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)

Granulosa cell proliferation during luteinization and terminal differentiation has historically been assumed to decline rapidly after an ovulatory stimulus. In contrast, terminal differentiation in other cell types has recently been associated with a transient increase in proliferation, suggesting that this may occur in the ovarian follicle. The goal of the current study was to test the hypothesis that an ovulatory stimulus to rats results in additional granulosa cell proliferation before cell cycle arrest. Immature rats were given a single injection of pregnant mare serum gonadotropin (PMSG) followed by human chorionic gonadotropin (hCG) to initiate periovulatory events. The proportion of granulosa cells in S phase did not change until 12 h after hCG, although the majority of the post-hCG proliferation was localized to cumulus granulosa cells for up to 10 h after hCG. The expression of cyclin D2 mRNA did not decline until 12 h after hCG, although both cyclin-dependent kinase (Cdk)4 and Cdk6 mRNA increased at 6 h. Protein levels of cyclin D2 and Cdk4 did not change as a result of hCG, whereas cyclin E increased 6 h after hCG. Kinase activity of Cdk2 dropped markedly by 4 h after hCG, but a slight increase in activity was evident 6-8 h after hCG. These data suggest that cumulus granulosa cells continue to proliferate for up to 10 h after an ovulatory stimulus, possibly via cyclin E/Cdk2. It is concluded that proliferation is maintained in granulosa cells in the proximity of the oocyte during luteinization of the rat follicle.
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PMID:Proliferation of rat granulosa cells during the periovulatory interval. 1537 25

Ets-2 controls the activities of many genes characteristically up-regulated in trophoblast. One apparent exception has been the gene for the human chorionic gonadotropin subunit alpha (hCGalpha). Here, we show that the hCGalpha gene contains two overlapping Ets binding sites adjacent to an activator protein-1-like site in its proximal promoter. Transactivation by Ets-2 is susceptible to truncation and mutation of these sites, which bind Ets-2 during in vitro mobility shift assays, as well as in vivo as determined by chromatin immunoprecipitation in choriocarcinoma cells. Knockdown of Ets-2 with short interfering RNA decreases both promoter activity and synthesis of hCGalpha. Ets-2 acts in combination with the protein kinase A (PKA) signal transduction pathway to activate the hCGalpha promoter expression. Mutation of the Ets-2 binding sites dramatically reduces up-regulation by PKA, whereas mutations within the two cAMP-responsive elements abolish responsiveness of the promoter to Ets-2. cAMP-responsive element binding protein (CREB) and Ets-2 form a complex that can be coimmunoprecipitated from choriocarcinoma cells, and association of CREB and Ets-2 is increased by activation of PKA. Regulation of hCGalpha subunit gene activity by cAMP involves the binding of CREB and Ets-2 to discrete elements in the promoter as well as a physical interaction between the two proteins. We propose that regulation of hCGalpha by Ets-2 and CREB enables coordinated expression of hCGalpha with its partner hCGbeta subunit.
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PMID:Coordinate regulation of basal and cyclic 5'-adenosine monophosphate (cAMP)-activated expression of human chorionic gonadotropin-alpha by Ets-2 and cAMP-responsive element binding protein. 1563 48

Toona sinensis (TS), a kind of arbor, widely distributes nowadays in Asia. The leaves of TS have been used as an effective nutritious food in Chinese society for a long time. It was reported that Toona sinensis can induce apoptosis of cancer cells, reduce plasma glucose in diabetic rats, and improve lipolysis of differentiated 3T3-L1 adipocyte and its uptake of glucose. It has also been shown that TS may increase dynamic activity of human sperm. Thus, we are interested to investigate whether Toona sinensis has any effect on mouse Leydig cell testosterone production, which correlates to sperm activity. Primary mouse Leydig cells were purified to conduct the in vitro experiments. Different concentrations of crude Toona sinensis were added to primary mouse Leydig cells and the testosterone production was determined. The results showed that crude TS significantly inhibited both basal and human chorionic gonadotropin (hCG)-stimulated testosterone productions in dose dependent manner, respectively (P<0.05). Crude TS also reduced the forskolin- and dibutyryl-cAMP (dbcAMP)-stimulated testosterone production (P<0.05), which indicated that crude TS might affect protein kinase A (PKA) signal transduction pathway at the site after the formation of cyclic AMP. Moreover, TS inhibited Leydig cell steroidogenesis by suppressing the activity of steroidogenic enzymes including P450 side chain cleavage enzyme, 3 beta-hydroxysteroid dehydrogenase, 17 alpha-hydroxylase, 20 alpha-hydroxylase and 17 beta-hydroxysteroid dehydrogenase (P<0.05). In summary, these results suggested that TS inhibited steroidogenesis by suppressing the cAMP-PKA signaling pathway and the activities of steroidogenic enzymes in normal mouse Leydig cells.
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PMID:Regulatory mechanism of Toona sinensis on mouse leydig cell steroidogenesis. 1568 Mar 12

This study investigated the roles of the protein kinase C (PKC) and protein kinase A (PKA) pathways in regulating constitutive steroidogenesis and steroidogenic acute regulatory (STAR; herein designated by its common name, StAR) protein in R2C Leydig tumor cells. Inhibition of PKC and phospholipase C resulted in significant decreases in steroid production, phosphorylation of cAMP-responsive element binding (CREB) protein, and Star gene transcription under basal conditions in R2C cells. These observations were corroborated in MA-10 and mLTC-1 Leydig tumor cell lines, in which activation of PKC by phorbol-12-myristate-13-acetate (PMA, 10 nM) increased CREB phosphorylation and total StAR (tot-StAR) protein expression. However, induction of StAR protein by PMA did not result in the expected concomitant increase in steroids because PKC failed to phosphorylate StAR, the biologically active form of the protein. However, in conjunction with PMA, minor increases in PKA activity using submaximal doses of (Bu)2cAMP (0.05-0.1 mM; a concentration range insufficient for induction of StAR), were able to stimulate dramatic increases in both phospho-StAR (P-StAR) and steroid production. Human chorionic gonadotropin stimulation also resulted in a further enhancement in P-StAR and progesterone production when added to PMA-treated MA-10 cells. Similar results for tot-StAR and P-StAR expression were observed in primary cultures of immature rat Leydig cells treated with PMA and submaximal doses of (Bu)2cAMP. In summary, the present study demonstrates that basal activities of both PKC and PKA play important roles in the constitutive steroidogenic characteristics of R2C cells. This study also demonstrates for the first time a role for PMA-induced PKC in StAR protein regulation and the requirement for submaximal doses of cAMP to produce steroids in Leydig cells.
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PMID:Involvement of protein kinase C and cyclic adenosine 3',5'-monophosphate-dependent kinase in steroidogenic acute regulatory protein expression and steroid biosynthesis in Leydig cells. 1581 1

Growth hormone (GH) is known to stimulate luteinizing hormone (LH) release via paracrine interactions between somatotrophs and gonadotrophs. However, it is unclear if LH can exert a reciprocal effect to modulate somatotroph functions. Here we examined the paracrine effects of LH on GH gene expression using grass carp pituitary cells as a cell model. LH receptors were identified in grass carp somatotrophs and their activation by human chorionic gonadotropin (hCG) increased 'steady-state' GH mRNA levels. Removal of endogenous LH by immunoneutralization using LH antiserum inhibited GH release and GH mRNA expression. GH secretagogues, including gonadotrophin releasing hormone (GnRH), pituitary adenylate cyclase-activating polypeptide (PACAP) and apomorphine, were effective in elevating GH mRNA levels but these stimulatory actions were blocked by LH antiserum. In pituitary cells pretreated with actinomycin D, the half-life of GH mRNA was not affected by hCG but was enhanced by LH immunoneutralization. Treatment with LH antiserum also suppressed basal levels of mature GH mRNA and primary transcripts. hCG increased cAMP synthesis in carp pituitary cells and hCG-induced GH mRNA expression was mimicked by forskolin but suppressed by inhibiting adenylate cyclase and protein kinase A. Similarly, the stimulatory actions of hCG and forskolin on GH mRNA expression were blocked by inhibiting Janus kinase 2 (JAK2) and MAP kinase (MAPK), including P42/44(MAPK) and P38 (MAPK). These results suggest that LH is essential for the maintenance of GH release, GH gene expression, and somatotroph responsiveness to GH-releasing factors. The paracrine actions of LH on GH mRNA expression are mediated by a concurrent increase in GH gene transcription and GH mRNA turnover, probably through JAK2/MAPK coupled to the cAMP-dependent pathway.
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PMID:Paracrine regulation of growth hormone gene expression by gonadotrophin release in grass carp pituitary cells: functional implications, molecular mechanisms and signal transduction. 1582 Nov 7

Individual and combined effects of chorionic gonadotropin (CG), estradiol, and progesterone on the production of IFNgamma and IL-4 by human peripheral blood lymphocytes was studied in vitro together with certain intracellular mechanisms underlying the hormonal effects. High CG dose (100 IU/ml) proved to significantly decrease IFNgamma level in the T cell culture supernatant, although this effect was not observed at the background of steroid hormones. In contrast, progesterone (100 ng/ml) increased IFNgamma production by activated T lymphocytes but proved inefficient in a physiological combination with CG and estradiol. IL-4 production was almost doubled by all studied hormones and their combinations, which considerably decreased the IFNgamma/IL-4 ratio in the culture. Inhibition analysis employing blockers of cAMP-dependent protein kinase (H-89) and L-type calcium channels (verapamil) as well as an antagonist of progesterone nuclear receptors (RU-486) demonstrated that the inhibitory (for IFNgamma) and stimulatory (for IL-4) effects of CG were mediated by cAMP, while the effects of steroid hormones on the production of these cytokines were realized through genomic and non-genomic mechanisms (the latter mechanisms were largely mediated by L-type calcium channel regulation). Overall, the studied reproductive hormones could efficiently regulate synthesis of the main Th1 (IFNgamma) and Th2 (IL-4) cytokines by T lymphocytes and seem to play the key role in changing the pregnancy-specific pattern of secreted cytokines.
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PMID:[Reproductive hormones in the control of Th1/Th2 cytokine balance]. 1600 57

One of the most prominent inflammatory reactions is the activation of the complement system. The activated complement system does not distinguish between pathogens and the host cell. In order to prevent autologous complement-mediated attack, host cells express a variety of both membrane-bound and fluid-phase complement regulatory proteins which control activity of the complement cascade by acting on convertase enzymes or the membrane-attack complex. Although the process of ovulation is facilitated by the inflammatory reaction, this reaction has the potential to cause serious damage to growing follicles, ovulated follicles, and other important ovarian tissues. This study was undertaken to characterize the expression and regulation of decay-accelerating factor (DAF), a complement regulator, as a potential mediator of ovarian tissue protection from ovulatory inflammation. DNA microarray and Northern blot analyses showed that an ovulatory gonadotropin stimulus dramatically yet transiently induced DAF mRNA expression in the immature rat ovary. Northern blot and PCR analyses revealed that of the three known DAF isoforms, glycosylphosphatidylinositol (GPI)-, soluble-, and transmembrane-(TM) DAF, GPI-DAF was the predominant form. In situ hybridization localized GPI-DAF mRNA expression in the theca-interstitial cells of the periovulatory ovary. Neither the anti-progestin RU486 nor the cyclooxygenase inhibitor indomethacin significantly inhibited human chorionic gonadotropin (hCG)-induced GPI-DAF mRNA expression in vivo. In vitro theca cell culture studies indicated that hCG induces GPI-DAF mRNA expression through the protein kinase A pathway. This study suggests that gonadotropin-induced GPI-DAF may be involved in the protection of ovarian tissues from the potential attack by the complement system activated by the inflammatory response associated with ovulation.
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PMID:Decay-accelerating factor in the periovulatory rat ovary. 1607 56

Cyclic GMP (cGMP)-dependent protein kinase II (Prkg2, cGK II) was identified as a potential target of the progesterone receptor (Nr3c3) in the mouse ovary based on microarray analyses. To document this further, the expression patterns of cGK II and other components of the cGMP signaling pathway were analyzed during follicular development and ovulation using the pregnant mare serum gonadotropin (PMSG)-human chorionic gonadotropin (hCG)-primed immature mice. Levels of cGK II mRNA were low in ovaries of immature mice, increased 4-fold in response to pregnant mare serum gonadotropin and 5-fold more within 12 h after hCG, the time of ovulation. In situ hybridization localized cGK II mRNA to granulosa cells and cumulus oocyte complexes of periovulatory follicles. In progesterone receptor (PR) null mice, cGK II mRNA was reduced significantly at 12 h after hCG in contrast to heterozygous littermates. In primary granulosa cell cultures, cGK II mRNA was induced by phorbol 12-myristate 13-acetate enhanced by adenoviral expression of PR-A and blocked by RU486 and trilostane. PR-A in the absence of phorbol 12-myristate 13-acetate was insufficient to induce cGK II. Expression of cGK I (Prkg1) was restricted to the residual tissue and not regulated by hormones. Guanylate cyclase-A (Npr1; GC-A) mRNA expression increased 6-fold by 4 h after hCG treatment in contrast to pregnant mare serum gonadotropin alone and was localized to granulosa cells of preovulatory follicles. Collectively, these data show for the first time that cGK II (not cGK I) and GC-A are selectively induced in granulosa cells of preovulatory follicles by LH- and PR-dependent mechanisms, thereby providing a pathway for cGMP function during ovulation.
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PMID:Cyclic guanosine 5'-monophosphate-dependent protein kinase II is induced by luteinizing hormone and progesterone receptor-dependent mechanisms in granulosa cells and cumulus oocyte complexes of ovulating follicles. 1621 Mar 44

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) has long been used as a traditional Chinese medicine for dysfunctions of the endocrine system and inflammation conditions. However, the effect of adlay seed on the endocrine system has not yet been reported. In the present study, the effects and the mechanisms of methanolic extract of adlay bran (ABM) on progesterone synthesis in rat granulosa cell were studied. ABM was further partitioned with different solvents including water, 1-butanol, ethyl acetate and n-hexane. Four subfractions named ABM-Wa (water fraction), ABM-Bu (1-butanol fraction), ABM-EA (ethyl acetate fraction) and ABM-Hex (n-hexane fraction) were obtained. ABM-Bu was further fractionated using Diaion HP-20 resin column chromatography with gradient elution. Granulosa cells were prepared from pregnant mare serum gonadotropin-primed immature female rats and challenged with different reagents including human chorionic gonadotropin (hCG 0.5 IU/ml), forskolin (10 microM), 8-bromo-adenosine-3',5'-cyclic monophosphate (8-Br-cAMP, 1 mM), A23187 (10 microM), phorbol 12-myristate 13-acetate (PMA, 0.01 microM), 25-OH-cholesterol (0.1-10 microM) and pregnenolone (0.1-10 microM) in the presence or absence of ABM-Bu (100 microg/ml). The functions of steroidogenic enzyme including protein expression of the steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage enzyme (P450scc) protein were investigated. Expressions of both P450scc and StAR mRNA have also been explored. We found that ABM decreased progesterone production via an inhibition on (1) the cAMP-PKA and PKC signal transduction pathway, (2) P450scc and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) enzyme activity, (3) P450scc and StAR protein and mRNA expressions and (4) the phosphorylation of ERK1/2 in rat granulosa cells.
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PMID:Downregulation of progesterone biosynthesis in rat granulosa cells by adlay (Coix lachryma-jobi L. var. ma-yuen Stapf.) bran extracts. 1625 70

We have shown previously that mRNA for peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in granulosa cells and downregulated by the luteinizing hormone (LH) surge. The current studies were undertaken to test the hypothesis that LH stimulates a decrease in the expression of PPARgamma, as well as its activity, in granulosa cells. Ovaries were collected from immature rats 0 and 48 h after they received pregnant mares' serum gonadotropin (PMSG), and 4 and 24 h after administration of human chorionic gonadotropin (hCG), and used for protein isolation or processed for immunolocalization of PPARgamma. The amount of phosphorylated PPARgamma was measured by immunoblot analysis to determine how LH affects the phosphorylation status, and therefore the activity, of PPARgamma. Granulosa cells were also collected from immature rats 48 h after PMSG. Cells were cultured with LH in the absence and presence of H89 and cycloheximide to investigate the role of PKA and protein synthesis in the LH-mediated decline in mRNA for PPARgamma respectively. Protein corresponding to PPARgamma was localized to nuclei of granulosa cells 0 and 48 h after PMSG. Expression was greatly reduced by 4 h after hCG, with expression in mural granulosa cells lost before that in cumulus cells. The amount of phosphorylated PPARgamma did not change during the periovulatory period. Blocking PKA activity had no effect on levels of mRNA for PPARgamma. However, levels of mRNA for PPARgamma were significantly increased in cells treated with cycloheximide (P < 0.05, ANOVA followed by Tukey's HSD). These data suggest that PPARgamma is tightly regulated in the ovary and that its expression is the primary mechanism by which LH influences the activity of PPARgamma. In addition, protein synthesis may be involved in modulating levels of PPARgamma in granulosa cells.
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PMID:Effects of luteinizing hormone on peroxisome proliferator-activated receptor gamma in the rat ovary before and after the gonadotropin surge. 1638 13


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