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)

Insulin-like growth factor I (IGF-I) and the gonadotropin, FSH, can synergize to stimulate progesterone production in primary cultures of maturing human, rat, and pig granulosa cells. These trophic hormones act by increasing the activity and production of proteins and their gene transcripts essential to sterol uptake, delivery, and utilization in steroidogenesis. We previously observed that FSH and IGF-I interact synergistically to promote the accumulation of steroidogenic acute regulatory protein (StAR) messenger RNA and protein in granulosa cells. Here we investigate potential mechanisms of IGF-I synergy with FSH and the protein kinase A (PKA) pathway in activating the porcine StAR gene promoter. To this end, we first cloned 1423 bp of the porcine StAR promoter upstream of the transcriptional start site using PCR and created 5'-deletional constructs coupled to a cytoplasmically targeted firefly luciferase reporter gene. FSH, 8-bromo-cAMP, and transient transfection of the protein kinase A (PKA) catalytic subunit (driven by the Rous sarcoma virus promoter) were used to activate the PKA effector pathway. All three agonists alone stimulated StAR promoter-driven luciferase activity in primary cultures of granulosa cells after 4-h treatment. IGF-I significantly augmented PKA pathway agonist activation of the StAR promoter, whereas IGF-I had no effect alone. Binding experiments with 125I-labeled ovine FSH-20 in IGF-I (100 ng/ml)-treated granulosa cells showed that FSH binding affinity and receptor number were unchanged by IGF-I treatment. However, IGF-I augmented FSH-stimulated, but not forskolin-stimulated, cAMP accumulation. Analysis of 5'-deletion constructs of the StAR promoter revealed three regions of stimulatory activity within the -139-bp fragment upstream of the transcriptional start site as well as another potentially inhibitory region upstream (-1115 to 905). Elimination of the putative SF-1 site (-48 to -41) virtually abolished StAR promoter responsiveness. In summary, our data indicate that IGF-I can act via two post FSH-binding mechanisms to augment FSH/PKA pathway-mediated StAR gene promoter transactivation: at the level of cAMP accumulation and distal to cAMP production and PKA activation.
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PMID:Mechanisms of insulin-like growth factor I augmentation of follicle-stimulating hormone-induced porcine steroidogenic acute regulatory protein gene promoter activity in granulosa cells. 988 19

FSH promoted the rapid phosphorylation of the nuclear protein histone H3 in immature rat ovarian granulosa cells under experimental conditions that lead to cellular differentiation and not proliferation. FSH-stimulated histone H3 phosphorylation correlated with cAMP-dependent protein kinase A (PKA) activation and translocation of the PKA catalytic subunit to a nuclear-enriched fraction and was inhibited by the PKA inhibitor H89, and histone H3 phosphorylation was stimulated in cells treated with agents that raise intracellular cAMP levels such as forskolin and 8-bromo-cAMP. FSH-stimulated histone H3 phosphorylation in granulosa cells mapped to ser-10, a site previously identified as the PKA phosphorylation site in various mitotically active cells as the mitosis-specific phosphorylation site. Injection of the FSH analog PMSG to immature rats, which is known to stimulate granulosa cell proliferation as well as differentiation, also promoted histone H3 phosphorylation on ser-10 in granulosa cells. These results establish that FSH-stimulated histone H3 phosphorylation in granulosa cells is linked not only to granulosa cell mitosis but also to granulosa cell differentiation and that FSH-stimulated histone H3 phosphorylation on ser-10 in isolated granulosa cells is mediated by PKA. These results also identify the PKA-dependent histone H3 phosphorylation as an early nuclear protein marker for FSH-stimulated differentiation of granulosa cells. Based on the recently described function of histone H3 as a coactivator of transcription, these results are consistent with the hypothesis that phosphorylated histone H3 may facilitate PKA-dependent gene transcription in granulosa cells leading to the preovulatory phenotype.
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PMID:Follicle-stimulating hormone promotes histone H3 phosphorylation on serine-10. 989 15

This review summarizes the new information on the studies of inhibin, activin, and follistatin production in the placenta during human pregnancy. Inhibin and activin exert suppressive and stimulatory effects, respectively, on the release of FSH in the pituitary. Follistatin is bound to inhibin and activin and indirectly modulates the FSH release. The placenta produces these three proteins. The serum levels of inhibin, activin, and follistatin are elevated in pregnant women and decrease after delivery. The trophoblast cells from term placenta secrete inhibin and activin in the primary cultures. The production and mRNA expression of inhibin and activin are regulated by several stimulatory and suppressive hormones and growth factors in placental tissues. cAMP, Ca2+, and protein kinase-C may be involved in intracellular signal transduction in trophoblasts. Activin receptors are present on placental cells. Follistatin inhibits the binding of activin to ActRII receptor. Abnormal levels of inhibin and activin in maternal serum are observed in problem pregnancies and gestational diseases. Inhibin, activin, and follistatin may play roles in the regulation of reproductive endocrinology in pregnant women and the embryo/fetal development.
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PMID:Advance in the study of inhibin, activin and follistatin production in pregnant women. 998 58

To assess the regulation of stem factor factor (SCF) gene expression during spermatogenesis, we tested the effects of hormones (FSH, testosterone, and 17beta-estradiol) and some growth factors [transforming growth factor-beta (TGF beta), TGF alpha, tumor necrosis factor-alpha, and activin] on SCF gene expression by using a transillumination-assisted microdisection technique, a seminiferous tubule culture system, and Northern hybridization. Our results showed that FSH (10 ng/ml) increased steady state levels of SCF messenger RNA (mRNA) in a stage-specific and time-dependent manner. 8-Bromo-cAMP could increase the SCF mRNA level in a similar way as FSH, whereas phorbol 12-myristate 13-acetate had no effect. Actinomycin D could abolish the stimulatory effect of FSH, whereas cyclohexamide could not. The half-life of SCF mRNA was apparently prolonged after FSH stimulation (FSH-treated tubules, 15.6 +/- 1.2 h; controls, 8.6 +/- 2.7 h). Nuclear run-on assay revealed 5- and 10-fold increases in the transcription rate after FSH stimulation for 8 and 30 h, respectively. Neither testosterone nor estradiol had significant effects on SCF gene expression in our tissue culture system. Activin, TGF beta, TGF alpha, and tumor necrosis factor-alpha had no effect on SCF gene expression in vitro. In conclusion, SCF gene expression in the rat seminiferous tubule is regulated by FSH through the cAMP/protein kinase A pathway. FSH regulates SCF gene expression at both transcriptional and posttranscriptional levels involving the increase in transcription rate and prolongation of half-life of SCF mRNA, but is independent of de novo protein synthesis.
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PMID:Stage-specific regulation of stem cell factor gene expression in the rat seminiferous epithelium. 1006 79

A pituitary glycoprotein hormone FSH stimulates ovarian granulosa cells to induce ovarian follicular development. In this study we identified rat ovarian genes that were rapidly induced by FSH in the cultured rat granulosa cells by means of subtraction cloning. Complementary DNA clones encoding cAMP responsive element binding modulator (CREM) were identified as one of the FSH inducible genes. Northern blotting and reverse transcription and polymerase chain reaction (RT-PCR) analyses revealed that only the repressor type of CREM gene products, ICER (inducible cAMP early repressor) isoforms, were induced by FSH treatment in cultured rat granulosa cells. The induction of ICER by FSH was mimicked by reagents known to increase intracellular cAMP levels, indicating that the induction is through cAMP and protein kinase A signal transduction system. Induction of ICER was also confirmed as the protein levels. Electrophoretic mobility shift assay of granulosa cell extracts with a radiolabeled double stranded oligonucleotide corresponding to somatostatin cAMP responsive element also revealed that only the ICER proteins were induced by FSH treatment, whereas levels of CREM proteins were nearly constant regardless of the FSH treatment. Our present study demonstrates that FSH-induced and cAMP-mediated induction and attenuation of transcriptional responses by CREM gene products may be a key mechanistic component for the granulosa cell differentiation and proliferation.
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PMID:Regulation of cAMP responsive element binding modulator isoforms in cultured rat ovarian granulosa cells. 1020 56

Melatonin inhibits GnRH-induced release of LH and FSH from the neonatal, but not the adult, rat anterior pituitary gland. This action of melatonin is mediated by the specific high-affinity membrane-bound receptors that are absent in adult rats. The intracellular mechanism of melatonin action involves a decrease in intracellular calcium [Ca2+]i in the gonadotrophs; melatonin inhibits GnRH-induced Ca2+ release from endoplasmic reticulum as well as Ca2+ influx through voltage-sensitive channels. Melatonin also inhibits GnRH-induced accumulation of cAMP, which may result in the decreased influx of Ca2+, because cAMP, acting through protein kinase A, stimulates Ca2+ influx into the gonadotrophs. This age-dependent effect of melatonin on gonadotrophin release from the pituitary may be involved in the timing of puberty.
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PMID:Inhibitory effect of melatonin on GnRH-induced LH release. 1035 93

Epidermal growth factor (EGF) has been shown to influence FSH-stimulated estradiol (E2) and progesterone (P4) production from granulosa cells. RG 50810, a tyrosine kinase inhibitor (TKI), has previously been shown to inhibit the EGF-receptor tyrosine kinase. RG 50810 has also been shown to inhibit FSH-stimulated increases in mRNA for steroidogenic enzymes, implying a functional role of tyrosine kinases in FSH action in granulosa cells. However, inhibition of FSH-stimulated steroidogenesis by TKIs has not been evaluated in connection with the effects of EGF in granulosa cells. In the present studies, FSH-stimulated E2 production was inhibited similarly by inhibitors of protein kinase A (H-89) and protein kinase C (calphostin C) and by TKIs, and none of the inhibitors were capable of reversing the EGF-induced inhibition of FSH-stimulated E2 production. FSH-stimulated P4 production was enhanced dramatically in serum-containing medium with concentrations of TKI that were near previously reported IC50s. The enhancing effect of TKIs was less evident in serum-free medium. Addition of EGF to serum-free medium enhanced FSH-stimulated P4 production, and the TKIs reversed EGF-enhanced P4 production, but in a manner similar to that of protein kinase A inhibitor H-89. Compared to results in serum-free medium, the potency of RG 50810 and genistein to inhibit the effects of EGF on P4 production was 3- to 8-fold greater relative to H-89. These studies have demonstrated that TKIs RG 50810 and genistein selectively inhibit the effects of EGF on FSH-stimulated P4 production in granulosa cell cultures. In contrast, these studies have demonstrated nonselective inhibition of FSH-stimulated E2 and P4 production by TKIs in serum-free medium, in which it is not clear which enzyme system is affected by the compounds tested.
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PMID:Diverse effects of tyrosine kinase inhibitors on follicle-stimulating hormone-stimulated estradiol and progesterone production from rat granulosa cells in serum-containing medium and serum-free medium containing epidermal growth factor. 1037 43

LH and FSH regulate via cyclic adenosine 3'5' cyclic monophosphate (cAMP) and cAMP-dependent protein kinase (PKA), steroid biosynthesis is Leydig and Sertoli cells, respectively. Cyclic AMP also regulates a number of different cellular processes such as cell growth and differentiation, ion channel conductivity, synaptic release of neurotransmitters, and gene transcription. The principle intracellular target for cAMP in mammalian cells is the PKA. The fact that this broad specificity protein kinase mediates a number of discrete physiological responses following cAMP engagement, has raised the question of how specificity is maintained in the cAMP/PKA system. Here we describe features of this signaling pathway that may contribute to explain how differential effects of cAMP may be contributed to features of the PKA signaling pathway.
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PMID:Cyclic-AMP-dependent protein kinase (PKA) in testicular cells. Cell specific expression, differential regulation and targeting of subunits of PKA. 1090 22

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

The production of male gametes depends on the concerted action of the two gonadotropins FSH and LH on the testis. The action of LH is mediated through the production of testosterone by the Leydig cells. Since male germ cells possess neither FSH nor androgen receptors, the action of FSH and testosterone occurs through the Sertoli cells. Although the precise function of these two hormones remains elusive, the existing evidence suggest that both FSH and testosterone are able to stimulate all phases of spermatogenesis. In the male FSH is required for the determination of Sertoli cell number, and for induction and maintenance of normal sperm production. The crucial role of FSH in male gonadal function has been clearly illustrated by the discovery of a patient with an activating mutation of the FSH receptor. This patient had been hypophysectomized because of a pituitary tumor and, under testosterone substitution was unexpectedly fertile in spite of undetectable serum gonadotropin levels and had fathered three children. In this patient we could demonstrate a heterozygous activating mutation of the FSH receptor which resulted in cAMP production independent of FSH stimulation. This finding represents the first description of an activating mutation of the FSH receptor and demonstrates that FSH alone maintains spermatogenesis in man. On the other hand, the effects of the lack of FSH action are unclear. Among five men with a homozygous inactivating mutation of the FSH receptor only one was infertile and spermatogenesis was variably affected in the others. However, serum inhibin B values in these men were not completely suppressed and serum FSH levels were only moderately elevated, indicating the possibility that FSH receptor function was not completely abolished by the mutation. Elimination of FSH action is a prerequisite to suppress completely spermatogenesis for contraceptive purposes, while administration of both LH and FSH is necessary to induce sperm production in patients with hypogonadotropic hypogonadism. Experimental immunization of male monkeys against FSH markedly reduced germ cell proliferation and even induced infertility. At the cellular level, FSH stimulates the cAMP-dependent activation of protein kinase A in Sertoli cells, but the molecular mechanism of FSH action is poorly understood. In the primate, the gonadotropin withdrawal achieved by administration of a GnRH antagonist leads to a premeiotic arrest of germ cell proliferation, probably due to inhibition of the mitotic division of A-pale spermatogonia. Therefore, FSH might be the prime inducer of spermatogonial proliferation, while the successive maturation process could proceed independently of FSH. In summary, clinical and experimental evidence support the concept of an irreplaceble role of FSH in the primate. Only the combination of FSH and testosterone, however, supports a qualitatively and quantitatively fully normal spermatogenesis.
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PMID:Role of FSH in male gonadal function. 1045 80


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