. These findings explain why aromatase activity is higher in cells with the PII-containing transcripts than is cells with the I.3-containing transcripts. Our results indicate that aromatase is functionally expressed in human ovarian surface epithelial cells and its expression is regulated at both the transcriptional and translational levels.
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PMID:Regulation of aromatase expression in human ovarian surface epithelial cells. 1113 58

Aminoglutethimide (AMG), a potent inhibitor of steroidogenesis used in the treatment of breast cancer and some adrenal pathologies, abolished the induction of ornithine decarboxylase (ODC) elicited by peptide hormones and by dibutyryl-cAMP in steroidogenic tissues. This effect seems to be related to an inhibition of cAMP-dependent protein kinase (IC50 = 287 microM) rather than blockade of the steroidogenic pathway. This inhibition may explain some of the effects observed in AMG treatment which cannot be ascribed to its direct effect on the cytochrome P450scc complex or aromatase. Taking into account that ODC, the rate-limiting enzyme in polyamine synthesis, is elevated in many types of cancer and that overexpression of this enzyme is associated with cell transformation, one may speculate that the inhibitory action of AMG on protein kinase A represents a positive colateral effect of this drug in cancer therapy.
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PMID:Aminoglutethimide, a steroidogenesis inhibitor, abolishes hormonal induction of ornithine decarboxylase in steroidogenic tissues: evidence for its role as cAMP-dependent protein kinase inhibitor. 1117 87


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