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)

Previously, we reported that administration of prolactin (PRL) during the early luteal phase in sows increases plasma progesterone concentrations. In the current study, we searched for the mechanisms by which PRL exerts this luteotrophic effect. The objectives of the study were (1) to examine the effect of PRL and/or low-density lipoproteins (LDL) on progesterone production by porcine luteal cells derived from early corpora lutea, and (2) to assess the ability of PRL to activate phosphoinositide-specific phospholipase C (PI-PLC) and protein kinase C (PKC) in these luteal cells. Ovaries with early corpora lutea (day 1-2 of the oestrous cycle) were obtained from the slaughterhouse. Progesterone production by dispersed luteal cells was measured after treatment with PRL, phorbol 12-myristate 13-acetate or inhibitors of PKC in the presence or absence of LDL. LDL increased progesterone concentration in the incubation medium (304.5 vs 178.6 ng/ml in control, P<0.05). PRL augmented LDL-stimulated progesterone secretion by luteal cells (to 416 ng/ml, P<0.05), but PRL alone did not affect progesterone production (209.6 ng/ml, P>0.05). Staurosporine, a PKC inhibitor, inhibited progesterone secretion stimulated by the combined action of LDL and PRL; however, such inhibition was not demonstrated when cells were treated with the PKC inhibitor, H-7. PKC activation was assessed by measuring the specific association of [H]phorbol dibutyrate (H-PDBu) with luteal cells after treatment with PRL or ionomycin (a positive control). PRL and ionomycin increased H-PDBu-specific binding in early luteal cells by 28+/-5.5% (within 5 min) and 70.2+/-19.3% (within 2 min) over control binding respectively (P<0.05). In addition, PRL did not augment the LDL-stimulated progesterone production in PKC-deficient cells. In contrast with PKC, total inositol phosphate accumulation, as well as intracellular free calcium concentrations, were not affected by PRL in the current study. We conclude that PRL, in the presence of LDL, stimulates progesterone production by early corpora lutea in vitro. Moreover, PRL appears to activate PKC, but not PI-PLC, in these cells. Thus intracellular transduction of the PRL signal may involve activation of PKC that is not dependent on PI-PLC.
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PMID:Assessment of the mechanism by which prolactin stimulates progesterone production by early corpora lutea of pigs. 979 59

Luteinizing hormone (LH) and insulin-like growth factor I (IGF-I) are recognized as major regulators of ovarian theca-interstitial (T-I) function. This study was designed to compare the effects of LH and IGF-I on T-I proliferation and steroidogenesis. Purified rat T-I cells were cultured in chemically-defined media. DNA synthesis was evaluated by a radiolabelled thymidine incorporation assay. The cells were also directly counted. Progesterone production was assessed using a specific radioimmunoassay. DNA synthesis of T-I cells was stimulated by IGF-I (10 nM) but modestly inhibited by LH (100 ng/ml). The inhibitory effect of LH was mimicked by 8Br-cAMP (10(-4) to 10(-3) M); forskolin (10(-5) M), cholera toxin (10 ng/ml) and 3-isobutyl-methylxanthine (10(-5) M). Stimulation of protein kinase C with phorbol 12-myristate 13-acetate (10(-7) M) had no significant effect on DNA synthesis. Furthermore, DNA synthesis was not affected by testosterone (10(-10) to 10(-9) M) or progesterone (10(-9) to 10(-8) M). Accumulation of progesterone was co-operatively stimulated by LH and IGF-I. These results suggest that LH-induced inhibition of T-I proliferation and/or survival is mediated via the cAMP system. IGF-I may be viewed as a co-gonadotrophin with respect to steroidogenesis but not with respect to proliferation/survival. The divergence of the effects on proliferation/survival versus steroidogenesis underscores the complexity of the interactions between LH and IGF-I signalling pathways.
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PMID:Divergent mechanisms regulate proliferation/survival and steroidogenesis of theca-interstitial cells. 1033 51

In previous studies in porcine granulosa cell cultures, endothelin-1 (ET-1) was shown to inhibit FSH-stimulated cAMP and progesterone accumulation, and to increase inositol phosphate formation and cytosolic calcium ion concentration. The latter results suggest an action of ET-1 via the activation of phospholipase C. Here we have investigated the following experimental questions. (1) Does ET-1 activate PKC in ovarian cells? (2) Does the cellular mechanism(s) whereby ET-1 interferes with the steroidogenic action of FSH in granulosa cells involve an impairment of cAMP generation or action? And (3) how does the site(s) of the inhibitory effect(s) of ET-1 and TPA on FSH-stimulated progesterone accumulation in cultured granulosa cells compare? In the present investigation, ET-1 (1 microM) induced rapid cytosol-to-membrane translocation of [3H]phorbol 12,13-dibutyrate binding sites, indicating protein kinase C (PKC) activation. At 24 or 48 h, ET-1 inhibited FSH-, but not forskolin (1 microM)-induced, cAMP accumulation. Cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) messenger RNA (mRNA) accumulation was stimulated by FSH, 8-bromo-cAMP (8Br-cAMP, 0.5 mM) and forskolin. ET-1 significantly inhibited this effect of FSH, but not the effects of 8Br-cAMP and forskolin. Progesterone production decreased commensurately with this inhibitory action of ET-1 on the FSH-stimulated accumulation P450scc mRNA. The PKC activator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), suppressed steroidogenesis stimulated by forskolin and 8Br-cAMP as well as FSH. In conclusion, ET-1 inhibited FSH-stimulated cAMP accumulation, P450scc expression, and progesterone production in porcine granulosa cell cultures. The data are compatible with pre-adenylate cyclase site of action. Although ET-1 activated PKC, TPA, unlike ET-1, seems to inhibit steroidogenesis by interfering with cAMP action.
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PMID:Mechanisms underlying endothelin's inhibition of FSH-stimulated progesterone production by ovarian granulosa cells. 1061 35

Angiotensin II (AngII) is known to act in the anteriorpituitary through phosphatidiloinositol breakdown, increasing the level of inositol-1,4,5-trisphosphate (IP(3)) and diacyloglycerol (DAG), a potential activator of protein kinase C (PKC). We examined the effect of estradiol and progesterone treatment in vivo on IP(3) levels and activity of PKC under the influence of AngII. Three groups of intact female rats received in vivo injections of 17-beta-estradiol, progesterone, and oil (control) for five days, and then the in vitro effect of AngII was examined using homogenate of the anterior pituitary. AngII increased either the IP(3) concentration or the synapsin I phosphorylation catalyzed by PKC. Estradiol enhanced the basal (without AngII) IP(3) level and PKC activity induced by AngII. Progesterone did not change the basal and AngII-induced IP(3) concentrations. On the other hand, it decreased the basal PKC activity and blocked the effect of AngII. Our data suggest that ovarian steroids can modulate the effect of AngII on the anterior pituitary gland.
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PMID:Effect of 17-beta-estradiol and progesterone on angiotensin II-induced changes in inositol-1,4,5-trisphosphate content and protein kinase C activity in anterior pituitary. 1094 31

Bone is a target tissue of progestins, but the mechanisms by which they act are still unclear. We examined the early (5-60 s) effects of progesterone and progesterone covalently bound to BSA (P-CMO BSA), which does not enter the cell, on the cytosolic free Ca(2+) concentration ([Ca(2+)]i) and the formation of inositol 1,4,5 trisphosphate (InsP3) and diacylglycerol (DAG) in confluent female and male rat osteoblasts. P-CMO BSA like free progesterone increased [Ca(2+)]i via Ca(2+) influx through L-type Ca(2+) channels and Ca(2+) mobilization from the endoplasmic reticulum. Both progestins increased InsP(3) and DAG formation within 10 s, and the increase was blocked by phospholipase C inhibitors (neomycin and U-73122). Progesterone and P-CMO BSA mobilized calcium from the endoplasmic reticulum via the activation of a phospholipase C linked to a pertussis toxin-insensitive G-protein in both osteoblast types, and this process was controlled by protein kinase C. Neither progestin had any effect on cAMP formation in male and female osteoblasts. The membrane effects were not blocked by a progesterone nuclear antagonist. They were independent of the concentration of nuclear receptors and not linked to gender. Thus, progesterone appears to act in female and male rat osteoblasts via unconventional cell-surface receptors which belong to the class of membrane receptors coupled to phospholipase C via a pertussis toxin-insensitive G-protein. The bifurcating pathways leading to the formation of InsP(3) and DAG may provide a certain flexibility in controlling cell responses, both by their nature and by their rates of formation and degradation.
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PMID:Membrane signalling and progesterone in female and male osteoblasts. I. Involvement Of intracellular Ca(2+), inositol trisphosphate, and diacylglycerol, but not cAMP. 1096 60

During gamete interaction, sperm acrosome reaction (AR) induced by oocyte investment is a prerequisite event for the spermatozoa to pass through the zona pellucida (ZP), fuse with and penetrate the oocyte. Progesterone (P4), secreted by cumulus cells, is an important cofactor for the occurrence of this exocytosis event. The AR results from the fusion between outer acrosomal and plasma membranes, leading to inner acrosomal membrane exposure. Binding of agonists, P4 or ZP3 glycoprotein, to plasma membrane sperm receptors activates intraspermatic signals and enzymatic pathways involved in the AR. Among the proteins or glycoproteins described as potential sperm receptors for ZP, Gi/Go protein-coupled and tyrosine kinase receptors have been described. Sperm receptors for P4 are poorly characterized, except a putative GABA(A)-like receptor. ZP- and P4-promoted AR is mediated by an obligatory intracellular calcium increase, appearing first at the acrosome equatorial segment and spreading throughout the head. The plasma membrane channels involved in calcium entry are operated by a plasma membrane depolarization and protein phosphorylations mediated by protein kinase C and tyrosine kinase protein. Part of the calcium increase could also be due to intracellular store release through IP3- and nucleotide (cAMP)-gated channels. Besides adenylate cyclase and phospholipase C activations, intracellular calcium increase also stimulates PLA2 activity and actin depolymerization, leading to membrane fusion. Evaluation of AR by staining or fluorescent probes can be useful to predict fertilization success and to direct the therapeutic strategy in male infertility.
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PMID:The acrosome reaction in human spermatozoa. 1104 13

In the ovary it has been demonstrated that PGF(2alpha) activates the phospholipase C (PLC)/diacylglycerol/protein kinase C pathway. However, little is known about the downstream signaling events that mediate subsequent cellular responses such as steroidogenesis. The present study was designed to examine the effect of PGF(2alpha) on activation of the mitogen-activated protein kinase (MAPK) signaling pathway and its physiological role in human granulosa-luteal cells (hGLCs). Human GLCs, obtained from women undergoing in vitro fertilization-embryo transfer, were treated with increasing concentrations of PGF(2alpha) (10 nmol/L to 10 micromol/L) for 5 min. For time-course experiments, hGLCs were treated with 1 micromol/L PGF(2alpha) for 1, 5, 10, or 20 min. Western blot analysis, using a monoclonal antibody that detected the phosphorylated forms of extracellular signal-regulated kinases 1 and 2 (p42(mapk) and p44(mapk), respectively), demonstrated that PGF(2alpha) activated MAPK in hGLCs in a dose- and time-dependent manner. Treatment of the cells with neomycin (10 mmol/L; a PLC inhibitor), bisindolylmaleimide I (5 micromol/L; a PKC inhibitor), or PD98059 (50 micromol/L; a MEK inhibitor and a MAPK kinase inhibitor) significantly attenuated the PGF(2alpha)-induced activation of MAPK. In contrast, MAPK activation was not significantly affected by pertussis toxin (200 ng/mL; a G(i) inhibitor) pretreatment. To determine the role of MAPK in steroidogenesis, hGLCs were treated with PGF(2alpha) (1 micromol/L), hCG (1 IU/mL), or PGF(2alpha) plus hCG in the presence or absence of PD98059. Progesterone levels in the culture medium were examined by RIA. Treatment of hGLCs with PGF(2alpha) significantly inhibited hCG-induced progesterone production. The presence of the MEK inhibitor, PD98059, reversed the inhibitory effect of PGF(2alpha) on hCG-induced progesterone production. To our knowledge, it is the first demonstration of PGF(2alpha)-induced activation of the MAPK signaling pathway in the human ovary. These results indicated that PGF(2alpha) activated MAPK subsequent to PLC and PKC activation through pertussis toxin-insensitive G protein in hGLCs. Further, we demonstrated that PGF(2alpha)-induced MAPK activation is associated with modulation of progesterone production. These results support the idea that the MAPK signaling pathway is involved in mediating PGF(2alpha) actions in the human ovary.
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PMID:Role of mitogen-activated protein kinase in prostaglandin f(2alpha) action in human granulosa-luteal cells. 1123 27

An increase in intracellular calcium is essential to trigger capacitation and the acrosome reaction. The aim of this study was to determine the progesterone effect mediated by the voltage-dependent calcium channel and protein kinase C on heparin-capacitated and noncapacitated spermatozoa. Protein kinase C was activated by 1-oleoyl-2-acetyl glycerol, a membrane-permeant diacyl-glycerol, and inhibited by GF-109203X. The percentage of true acrosome reaction was evaluated using differential-interferential optical contrast microscopy and trypan blue stain. The calcium concentration was evaluated by FURA-2AM and methoxyverapamil was used as a voltage-dependent calcium channel inhibitor. A rapid calcium increase and acrosome reaction were induced by progesterone in capacitated and noncapacitated spermatozoa, a higher intracellular calcium increase being observed in capacitated than in noncapacitated samples (P < 0.05). The calcium increase and acrosome reaction were blocked significantly by GF-109203X in noncapacitated and capacitated spermatozoa by the addition of progesterone and/or 1-oleoyl-2-acetylglycerol. Methoxyverapamil blocked calcium influx in samples treated with progesterone and heparin/progesterone, but not in those treated with 1-oleoyl-2-acetyl glycerol. Progesterone induces the acrosome reaction in noncapacitated cryopreserved bovine spermatozoa through intracellular mechanisms dependent on protein kinase C and the voltage-dependent calcium channel.
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PMID:Progesterone effect mediated by the voltage-dependent calcium channel and protein kinase C on noncapacitated cryopreserved bovine spermatozoa. 1135 Mar 74

Previously, we observed that 70-kDa ribosomal protein S6 kinase (p70(s6k)) plays an essential role during the early phase of oocyte maturation in Rana dybowskii. To investigate further the early signal transduction components involved in this process, the possible role of phosphatidylinositol-3 kinase (PI3 kinase) during oocyte maturation was examined. Progesterone-induced oocyte maturation was significantly inhibited by wortmannin and LY294002, specific inhibitors of PI3 kinase. In contrast, protein kinase C activator 12-0-tetradecanoylphorbol-13-acetate-induced oocyte maturation was not inhibited by wortmannin. Protein synthesis was also significantly suppressed by wortmannin treatment during oocyte maturation. Moreover, PI3 kinase inhibitor suppressed progesterone-induced phosphorylation of S6 kinase in a dose-dependent manner. Likewise, PI3 kinase inhibitors significantly inhibited the phosphorylation of mitogen-activated protein (MAP) kinase which was increased during oocyte maturation. Finally, progesterone-induced H1 kinase activity was also inhibited by PI3 kinase inhibitors in a dose-dependent manner. Taken together, these results suggest that PI3 kinase is an initial component of the signal transduction pathway which precedes p70(s6k), MAP kinase, and MPF production during progesterone-induced maturation of amphibian oocyte.
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PMID:Involvement of phosphatidylinositol 3 kinase in the progesterone-induced oocyte maturation in Rana dybowskii. 1203 Jul 77

To investigate whether the various steroid hormones can modulate the basal and angiotensin II-induced protein kinase C (PKC) activity in the anterior pituitary of the rat, female and male intact and ovariectomized female Wistar rats were treated in vivo with estradiol (E2), progesterone (P), dehydroepiandrostendione sulfate (DHEA-S), and pregnenolone sulfate (PREG-S). Estradiol caused the increase of basal PKC activity in intact and ovariectomized females, but did not change the enzyme activity in males. In ovariectomized animals the increase of PKC activity was lower than in intact females. Progesterone decreased PKC activity only in intact animals. DHEA-S strongly enhanced activity of PKC in ovariectomized females. Pregnenolone sulfate did not significantly change PKC function of all studied groups. Incubation with AngII enhanced the PKC activity in intact (without steroid treatment) animals of both genders. In females, AngII and estradiol together rise the PKC-stimulated phosphorylation in greater degree than used separately. Treatment with other investigated steroids reduced the effect of AngII. In intact males every examined hormone turned back the stimulatory effect of AngII on PKC activity. These data suggest that gender differences in PKC activity are likely related to hormonal milieu of experimental animals and may depend in part on the basic plasma level of estrogens.
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PMID:Gender differences in steroid modulation of angiotensin II-induced protein kinase C activity in anterior pituitary of the rat. 1205 46


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