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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In previous studies, we observed that the stimulatory effect of (Bu)2cAMP on aromatase activity of human adipose stromal cells was markedly attenuated when fetal calf serum was present in the culture medium. To determine whether growth factors may be the inhibitors of (Bu)2cAMP-stimulated aromatase activity in serum, the effects of growth factors and phorbol esters on aromatase activity of human adipose stromal cells in monolayer culture were investigated. Epidermal growth factor (EGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) were all without effect on aromatase activity when added by themselves, but markedly inhibited aromatase activity stimulated by (Bu)2cAMP. On the other hand, nerve growth factor, multiplication-stimulating activity, relaxin, and insulin had no effect on aromatase activity, either by themselves or in the presence of (Bu)2cAMP. Thus, EGF, PDGF, and FGF can mimic the inhibitory action of fetal calf serum on (Bu)2cAMP-stimulated aromatase activity of these cells. By contrast, none of these substances was capable of mimicking the effect of serum to facilitate the stimulatory action of dexamethasone on aromatase activity of these cells. The phorbol esters phorbol-12-myristate-13-acetate, phorbol-12,13-didecanoate, and phorbol-12,13-diacetate were also capable of facilitating the action of (Bu)2cAMP to stimulate aromatase activity, but had little or no action on dexamethasone-stimulated aromatase activity or when added by themselves. It is concluded that aromatase is under multifactorial regulation in human adipose stromal cells. The activity is induced by glucocorticoids and by agents that stimulate cAMP-dependent protein kinase; the latter effect is potentiated by factors that stimulate protein kinase C, but is suppressed by growth factors such as EGF, FGF, and PDGF, whose actions are believed to be mediated by receptor-linked tyrosine kinase activity.
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PMID:Growth factors suppress and phorbol esters potentiate the action of dibutyryl adenosine 3',5'-monophosphate to stimulate aromatase activity of human adipose stromal cells. 300 2

Follicle stimulating hormone (FSH) induces estradiol (E2) production in rat, porcine and human granulosa cells with a concomitant increase in cAMP. In human granulosa cells insulin like growth factor-I (IGF-I) induces E2 production without cAMP accumulation. In the current study we report that IGF-I and FSH effects on aromatase activity both involve activation of a cytosolic soluble protein tyrosine kinase (CytPTK). This FSH and IGF-I stimulated CytPTK activity was blocked by AG-82 (a tyrosine kinase inhibitor) and by staurosporine (STS) (a non specific protein kinase inhibitor) at concentrations which inhibited E2 production. These new findings strengthen the concept of fail-safe mechanism in E2 production in human granulosa cells by an involvement of tyrosine kinase(s) activity downstream of cAMP formation and protein kinase A (PKA) activation.
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PMID:A cytosolic protein tyrosine kinase activity is induced by follicle stimulating hormone and insulin like growth factor-I in human granulosa cells. 766 93

During the development of preovulatory follicles, tonic levels of FSH (and steroid) induce expression of aromatase, the LH receptor, and RII beta in a coordinate manner. Despite the similar temporal increase in steady-state levels of mRNA encoding these proteins, the cis-acting DNA elements and trans-acting factors regulating each gene are distinct (Richards, 1993). Whereas the aromatase gene has a TATA motif and a single transcriptional initiation site (Fitzpatrick and Richards, 1993), both the LH receptor (Wang et al., 1992; Tsai-Morris et al., 1993) and RII beta (Kurten et al., 1992; Luo et al., 1992) genes have promoters that are GC rich, lack TATA motifs, and initiate transcription at multiple sites. The aromatase promoter appears to be regulated, in part, by SF-1, a CRE-like region, and possibly another or overlapping region binding an Ad3BP-like factor. The RII beta promoter has a region that binds several nuclear proteins, whose identity is not yet known. Likewise, the LH receptor promoter elements have yet to be clearly defined (Figures 2, 4, and 25; Kurten et al., 1992). FSH can also induce the expression of at least three immediate-early genes that encode novel kinases or kinase-like proteins (Figure 25). One of these is called serum-inducible kinase (snk) (Simmons et al., 1992), another is serum and glucocorticoid regulated kinase (sgk) (Webster et al., 1993), and a third is called pole kinase (Clay et al., 1993). Steady-state levels of snk and sgk mRNA are induced rapidly (within a few hours) by FSH in granulosa cells prior to the appearance of transcripts for aromatase, LH receptor, and RII beta (T. Alliston and J. S. Richards, in preparation). The functional role of these kinases in the initial response of granulosa cells to tonic (not surge) levels of FSH remains to be elucidated. The cellular signaling pathways mediating the effects of the LH surge appear equally or more complex (Fig. 25). Based on data presented herein, as well as on analyses of the cloned and expressed LH receptor (Guderman et al., 1992), it is clear that low concentrations of LH stimulate adenylyl cyclase, cAMP production, and activation of protein kinase A. Higher (surge) concentrations of LH also increase IP3 and activation of protein kinase C. GnRH has been used in several studies to examine the ability of the protein kinase C pathway to mimic effects of high LH.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ovarian cell differentiation: a cascade of multiple hormones, cellular signals, and regulated genes. 774 Jan 59

Evaluation of the intracellular signalling mechanisms of follicle stimulating hormone (FSH) and insulin-like growth factor-I (IGF-I) was performed in luteinized and non-luteinized human granulosa cells. A severalfold increase in estradiol production from androstenedione was induced by both hormones in these cells, while only FSH led to a concomitant increase in cAMP. IGF-I bound specifically to its receptor in these cells. Specific tyrosine kinase inhibitors (tyrphostins) blocked the effects of both FSH and IGF-I on aromatase activity without altering FSH-induced cAMP accumulation. These findings demonstrate an involvement of a tyrosine kinase pathway in the intracellular signalling mechanism of the IGF-I effect on aromatase activity. Furthermore, since FSH induction of aromatase activity can be blocked by a tyrosine kinase inhibitor without affecting the level of cAMP production, it can be suggested that tyrosine kinase(s) act downstream of cAMP production and protein kinase A activation.
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PMID:Induction of aromatase in human granulosa cells by both follicle stimulating hormone and insulin-like growth factor-I involves tyrosine phosphorylation. 784 3

The original 'two-cell mechanism' explained the endocrine regulation of follicular oestrogen synthesis and implied paracrine signalling in the follicle wall. It is now known that the CYP17 gene encoding 17-hydroxylase/C17-20-lyase activity crucial to androgen synthesis, is expressed exclusively in thecal cells. 17-Hydroxylase/C17-20-lyase activity is regulated by LH and subject to local modulation by a factor(s) emanating in FSH-stimulated granulosa cells. The FSH receptor gene is expressed exclusively in granulosa cells, where FSH acts directly to induce cytoproliferation and differentiation via cyclic AMP/protein kinase-A mediated post-receptor signalling. Granulosa cells also express androgen receptors, and theca-derived androgen has the potential to modulate locally differentiative responses to FSH. When follicles are recruited to preovulatory development by FSH, their granulosa cells develop LH receptors functionally coupled to aromatase activity and inhibin production. Thereby they simultaneously undertake LH-responsive aromatization and inhibin synthesis. Inhibin has the potential to potently enhance LH-stimulated thecal androgen synthesis. Granulosa-derived inhibin may therefore participate in a paracrine mechanism that locally amplifies androgen synthesis, and hence oestrogen formation, in the preovulatory follicle(s).
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PMID:Follicular oestrogen synthesis: the 'two-cell, two-gonadotrophin' model revisited. 805 58

Ovarian granulosa cells are the primary site of estrogen and progesterone synthesis and play an essential role in the maturation of the developing ovum. Freshly isolated granulosa cells are often used to study the regulation of steroid and protein biosynthesis, but the small number of cells available for these cultures has proven inadequate for many detailed gene regulatory studies. The goal of this study was to develop human granulosa (HG) cell lines that maintain differentiated function. The E6 and E7 open reading frames of high risk strains of human papillomavirus have been used to produce immortalized cell lines. Primary cultures of human luteinized granulosa cells were infected with defective retroviruses containing the E6 and E7 regions of human papillomavirus 16 and with the neomycin phosphotransferase gene to confer G418 resistance. Three of eight clones that were isolated after selection in medium containing G418 were found to produce progesterone following treatment with forskolin or dibutyryl cAMP for 48 h. Forskolin caused these cells to retract in the characteristic rounding response, as described in primary HG cultures. One clone, HGL5, was used for a detailed characterization of differentiated function. HGL5 cells retained the ability to increase progesterone production and convert exogenously added androstenedione to estradiol in response to agonists of the protein kinase-A pathway (forskolin and dibutyryl cAMP), but were not responsive to FSH or LH treatment. A key enzyme in the production of estradiol, cytochrome P450 aromatase, has proven difficult to maintain in long term cultures of granulosa cells. For that reason, we examined the expression of aromatase in the transformed HGL5 clone by monitoring mRNA levels. Aromatase mRNA increased by 4- to 5-fold after forskolin treatment, as determined by Northern analysis. This human granulosa cell culture line maintains many of the functions of normal cells and should provide an important model to study the molecular events controlling granulosa cell differentiation and function.
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PMID:Transformation of human granulosa cells with the E6 and E7 regions of human papillomavirus. 812 45

NCI-H295 is a recently described human adrenocortical carcinoma cell line that makes a variety of steroid hormones. We sought to determine if steroidogenesis in these cells employs the same enzymes as those used in normal adrenal steroidogenesis, and if the genes encoding those enzymes exhibit characteristic responsiveness to activators of the protein kinase-A and -C pathways of intracellular second messengers. Northern blots show that NCI-H295 cells contain abundant mRNAs for three key steroidogenic enzymes, cytochrome P450scc, cytochrome P450c17, and cytochrome P450c21. These mRNAs accumulated in a time- and dose-dependent fashion in response to 8-bromo-cAMP (8Br-cAMP), forskolin, cholera toxin, and 3-isobutyl-1-methylxanthine, all activators of the protein kinase-A pathway. Nuclear run-on assays and actinomycin-D transcriptional inhibition experiments show that cAMP regulates the expression of all three genes primarily at the transcriptional level. Inhibition of protein synthesis with cycloheximide did not prevent the cAMP-induced accumulation of P450scc or P450c17 mRNAs, but did inhibit accumulation of P450c21 mRNA, suggesting that cAMP is acting through a mechanism dependent on protein synthesis to promote accumulation of P450c21 mRNA. Stimulation of the protein kinase-C pathway with phorbol ester decreased P450scc and P450c17 mRNAs, but stimulated the accumulation of P450c21 mRNA. RNase protection experiments, Northern blot hybridizations, and reverse transcription-polymerase chain reaction show that NCI-H295 cells express both the 11 beta-hydroxylase (P450c11 beta) encoded by the P450c11B1 gene and the aldosterone synthetase (P450c11AS) encoded by the P450c11B2 gene. 8Br-cAMP increased the abundance of both of these mRNAs with similar kinetics, with maximal accumulation of both after about 24 h. NCI-H295 cells also contain the mRNAs for aromatase and insulin-like growth factor-II. 8Br-cAMP increased the abundance of aromatase mRNA and decreased the abundance of IGF-II mRNA. These studies show that NCI-H295 cells express most of the enzymes needed for human adrenal steroidogenesis, and that the genes encoding these enzymes respond to stimulation of second messenger pathways in a manner similar to that of human adrenals. NCI-H295 cells appear to be a good model for studying the molecular regulation of human adrenal steroidogenesis.
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PMID:Regulation of steroidogenesis in NCI-H295 cells: a cellular model of the human fetal adrenal. 838 59

The effects of steroids and peptide growth factors on aromatase activity in an androgen sensitive human prostate cancer cell line (LNCaP) were investigated. Factors were selected based on their observed modulation of the enzyme in other tissues. Incubation with epidermal growth factor and transforming growth factor-I decreased aromatase activity in LNCaP cells by 25-40%. Insulin like growth factor-1, dexamethasone, dibutyryl cAMP and phorbol 12-myristate 13-acetate, all of which are modulators of aromatase in other tissues, had no significant effect on aromatase activity in LNCaP cells. In addition, the cAMP-dependent protein kinase and protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2 methylpiperazine (H-7) had no effect on the enzyme activity. Factors affecting prostatic aromatase may be distinct from those for other known species.
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PMID:Modulation of aromatase activity by growth factors in an androgen sensitive human prostate cancer cell line, LNCaP. 860 65

Transforming growth factor-beta (TGF-beta) and activin-A, two members of a ubiquitous family of regulators of growth, differentiation and hormonogenesis, are produced by the human placenta. Their effects on placental hCG, inhibin, and oestrogen production in vitro, either alone or in combination, were investigated using cultured Percoll-purified placental trophoblasts. Inhibin and hCG were measured by immunoassay, while aromatase activity (i.e. oestrogen production) was measured using the tritiated water method. Aromatase activity and production of hCG, but not inhibin, were inhibited (up to approximately 30 per cent) in a dose-dependent fashion by 48 h treatment with TGF-beta. The effects were significant at all doses tested, from 0.1-10 ng/ml. In contrast, activin stimulated hCG production and aromatase activity over the doses tested (0.25-25 ng/ml). The maximum effect (approximately 50 per cent stimulation above control) was seen at the 2.5 ng/ml dose, with lesser effects seen at the lower and higher doses. This characteristic bell-shaped dose-response curve was maintained in the presence of TGF-beta (10 ng/ml) or a maximally-effective dose of forskolin (6.7 microM). This suggests that the actions of activin were independent of those of TGF-beta, and were not mediated by the protein kinase-A pathway. Activin had a weak stimulatory effect on inhibin production. The results indicate that in the placenta activin and TGF-beta have opposing actions on hormonogenesis. Both factors may play a role in regulating placental function and the timing and progression of labour.
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PMID:Activin-A stimulates, while transforming growth factor beta 1 inhibits, chorionic gonadotrophin production and aromatase activity in cultured human placental trophoblasts. 891 9

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 maximal expression of promoter II-specific CYP19 transcripts. Since 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:Estrogen biosynthesis proximal to a breast tumor is stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene. 894 Apr 10


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