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)

In the ruminant ovary, synthesis and secretion of oxytocin begin in the granulosa cells of the preovulatory follicle and are markedly stimulated by the surge of LH and FSH. Luteinization of the granulosa cells results in a further increase in oxytocin gene expression, but translation of mRNA appears to be retarded because the peak concentration of luteal oxytocin occurs later than the maximal accumulation of the message. Several hormones have been shown to stimulate oxytocin secretion from granulosa and luteal cells in vivo or in vitro. However, the role of prostaglandin F2 alpha (PGF2 alpha) in regulating luteal oxytocin secretion has perhaps received more study than other hormones. The mechanism of action of PGF2 alpha has been shown to encompass a phosphoinositide cascade and activation of protein kinase C, events that are associated with luteal secretion of oxytocin. Protein kinase C phosphorylation of the actin-binding protein myristolated alanine-rich C kinase substrate (MARCKS) may be required for exocytosis of oxytocin.
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PMID:Dynamics of molecular mechanisms underlying ovarian oxytocin secretion. 762 28

In earlier studies in cultures of porcine granulosa cells prepared from small antral follicles, steroidogenesis-related loci were inhibited by treatment for 48 h with 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a potent activator of protein kinase C (PKC). In the present investigation, cells were incubated in serum-free medium for 48 h, with various agents present during the last 2-24 h. With TPA at 30 ng/ml, the FSH-stimulated cAMP accumulation was markedly enhanced at all time points. FSH increased the concentration of cytochrome P450 cholesterol side-chain cleavage (P450scc) mRNA throughout the 24-h incubation. At 4 and 8 h, TPA increased the accumulation of P450scc mRNA, having an additive effect with FSH. However, at 24 h, TPA markedly suppressed the FSH-induced increased in P450scc mRNA. Pretreatment of cells with FSH did not shorten the time required for TPA to become inhibitory. The stimulatory effect of 8-bromo-cAMP on P450scc mRNA also was augmented by TPA at 4 h, but significant inhibition was not observed at 24 h. The concentration of glyceraldehyde-3-phosphate dehydrogenase mRNA, intended to be used for correction of gel loading, was stably increased by both cAMP and TPA. These effects of TPA suggest multiple actions of PKC(s) on the regulation of P450scc expression and other endpoints in ovarian granulosa cells.
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PMID:Dual actions of phorbol ester on cytochrome P450 cholesterol side-chain cleavage messenger ribonucleic acid accumulation in porcine granulosa cells. 762 23

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

Follistatin is a 35-kilodalton monomer isolated from follicular fluid that acts on pituitary gonadotropes to suppress the production of FSH. Transfection of rat granulosa cells with specific oncogenes, such as simian virus 40 (SV40) DNA and Ha-ras oncogene, leads to their immortalization concomitant with preservation of their capacity for inducible steroidogenesis. Experiments were designed to investigate the regulation of follistatin messenger RNA (mRNA) accumulation upon stimulation with forskolin, 2-O-tetradecanol-phorbol-13-acetate (TPA), FSH, and hCG in four different granulosa cell lines. Granulosa cells were transfected with SV40 DNA alone (POGS5); with SV40 DNA and Ha-ras oncogene (POGRS1); with SV40 DNA, Ha-ras oncogene, and LH/CG receptor (GLHR15); or with FSH receptor (GFSHR17) expression plasmid. Cells were cultured to reach confluence and then stimulated for 6 or 24 h with ovine FSH (oFSH; 0.004-4 nM), hCG (9 nM), forskolin (50 microM), and TPA (50 nM), alone or in combination. In the POGS5 cell line, forskolin caused a 15-fold stimulation of follistatin mRNA after 24-h incubation. The POGRS1 cell line showed a time-dependent stimulation of follistatin gene expression induced by both forskolin (5.7-fold) and TPA (9.4-fold). In the GFSHR17 cells, forskolin, oFSH, and TPA induced an increase in follistatin mRNA. When oFSH (1.6 nM) was added to cells treated with forskolin (50 microM) or TPA (50 nM), no additional stimulation was observed. The GLHR15 cell line treated with hCG showed a 2.7-fold increase in follistatin mRNA accumulation within 6 h. Our data demonstrate that 1) follistatin mRNA is detectable and induced by forskolin and TPA in transformed granulosa cell lines that do not express the FSH or LH receptors; 2) in the GFSHR17 cell line, FSH, forskolin, and TPA caused a time- and dose-dependent regulation of the gene; and 3) follistatin gene expression is up-regulated by hCG in the GLHR15 cell line. We conclude that these transformed steroidogenic cell lines can serve as a useful model to study the regulation of follistatin gene expression, a peptide known to regulate pituitary and ovarian hormone secretion and differentiation of granulosa cells by its activin-binding action. Moreover, this gene can be regulated in immortalized granulosa cells by both the protein kinase A and protein kinase C pathways, although these cells express the large T antigen and the Ha-ras oncogenic proteins.
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PMID:Regulation of follistatin messenger ribonucleic acid in steroidogenic rat granulosa cell lines. 778 14

A mesenchymal-epithelial cell interaction exists in the testis between the Sertoli cells that form the seminiferous tubule and the mesenchymal-derived peritubular myoid cells that surround the tubule. Analysis of the mesenchymal-epithelial interactions between these cells revealed the local production of a mesenchymal factor, PModS. PModS modulates the differentiated functions of Sertoli cells in vitro, including stimulation of the iron-binding protein transferrin (Tf). Previous results have indicated that PModS-induced Tf gene expression involves the activation of immediate early genes. One of the immediate early genes was identified as c-fos. The importance of c-fos was demonstrated in the current study when a c-fos antisense oligonucleotide was found to inhibit the ability of PModS to induce the expression of a Tf promoter-chloramphenicol acetyltransferase (CAT) construct. The regulation of c-fos by PModS was investigated with various CAT constructs containing segments of the c-fos promoter, such as the serum response element (SRE), sis-inducible element (SIE), cAMP response element (CRE), and phorbol ester/TPA response element (TRE), transfected into cultured Sertoli cells. PModS has no effect on cAMP response element-CAT or TRE-CAT, suggesting that PModS does not act through stimulation of cAMP and protein kinase C pathways. PModS was found to activate the c-fos SRE-CAT construct and the SIE-CAT construct. A construct containing both SIE and SRE was stimulated to the same degree as either element alone. Gel mobility shift assays using nuclear extracts from PModS-stimulated Sertoli cells and a radiolabeled SRE oligonucleotide resulted in retarded mobility of a DNA-protein complex. A gel shift with a SRE oligonucleotide containing an ETS domain resulted in a unique shift only detected in PModS stimulated cells. PModS also promoted a gel shift with the SIE that is adjacent to the SRE on the c-fos promoter. The data imply that PModS can activate the c-fos promoter through the SRE and SIE. PModS caused a labeled activating protein 1 (AP1) oligonucleotide to form a DNA-protein complex, indicating activation of the c-fos gene and binding of the c-fos/jun complex. To study the downstream regulation of Sertoli cell differentiation, Tf gene expression was examined. CAT constructs containing deletion mutants of a 3-kilobase (kb) mouse Tf promoter were used. When transfected into Sertoli cells the 581-base pair Tf minimal promoter had only a slight response to PModS, but was activated by FSH. The 2.6-kb Tf promoter construct responded to PModS.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Role of specific response elements of the c-fos promoter and involvement of intermediate transcription factor(s) in the induction of Sertoli cell differentiation (transferrin promoter activation) by the testicular paracrine factor PModS. 778 31

In granulosa cells, growth factor IGF I plays a major role in both growth and differentiation, acting through an autocrine/paracrine mechanism, and its production is regulated by FSH, via cyclic AMP (cAMP). As protein kinase C is also involved in granulosa cell function, we investigated the possibility that its activation could balance the positive effects of FSH. Using pig granulosa cells cultured in vitro, we studied the effects of protein kinase C activation by tetradecanoylphorbol acetate (TPA) on IGF I mRNA level. We also checked morphological modifications, cAMP production and steroidogenesis at the P450 side chain cleavage mRNA and progesterone levels. Our data demonstrate that protein kinase C activation antagonizes the in vitro FSH-induced differentiation, particularly morphological modifications and accumulation of IGF I mRNA. These inhibitory effects on FSH responses suggest that there could be a balance between protein kinase A and protein kinase C pathways in regulating differentiation in pig granulosa cells.
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PMID:Protein kinase C inhibition of in vitro FSH-induced differentiation in pig granulosa cells. 779 38

We have recently shown that FSH, LH, and prolactin (PRL)--alone or combined--act as luteotropins when incubated with luteal cells from pregnant hamsters (Yuan and Greenwald, Biol Reprod 1994; 51:43-49). The purpose of the present study was to determine which second messenger systems are affected by these hormones with progesterone (P4) synthesis as the principal endpoint after 4 h of incubation with 100,000 luteal cells. Luteal cells on Days 4, 10, or 12 of pregnancy were incubated with the following reagents: 10 ng of recombinant human FSH (r-hFSH), ovine (o) FSH, oLH, oPRL, forskolin, db-cAMP, protein kinase A inhibitor (PKI), protein kinase C activator (phorbol 12-myristate 13-acetate; PMA), or various combinations of the reagents. Forskolin and db-cAMP each stimulated P4 in a dose-dependent manner, while PKI significantly inhibited forskolin-, r-hFSH-, oFSH-, and oLH-stimulated P4 on Day 4 of pregnancy. PMA (0.001-1.0 microM) did not affect basal P4 on Day 4, 10, or 12 of pregnancy; however, 100 nM PMA inhibited db-cAMP-, forskolin-, oFSH-, and oLH-stimulated P4 synthesis on Days 4 and 12. The antagonistic effects of PMA were reversed in all cases by concurrent incubation with a PKC inhibitor, H-7. On Day 4 of pregnancy, P4 was stimulated by oFSH and oLH with the highest levels observed in medium stimulated by the luteotropic complex of oFSH, oLH, and oPRL. Recombinant hFSH enhanced P4 production in a dose-dependent manner; doses of 10 ng and above resulted in statistically significant differences from the control values (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Luteotropic effects of follicle-stimulating hormone (FSH): II. FSH luteinizing hormone, and prolactin effects on second messenger systems in the corpus luteum of the pregnant hamster. 780 18

Transforming growth factor-beta (TGF-beta) has been implicated in the regulation of ovarian follicle development. Little, however, is known regarding the regulation of TGF-beta expression within the follicle. To investigate this, granulosa and theca cells were isolated from small antral follicles of prepubertal porcine ovaries, maintained in monolayer culture, and treated with gonadotropins or intracellular activators of the protein kinase A and C pathways. TGF-beta secreted into the medium was measured using a proliferation inhibition bioassay with MvLu1 epithelial cells. Over a broad dose range, FSH and LH were ineffective in stimulating TGF-beta secretion relative to controls in granulosa and theca cells, respectively. Additionally, 8-bromo-cAMP, a direct activator of protein kinase A, was ineffective in stimulating TGF-beta secretion in either cell type. In marked contrast, PMA, a stimulator of protein kinase C, dose-dependently stimulated TGF-beta secretion in theca cells. Interestingly, however, PMA had virtually no effect upon granulosa cells. The stimulatory effect of PMA on theca cell TGF-beta secretion was not observed with the inactive derivitive 4 alpha-PMA, and the PMA effect was inhibited by chelerythrine chloride, an inhibitor with high specificity toward protein kinase C. Taken together, these results argue against a direct role of the protein kinase A pathway in the regulation of TGF-beta expression in porcine follicle cells and support direct involvement of the protein kinase C pathway. Moreover, there appears to be marked differences in the regulation of this growth factor between theca and granulosa cells.
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PMID:Differential involvement of protein kinase C in the regulation of transforming growth factor-beta (TGF-beta) secretion by porcine theca and granulosa cells in vitro. 786 87

In the present study, we have examined regulatory effects of protein kinase A and protein kinase C activation by 8-CPTcAMP and TPA, respectively, on mRNAs for various G protein alpha-subunits and corresponding immunoreactive proteins in rat Sertoli cells. Gs alpha and Go alpha mRNA levels were transiently increased 1.5-fold and 4-fold, respectively, by 8-CPTcAMP in cultured Sertoli cells. This up-regulation of mRNAs for Gs alpha and Go alpha was also observed when Sertoli cells were incubated in the presence of FSH. When protein synthesis was inhibited by cycloheximide, the cAMP-mediated stimulation of Gs alpha mRNA was abolished, whereas Go alpha mRNA was superinduced to a 50- to 100-fold higher level than basal. Activation of protein kinase C with TPA had a strong, synergistic effect on cAMP-mediated stimulation of Gs alpha mRNA, whereas the cAMP-mediated stimulation of Go alpha mRNA was completely blocked. Surprisingly, changes in mRNA levels were not accompanied by any alterations in the levels of immunoreactive Gs alpha and Go alpha proteins.
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PMID:The alpha-subunit mRNAs for Gs and Go2 are differentially regulated by protein kinase A and protein kinase C in rat Sertoli cells. 787

Transferrins are a class of related metal-binding transport glycoproteins for transporting iron to various organs and tissues of the body. In recent years, it has been reported that the transferrin can play an important role in the local regulation of ovarian function, apart from its iron-binding characteristic. Transferrin could attenuate FSH-induced differentiation of rat and human granulosa cells and its mechanisms were considered as follows: (1) Transferrins partially blocked the binding of FSH with its receptors on granulosa cells and reduced the formation of intracellular cAMP, and therefore inhibited the expression of FSH receptors. (2) Acting sites beyond cAMP formation also existed for the inhibitory effect of transferrin on inhibin and estradiol production. (3) The inhibitory effect of transferrin seemed not to be involved in the changes of protein kinase C activity, the calcium release and "proliferation-differentiation reversed mechanism" in granulosa cells.
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PMID:[The inhibitory effect and its mechanism of transferrin on FSH-induced differentiation of granulosa cells]. 797 6


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