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)

Previously we found that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces rapid inflammatory cellular responses in MCF10A mammary epithelial cells through a distinct nongenomic pathway by activating cytosolic phospholipase A2 and Src kinase within 30 min. In the current study we investigated how such an initial, seemingly transient signaling induced by TCDD is subsequently converted into more stable long-term messages. We found that TCDD causes prolonged activation of the binding activity of nuclear proteins to the oligonucleotide probes representing consensus activator protein 1 and CCAAT enhancer binding protein response element sequences, followed by later induction of some diagnostic marker including cyclooxgenase-2, matrix metalloproteinase-2, colony stimulating factor-1, and cytochrome P450 19 (or aromatase). Blocking the early steps of the nongenomic pathway inhibits this action of TCDD. It was also found that Src kinase is mainly responsible for the increase of binding activity to the activator protein 1 probe, and another kinase, protein kinase A (PKA), is accountable for most of the increase of binding activity to the CCAAT enhancer binding protein probe. The induction of those diagnostic markers is also affected by 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (a Src kinase inhibitor) or H89 (a PKA inhibitor). These results indicate that Src kinase and PKA act as the second messengers in propagating the initial nongenomic signaling of TCDD.
 ...
PMID:The conversion of rapid TCCD nongenomic signals to persistent inflammatory effects via select protein kinases in MCF10A cells. 1914 1

Aromatase is the rate-limiting enzyme in estrogen biosynthesis and a key target in breast cancer treatment. Its ovary-specific promoter, PII, is induced in response to protein kinase A (PKA) activation. It has been proposed that breast cancer susceptibility gene 1, BRCA1, is involved in negative regulation of aromatase PII activity. Surprisingly, inhibition of PKA pathway by inhibitor H89 elevates basal aromatase expression while abolishes cAMP-mediated aromatase induction in an ovarian granulosa cell line, KGN. In this report, we decipher the mechanism by which the PKA pathway negatively regulates aromatase basal expression. We show that PKA pathway plays a positive role in the expression of BRCA1. H89 effectively reduces endogenous BRCA1 mRNA levels as well as reporter gene expression from a BRCA1 promoter. Mutation of a cAMP-responsive element (CRE) in the BRCA1 promoter reduces BRCA1 expression. Chromatin immunoprecipitation (ChIP) shows that CRE-binding protein, CREB, binds to the BRCA1 promoter. Furthermore, knockdown of CREB in KGN cells leads to decreased BRCA1 level as well as elevated basal aromatase mRNA expression. These data demonstrate that both the CRE site in the BRCA1 promoter and CREB are required for BRCA1 constitutive expression. Our study suggests that PKA pathway exerts its negative impact on basal aromatase expression indirectly by contributing to the constitutive expression of BRCA1.
 ...
PMID:A Role of CREB in BRCA1 Constitutive Promoter Activity and Aromatase Basal Expression. 1956 23

Follicle-stimulating hormone (FSH) is a glycoprotein that transmits its signals via a G protein-coupled receptor. As yet, not many targets of FSH have been identified, able to justify the critical role of this hormone on reproductive events. On the other hand, among the biological activities of the endocannabinoid anandamide (AEA), growing interest has been attracted by the regulation of mammalian fertility. Recently, we have shown that treatment of mouse primary Sertoli cells with FSH enhances the activity of the AEA hydrolase (fatty acid amide hydrolase, FAAH), whereas it does not affect the enzymes that synthesize AEA, nor the level of the AEA-binding type-2 cannabinoid and type-1 vanilloid receptors. In addition, diacylglycerol lipase and monoacylglycerol lipase, which, respectively, synthesize and degrade the other major endocannabinoid 2-arachidonoylglycerol, were not regulated by FSH. Interestingly, FAAH stimulation by FSH occurred through protein kinase A and aromatase-dependent pathways that were able to modulate FAAH activity (via phosphorylation of accessory proteins) and faah gene expression (via an estrogen response element on the promoter region). Taken together, these data identify FAAH as the only target of FSH among the elements of the endocannabinoid system, with a critical impact on Sertoli cell proliferation, and thus spermatogenesis and male reproduction.
 ...
PMID:Modulation of the endocannabinoid-degrading enzyme fatty acid amide hydrolase by follicle-stimulating hormone. 1964 15

Endocrine therapies, which inhibit estrogen receptor (ER)alpha signaling, are the most common and effective treatment for ERalpha-positive breast cancer. However, the use of these agents is limited by the frequent development of resistance. The cyclin-dependent kinase family member CRK7 (aka CRKRS) was identified from an RNA interference screen for modifiers of tamoxifen sensitivity. Here, we demonstrate that silencing of CRK7 not only causes resistance to tamoxifen but also leads to resistance to additional endocrine therapies including ICI 182780 and estrogen deprivation, a model of aromatase inhibition. We show that CRK7 silencing activates the mitogen-activated protein kinase (MAPK)-signaling pathway, which causes a loss of ER dependence, resulting in endocrine therapy resistance. This study identifies a novel role for CRK7 in MAPK regulation and resistance to estrogen signaling inhibitors.
 ...
PMID:CRK7 modifies the MAPK pathway and influences the response to endocrine therapy. 1965 20

Our recent studies have revealed that estrogens stimulate an autocrine mechanism determining Leydig tumor cell proliferation. Estrogen overproduction is due to an elevated steroidogenic factor-1 (SF-1) expression and cAMP-response element-binding protein (CREB) phosphorylation, both inducing aromatase overexpression. Although we have shown that increased SF-1 expression depends mainly on higher local insulin-like growth factor I production, the mechanisms and factors determining increased CREB activation in Leydig tumor cells are not completely understood. In this study, we investigated the role of cyclooxygenase-2 (COX-2) in CREB dependent-aromatase expression in Leydig tumor cells. We found that COX-2 is expressed in rat and human Leydigiomas as well as in the rat Leydig tumor cell line R2C, but not in normal testis. Our data indicate that in R2C cells the COX-2-derived prostaglandin E2 (PGE2) binds the PGE2 receptor EP4 and activates protein kinase A (PKA) and ultimately CREB. Inhibitors for COX-2 (NS398), EP4 (AH23848), and PKA (H89) decreased aromatase expression and activity as a consequence of a decreased phosphorylated CREB recruitment to the PII promoter of the aromatase gene. The COX-2/PGE2/PKA pathway also seems to be involved in aromatase post-translational activation, an observation that requires further studies. The reduction in aromatase activity was responsible for a drop in estrogen production and subsequent reduction in cyclin E expression resulting in a decrease in tumor Leydig cell proliferation. Furthermore, COX-2 silencing caused a significant decrease in CREB phosphorylation, aromatase expression, and R2C cell proliferation. These novel findings clarify the mechanisms involved in the growth of Leydig cell tumors and should be taken into account in determining new therapeutic approaches.
 ...
PMID:Inhibition of cyclooxygenase-2 down-regulates aromatase activity and decreases proliferation of Leydig tumor cells. 1967 53

Activating transcription factor / cyclic-AMP response element-binding protein (ATF/CREB) has been implicated as a key regulator in the transcriptional control of many genes. In this study, we isolated and characterized a full-length cDNA that encodes a CRE-binding protein 2 (CREB2) called ATF4 in Xenopus embryos. Like other CREB 2 transcription factors, the 342-amino acid ATF4 protein contains a carboxyl terminal leucine-zipper motif, an adjacent basic domain, and an amino terminal leucine-zipper motif. Unlike other CREB2 (ATF4) proteins, the ATF4 isolated from the gonads of Xenopus embryos contains a consensus phosphorylation site for protein kinase A (PKA). In a gel shift analysis, ATF4 bound to a CLS sequence in the promoter of Xenopus aromatase.
 ...
PMID:Characterization of an activating transcription factor 4 gene containing a consensus phosphorylation site for PKA in the gonads of Xenopus embryos. 2006 4

Bisphenol A (4,4'-dihydroxy-2,2-diphenylpropane; BPA) is an endocrine disruptor that affects the reproductive health of wildlife and possibly of humans. Evidence suggests that BPA interrupts ovarian steroidogenesis by altering steroidogenic enzymes. We evaluated the effect of BPA on aromatase expression in rat testicular Leydig cells. In addition, we investigated whether cyclooxygenase-2 (COX-2) was involved in BPA-induced aromatase expression. BPA induced a time- and concentration-dependent increase in aromatase protein expression in rat testicular Leydig R2C cells. It also increased aromatase gene expression and its enzyme and promoter activity, but reduced testosterone synthesis; increased COX-2 mRNA expression and promoter activity, the production of prostaglandin E(2) (PGE(2)), and the gene expression of PGE(2) (EP2 and EP4) receptors; induced the activation of cyclic adenosine monophosphate (cAMP) response element (CRE) and CREB binding; and increased the phosphorylation of protein kinase A (PKA), Akt, and mitogen-activated protein (MAP) kinase signaling pathways. BPA activation of aromatase was reversed by various inhibitors (COX-2, PKA, Akt, ERK, JNK, and p38). Taken together, these results suggest that BPA increases aromatase activity, which is correlated with COX-2 up-regulation mediated by the CRE, PKA, Akt, and MAP kinase signaling pathways in rat testicular Leydig cells.
 ...
PMID:Bisphenol A-induced aromatase activation is mediated by cyclooxygenase-2 up-regulation in rat testicular Leydig cells. 2009 55

Aromatase, the enzyme responsible for the transformation of androgens into oestrogens, is encoded by the cyp19 gene expressed in the testis. The aim of the present study was to analyse the evolution of aromatase gene expression under FSH control in rat Sertoli cells between 10 and 30 days post partum, corresponding to the end of the proliferative period of Sertoli cells, establishment of the blood-testis barrier and acquisition of the mature phenotype. The maximum stimulatory effect of FSH on aromatase gene expression was obtained in 20-day-old rat Sertoli cells, compared with cells from 10- and 30-day-old rats, in parallel with the differentiation of Sertoli cells. Using two effectors of the protein kinase A pathway (i.e. forskolin and dibutyryl-cAMP) revealed differential effects between cells from rats aged 20 and 30 days, implying the involvement of another signalling pathway. Experiments using the specific phosphatidylinositol 3-kinase (PI3-K) inhibitor LY294002 revealed that PI3-K is strongly involved in FSH-induced aromatase expression in Sertoli cells from both 20- and 30-day-old rats. In vivo, this decrease could be explained by a negative effect exerted by germ cells because, in coculture, aromatase gene expression in 20-day-old Sertoli cells is greatly diminished.
 ...
PMID:Aromatase gene expression in immature rat Sertoli cells: age-related changes in the FSH signalling pathway. 2018 23

Estrogen receptor-related receptor alpha (ERRalpha) is an orphan member of the nuclear receptor superfamily of transcription factors. ERRalpha is highly expressed in the prostate, especially in prostate stromal cells. However, little is known about the regulation and function of ERRalpha, which may contribute to the progression of prostatic diseases. We previously found that prostaglandin E2 (PGE2) up-regulated the expression of aromatase in prostate stromal cells. Here we show that PGE2 also up-regulates the expression of ERRalpha, which, as a transcription factor, further mediates the regulatory effects of PGE2 on the expression of aromatase. ERRalpha expression was up-regulated by PGE2 in prostate stromal cell line WPMY-1, which was mediated mainly through the protein kinase A signaling pathway by PGE2 receptor EP2. Suppression of ERRalpha activity by chlordane (an antagonist of ERRalpha) or small interfering RNA knockdown of ERRalpha blocked the increase of expression and promoter activity of aromatase induced by PGE2. Overexpression of ERRalpha significantly increased aromatase expression and promoter activity, which were further augmented by PGE2. Chromatin immunoprecipitation assay demonstrated that ERRalpha directly bound to the aromatase promoter in vivo, and PGE2 enhanced the recruitment of ERRalpha and promoted transcriptional regulatory effects on aromatase expression in WPMY-1. 17Beta-estradiol concentration in WPMY-1 medium was up-regulated by ERRalpha expression, and that was further increased by PGE2. Our results provided evidence that ERRalpha contributed to local estrogen production by up-regulating aromatase expression in response to PGE2 and provided further insights into the potential role of ERRalpha in estrogen-related prostatic diseases.
 ...
PMID:Estrogen receptor-related receptor alpha mediates up-regulation of aromatase expression by prostaglandin E2 in prostate stromal cells. 2035 Nov 96

Bone morphogenetic proteins (BMPs) have been recognized as crucial molecules in regulating ovarian physiology, with different BMPs having differential actions in FSH-induced estradiol production. To identify the roles of oocyte factors that modulate steroidogenesis controlled by BMPs, we here investigated the effects of FGF-8 in rat granulosa/oocyte co-cultures. FGF-8 potently suppressed FSH-induced estradiol production, but did not affect cAMP-induced estradiol produced by rat granulosa cells. FGF-8 had no effects on progesterone and cAMP production induced by FSH and forskolin. The inhibitory effects of FGF-8 on FSH-induced estradiol production were not altered by BMP-2, -4, -6 or -7. In the presence of FGF-8, BMPs suppressed FSH-induced progesterone by reducing cAMP, suggesting that FGF-8 and BMP independently regulate FSH receptor signaling. Notably, FGF-8-induced ERK and SAPK/JNK phosphorylation in granulosa cells, in which ERK activation was further enhanced by FSH and oocytes. Inhibition of ERK and SAPK/JNK reduced FSH-induced progesterone and cAMP levels, suggesting that the activation of these pathways enhances FSH-induced cAMP signaling. In addition, ERK inhibition upregulated FSH-induced estradiol synthesis, indicating that ERK pathway is also involved in suppressing aromatase activity in granulosa cells. Interestingly, FGF-8 enhanced BMP-induced Smad1/5/8 and Id-1-promoter activities with decreased expression of Smad6/7. Since the SAPK/JNK inhibitor inhibited FGF-8 effects in upregulating Id-1 transcription, SAPK/JNK appears to be involved in the mechanism by which FGF-8 enhances BMP-Smad signaling. Furthermore, in the presence of oocytes, the inhibition of endogenous FGF receptor signaling suppressed FSH- and forskolin-induced progesterone and cAMP, showing that endogenous FGF system is involved in activation of FSH-induced cAMP-PKA signaling via ERK and SAPK/JNK. Thus, the oocyte factor, FGF-8, not only suppresses FSH-induced estradiol production by activating ERK, but also enhances BMP-Smad signaling in granulosa cells. This interaction between FGF-8 and BMPs may play a key role in regulating steroidogenesis through oocyte-granulosa cell communication.
 ...
PMID:Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells. 2043 19


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>