Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Follistatins, activins, and inhibins are expressed in a wide range of tissues where they function as autocrine and/or paracrine factors. Activin B (beta B beta B) and inhibin B (alpha beta B) are the predominant forms expressed in the rat anterior pituitary. This study was designed to evaluate the regulation of the messenger RNAs (mRNAs) for inhibin alpha and beta B, and follistatin, relative to each other, using cultured rat anterior pituitary cells. Activin A stimulated follistatin (a maximal 4-fold stimulation by 6 h) and beta B (a maximal 1.7-fold stimulation after 2 h) mRNA levels. Although inhibin A dramatically decreased follistatin mRNA levels (34% of the control value after 24 h), it only marginally affected those of beta B (86% of the control value after 2 h). Follistatin inhibited the accumulation of its own mRNA (46% of the control value after 6 h), but had no statistically significant effect on beta B or alpha mRNA levels. Inhibin A was the only treatment that had an effect on alpha mRNA levels, causing a slight decrease (82% of the control value by 24 h). The effects of activin A and inhibin A on follistatin and beta B mRNA levels were dose dependent. Moreover, follistatin and inhibin A blocked the effects of activin A. Immunoneutralization experiments were performed to determine whether locally secreted activin B regulates the expression of these three mRNAs. A monoclonal antibody to activin B reduced follistatin and beta B mRNA levels (37% and 73% of the control value, respectively) and enhanced the stimulatory effect of exogenous activin A on these mRNAs (840% vs. 300% and 170% vs. 145% of the control value, respectively); there was no change in alpha mRNA accumulation. GnRH and activators of the protein kinase A (forskolin) and protein kinase C (12-O-tetradecanoylphorbol acetate) pathways also had differential effects on follistatin, beta B, and alpha mRNA levels. GnRH stimulated follistatin mRNA levels, but suppressed those of beta B. 12-O-Tetraphorbol acetate had no effect on beta B, but stimulated follistatin mRNA levels to the same extent as forskolin. Of these agents, only forskolin produced a marginal inhibitory effect on alpha mRNA accumulation. Testosterone decreased both follistatin and beta B mRNA levels without affecting those of alpha. The results of this study demonstrate that the local production of rat anterior pituitary follistatin, activin B, and inhibin B is regulated by hypothalamic, peripheral, and local factors in such a way that the ratios between activin B and its two inactivators, follistatin and inhibin B, are very tightly maintained.
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PMID:Pituitary follistatin and inhibin subunit messenger ribonucleic acid levels are differentially regulated by local and hormonal factors. 882 87

The acquisition of follicle-stimulating hormone (FSH) receptors during folliculogenesis is believed to be a key event in follicle development. We have examined the effects of FSH and activin on FSH receptor mRNA in cultured rat granulosa cells. Treatment of granulosa cells with FSH resulted in transient suppression of the FSH receptor mRNA levels 2-6 h after treatment, with subsequent recovery at 24 h. We could not detect a similar effect on FSH receptor mRNA by 8-bromoadenosine 3,5-cyclic monophosphate, which continuously stimulated FSH receptor mRNA over a similar time course. On the other hand, stimulation of the protein kinase C (PKC) pathway with phorbol myristate acetate mimicked the time course of the effects of FSH on the levels of FSH receptor mRNA. Taken together, these results suggest that the cAMP cascade may increase the mRNA levels of FSH receptor and, at the same time, the other cascade, PKC, may decrease FSH receptor mRNA levels. To further investigate the role of activin in the regulation of granulosa cell function, we studied the effect of activin on FSH receptor mRNA levels. Compared to the control, treatment with activin (100 ng/ml) increased FSH receptor mRNA in a time-dependent manner with a maximum circa 4-fold increase at 24 h. Treatment of granulosa cells with activin (20-300 ng/ml) for 24 h increased FSH receptor mRNA in a dose-dependent manner to a maximum circa 4-fold increase at concentrations of 100-300 ng/ml. Although follistatin alone had no detectable effect on FSH receptor mRNA levels, combination of follistatin (0-200 ng/ml) with activin (100 ng/ml) caused a significant reduction in the levels of activin-induced FSH receptor mRNA in a dose-dependent manner.
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PMID:Regulation of follicle-stimulating hormone receptor. 886 47

Granulosa cell-derived inhibin A (a dimer of alpha- and beta A-subunits), activin A (a homodimer of beta A-subunits) and the activin-binding protein follistatin are important regulators of human ovarian steroidogenesis. We here studied how 8-bromo-cAMP (8br-cAMP), a protein kinase A activator, and 12-O-tetradecanoylphorbol 13-acetate (TPA), a protein kinase C activator, affect the steady-state levels of alpha- and beta A-subunit and follistatin mRNAs in cultured human granulosa-luteal cells. 8br-cAMP induced alpha- and beta A-subunit and follistatin steady-state mRNA levels in a time- and concentration-dependent manner. The levels of alpha-subunit mRNAs were stimulated by 8br-cAMP in a sustained manner with a maximal induction seen at the time points 24 and 48 h. By contrast, beta A-subunit and follistatin mRNA levels were rapidly and transiently induced by 8br-cAMP with maximal effects observed at 3 h and 8 h, respectively. TPA did not affect basal alpha-subunit mRNA levels but it rapidly induced beta A-subunit mRNAs at 3 h and the stimulation was still evident at 48 h. TPA induced follistatin mRNA levels with kinetics similar to 8br-cAMP but to a lesser extent. Moreover, 8br-cAMP and TPA stimulated beta A-subunit and follistatin mRNA levels synergistically at 3 h. By contrast, TPA had a potent inhibitory effect on 8br-cAMP- and hCG-induced alpha-subunit levels. Neither 8br-cAMP nor TPA regulated inhibin/activin beta B-subunit mRNA levels. Taken together the activation of protein kinase-A and -C by 8br-cAMP and TPA, respectively, lead to clearly differential responses in the steady-state levels of inhibin activin alpha- and beta A-subunit and follistatin mRNAs. These results suggest that the inhibin A vs. activin A ratio as well as follistatin levels are regulated by multiple second-messenger pathways in the human ovary.
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PMID:Differential regulation of inhibin/activin alpha- and beta A-subunit and follistin mRNAs by cyclic AMP and phorbol ester in cultured human granulosa-luteal cells. 886 60

Expression of the RNA-helicase translation initiation factor, eIF4AII, in animal cap explants of Xenopus specifically upregulates genes expressed early in the neural plate border such as Xsna, Xslu, Pax-3 and XANF and also the cement gland marker XCG-1. eIF4AII is expressed specifically in the prospective neurectoderm from stage 11.5 and appears to have a significant role in mediating early patterning of the neurectoderm. It is induced by all known neural inducing regimes including secreted factors such as noggin, follistatin and chordin, transcription factors such as XlPou-2 and constructs that overcome repression of neural induction (tBMP-4R, lim-m3 and Xbra delta 304). It is also upregulated when neurulization occurs in embryonic ectoderm that has been disaggregated and reaggregated. While high amounts of injected mRNA of the neural inducers noggin, tBMP-4R and Xlpou-2 downregulate Xslu and upregulate the neural plate NCAM, smaller amounts of these mRNAs activate expression of eIF4AII and Xslu and suppress expression of epidermal keratin in animal cap assays. Ectopic expression of eIF4AII mRNA also upregulates transcription of the PKC alpha and beta genes. The sensitivity of the upregulation of neurectodermal markers to GF109203X indicates that the activity of a calcium activated protein kinase C (PKC) is also required. Furthermore ectopic expression of mouse eIF4AII mRNA upregulates the endogenous eIF4AII gene by a process that requires the activity of PKC. The effects of eIF4AII appear to be direct as conditional expression of eIF4AII in animal cap explants at the equivalent of stage 11.5 induces the endogenous eIF4AII and neural fold genes within 40 minutes. Expression of eIF4AII and activation of PKC sensitizes the embryonic ectoderm to the neuralising effect of noggin. We suggest that in developing embryos the neuralizing signal emanating from the organiser at first induces eIF4AII and the prospective neural crest in an arc low on the dorsal aspect of the embryo. As the neuralizing signal increases in intensity close to the organizer region, the tissue becomes committed to a neural plate phenotype. Expression of Xash-3A may suppress further expression of neural plate border genes within the prospective neural plate thereby subdividing the neurectoderm into two distinct regions.
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PMID:The role in neural patterning of translation initiation factor eIF4AII; induction of neural fold genes. 922 46

Activins and inhibins are glycoprotein hormones produced mainly in gonads but also in other organs. They are believed to be important para/autocrine regulators of various cell functions. We investigated activin/inhibin receptor and binding protein gene expression and the regulation of activin/inhibin secretion in human adrenal cells. RT-PCR revealed inhibin/activin alpha-, betaA/B-subunit, follistatin, activin type I/II receptor, and inhibin receptor (betaglycan and inhibin-binding protein) mRNA expression in fetal and adult adrenals and cultured adrenocortical cells. Cultured cells secreted activin A and inhibin A/B as determined by specific ELISAs. ACTH stimulated inhibin A/B secretion in fetal (1.8- and 1.8-fold of control, respectively) and in adult cells (3.4- and 1.7-fold of control, respectively) without significant effect on activin A. 8-bromoadenosine cAMP (protein kinase A activator) increased activin A and inhibin A/B secretion in the human adrenocortical NCI-H295R cell line (32-, 17-, and 3-fold of control, respectively). 12-O-tetradecanoyl phorbol-13-acetate (protein kinase C activator) stimulated both activin A and inhibin A secretion (764- and 32-fold of control, respectively), and activin treatment increased inhibin B secretion in these cells (25-fold of control). In conclusion, human adrenocortical cells produce dimeric activins and inhibins. ACTH stimulates inhibin secretion and decreases activin/inhibin secretion ratio, probably via the protein kinase A signal transduction pathway. This, together with the adrenocortical activin/ inhibin receptor and binding protein expression, suggests a physiological role for activins and inhibins in the human adrenal gland.
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PMID:Expression of activin/inhibin receptor and binding protein genes and regulation of activin/inhibin peptide secretion in human adrenocortical cells. 1221 82

Activin and its binding protein follistatin may act as local regulators of cell growth and steroidogenesis in the human ovary. The recently identified follistatin-related gene (FLRG) is expressed abundantly in the human ovary, has high affinity for activin, and is able to inhibit activin-induced transcriptional responses. However, little is known about the regulation of FLRG expression in specific cell types in the ovary, while it is known that gonadotrophins induce follistatin gene expression in human granulosa-luteal cells. In this study, we investigated the expression of FLRG mRNA in granulosa-luteal cells of preovulatory follicles obtained from women undergoing IVF. FLRG mRNA was detected by RT-PCR in fresh and cultured granulosa-luteal cells, as well as in normal ovarian stroma, theca and granulosa cells. Northern blot analysis revealed a 2.5 kb transcript of the FLRG in cultured granulosa-luteal cells. The protein kinase C activator, 12-O-tetradecanoyl phorbol 13-acetate (TPA, 160 nmol/l), and prostaglandin E(2) (PGE(2), 1 micromol/l) increased FLRG mRNA accumulation up to 3-8 fold over the control level after 24 h of treatment, and these stimulatory effects were dose-dependent. Co-treatment with the protein kinase C inhibitor, Ro-31-8220 (3 micromol/l), blocked the stimulatory effect of TPA. Although short term treatment with the protein kinase A activator, (Bu)(2)cAMP (1 mmol/l), slightly reduced FLRG mRNA expression in most experiments, long term treatment with FSH (100 IU/l), LH (100 IU/l), or (Bu)(2)cAMP had no significant effect on the FLRG mRNA levels. As expected, gonadotrophins, protein kinase A and C activators and PGE(2) increased granulosa-luteal cell progesterone secretion into the culture media. Taken together, previous and our present data suggest that protein kinase C and A signal transduction pathways differently regulate the expression of FLRG and follistatin genes in human ovarian granulosa-luteal cells.
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PMID:Regulation of follistatin-related gene (FLRG) expression by protein kinase C and prostaglandin E(2) in cultured granulosa-luteal cells. 1239 11

In vertebrates, neural induction occurs during gastrulation when ectodermal cells choose between two fates, neural and epidermal. In Xenopus, neural induction has been regarded as a default pathway as it occurs, in dorsal ectoderm, when ventralizing signals (mainly Bone Morphogenesis Proteins, BMPs, potent epidermal inducers) are inhibited by dorsalizing signals, including factors such as noggin, chordin, and follistatin. However, our previous studies demonstrated that an instructive signal triggered by the activation of L-type voltage-sensitive calcium channels, resulting in a transient increase in intracellular free calcium, appears to be a necessary and sufficient requirement to induce the competent ectoderm toward the neural pathway. Here we further explore the relationship between the Ca2+ transient signals observed and the expression of early neural genes. We have performed a subtractive approach to identify the genes which are transcribed early after the calcium signal and involved in neural determination. We have analyzed a candidate gene (xMLP) which encodes a MARCKS-like protein, a substrate for PKC. We show that this gene is activated by a calcium transient signals and induced by noggin overexpression. xMLP is expressed at the right time in presumptive neural territories. The putative role of xMLP in the process of neural induction is discussed.
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PMID:[xMLP is an early response calcium target gene in neural determination in Xenopus laevis]. 1470 50

FSH is induced by activin, and this expression is modulated by GnRH through FSHB expression. This report focuses on the inhibitory effect of GnRH on activin-induced FSHB expression. Activin-treated primary murine pituitary cultures robustly express mutant ovine FSHBLuc-DeltaAP1, a luciferase transgene driven by 4.7 kb of ovine FSHB promoter. This promoter lacks two GnRH-inducible activator protein-1 sites, making it easier to observe GnRH-mediated inhibition. Luciferase expression from this transgene was decreased 94% by 100 nM GnRH with a half-time of approximately 4 h in pituitary cultures, and this inhibition was independent of follistatin. Activators of cAMP and protein kinase C like forskolin and phorbol 12-myristate 3-acetate (PMA), respectively, mimicked GnRH action. Kinetic studies of wild-type ovine FSHBLuc in LbetaT2 cells showed continuous induction by activin (4-fold) over 20 h. Most of this induction (78%) was blocked, beginning at 6 h. cAMP response element binding protein (CREB) was implicated in this inhibition because overexpression of its constitutively active mutant mimicked GnRH, and its inhibitor (inducible cAMP early repressor isoform II) reversed the inhibition caused by GnRH, forskolin, or PMA. In addition, GnRH, forskolin, or PMA increased the expression of a CREB-responsive reporter gene, 6xCRE-37PRL-Luc. Inhibition of nitric oxide type I (NOSI) by 7-nitroindazole also reversed GnRH-mediated inhibition by 60%. It is known that GnRH and CREB induce production of NOSI in gonadotropes and neuronal cells, respectively. These data support the concept that chronic GnRH inhibits activin-induced ovine FSHB expression by sequential activation of CREB and NOSI through the cAMP and/or protein kinase C pathways.
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PMID:Chronic gonadotropin-releasing hormone inhibits activin induction of the ovine follicle-stimulating hormone beta-subunit: involvement of 3',5'-cyclic adenosine monophosphate response element binding protein and nitric oxide synthase type I. 1744 83

GnRH applied continuously or in pulses of high frequency increases follistatin, and thereby differentially regulates FSH and LH. This study was conducted in alphaT3-1 and LbetaT2 gonadotroph cells to begin to understand the signaling pathways through which GnRH stimulates follistatin synthesis. GnRH increased follistatin expression and stimulated a follistatin-LUC reporter in LbetaT2 cells, but was inactive in alphaT3-1 cells. GnRH also increased cAMP levels and stimulated a cAMP-responsive promoter only in LbetaT2 cells. Forskolin stimulated follistatin in both cell lines. GnRH activation of follistatin was blocked by the PKA inhibitor H89 and by over-expression of a dominant-negative inhibitor of CREB (A-CREB). Activation was also suppressed by PKC depletion, and was reduced by the PKC inhibitor bisindolylmaleimide. The MEK inhibitor PD98059 blocked activation by GnRH or forskolin implying that MAPK contributes to cAMP/PKA-mediated activation of follistatin. When LbetaT2 cells were transfected with follistatin-LUC together with A-CREB, and perifused with GnRH, activation was blocked during continuous GnRH, but stimulation by hourly GnRH pulses was unaffected. These experiments provide evidence that GnRH stimulates follistatin through multiple signaling pathways, and that cAMP-CREB activation is obligatory when GnRH is applied continuously. The finding that follistatin transcription was CREB-dependent with continuous but not pulsatile GnRH implies that the mode of ligand activation of GnRH receptors modifies the transcriptional response by changing the signaling network. These results provide a mechanism linking GnRH pulsatility to the differential control of FSH-beta and LH-beta gene expression through follistatin.
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PMID:Transcriptional regulation of follistatin expression by GnRH in mouse gonadotroph cell lines: evidence for a role for cAMP signaling. 1748 56

In teleosts, gonadotropin (GTH) secretion and synthesis is controlled by multiple neuroendocrine factors from the hypothalamus, pituitary and peripheral sources. Pituitary gonadotropes must be able to differentiate and integrate information from these regulators at the cellular and intracellular level. In this article, the intracellular signal transduction mechanisms mediating the actions of some of these regulators, including GTH-releasing hormones, pituitary adenylate cyclase-activating polypeptide, dopamine, ghrelin, sex steroids, activin, and follistatin from experiments with goldfish are reviewed and discussed in relation with recent findings. Information from other teleost models is briefly compared. Goldfish gonadotropes possess multiple pharmacologically distinct intracellular Ca2+ stores that together with voltage-sensitive Ca2+ channels, Na+/H+ exchangers, protein kinase C, arachidonic acid, NO, protein kinase A, ERK/MAPK, and Smads allows for integrated control by different neuroendocrine factors.
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PMID:Signal transduction in multifactorial neuroendocrine control of gonadotropin secretion and synthesis in teleosts-studies on the goldfish model. 1883 74


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