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

The purification and identification of human prolactin (hPRL) had been delayed, compared with other pituitary hormones, until the determination of total amino acid sequence of hPRL in 1977. A full-length cDNA for the hPRL receptor was identified from hepatoma and breast cancer cell lines in 1989. Subsequent identification of cDNAs for PRL receptor of several species revealed that molecular size of PRL receptors could be classified into three forms, i.e., long, short and intermediate, according to the length of intracellular domain. The mechanism of post-receptor signal transduction has not been clarified yet. However, protein kinase C may be involved in this process. Further studies are necessary to investigate the relationship between molecular size of PRL receptor and postreceptor events.
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PMID:[Action mechanism of pituitary hormones--receptor and signal transduction--prolactin]. 825 31

We studied the effects of TRH on intracellular pH (pHi) in individual cells of the GH3 pituitary clonal cell line using the seminaphtorhodafluor pH indicator. We show that, in a majority of cells, TRH action on pHi occurs in two phases: first acidification then alkalinization. Acidification and Ca2+ mobilization are related in time. K+ depolarization (KCl, 50 mM), and Ca2+ ionophores, A23187 (10 microM) or ionomycin (5 microM) lead to acidification. We conclude that a marked increase in [Ca2+]i can induce acidification and that the TRH-induced acidification is due to Ca2+ mobilization. TRH-induced alkalinization is due to Na+/H+ exchanger activation, since it is inhibited by amiloride (200 microM) and Na(+)-free medium. We show that this alkalinization does not occur after a 20-h pretreatment with phorbol myristate acetate (1 microM) which depletes protein kinase C. We also show that blocking Ca2+ entry does not affect the TRH-induced alkalinization, but an increase in [Ca2+]i concomitant with the activation of protein kinase C mimics TRH-induced alkalinization. We conclude that both Ca2+ mobilization and protein kinase C activation are necessary for TRH-induced alkalinization. Studies of secretion in Na(+)-free medium or with amiloride (200 microM) show that pHi does not seem to be involved in PRL short-term release (30 min) but suggest that activation of the Na+/H+ exchanger leading to cytoplasmic alkalinization may have an important role in PRL synthesis.
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PMID:Biphasic changes in intracellular pH induced by thyrotropin-releasing hormone in pituitary cells. 838 Oct 76

Oncogenic Ras appears to act via protein kinase C (PKC)-dependent and PKC-independent pathways. In several systems, oncogenic Ras cooperates with c-Jun to activate gene transcription from promoters containing an AP-1 site by augmenting phosphorylation of the transcriptional activation domain of c-Jun. We have previously shown that oncogenic valine 12 Ras and PKA each separately activate the rat PRL (rPRL) promoter but together are mutually antagonistic. The goal of this study was to determine whether oncogenic Ras acts through PKC and c-Jun to activate transcription of an rPRL-luciferase reporter construct transiently transfected into GH4 rat pituitary cells. Our results show that phorbol 12-myristate 13-acetate (TPA) activates rPRL promoter activity through PKC, and that TPA activation of PKC diminishes the Ras response in a dose-dependent manner. Additionally, inhibition of PKC with staurosporine does not block the oncogenic Ras effect. Similarly, rPRL promoter activity in GH4 cells expressing oncogenic Ras fails to respond to TPA activation of PKC. Finally, cotransfection of a c-Jun expression vector results in inhibition of basal, TPA, and oncogenic Ras-stimulated activity of the rPRL promoter. Thus, we show that the mechanism of Ras signaling does not involve PKC, and that PKC does not signal via Ras. Taken together, these results verify that the Ras and PKC signaling pathways are separate and mutually antagonistic, and that c-Jun is not the nuclear mediator of either the Ras or PKC signal. These findings emphasize the possibility that the roles and/or functions of specific components in signaling pathways may be different in distinct cell types.
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PMID:The Ras and protein kinase C signaling pathways are functionally antagonistic in GH4 neuroendocrine cells. 841 16

Interleukin-6 (IL-6) is a B-cell differentiation-inducing cytokine that affects the secretion of several neuroendocrine hormones. Normal rat anterior pituitary (AP) cells synthesize and release IL-6, suggesting a paracrine role for the stimulation of AP hormone release by this cytokine. We have previously reported that IL-1 beta enhances IL-6 release and phospholipase A2 (PLA2)-mediated hydrolysis of phosphatidylcholine (PC) in AP cells. Because lysophosphatidylcholine (LPC) may function as a second messenger for IL-1 beta, we have investigated the effects of exogenous LPC on IL-6 release from AP cells in vitro. AP cells from male Long-Evans rats were dispersed and cultured for 5-6 days in 96-well (100,000 cells/well) culture plates. Cells were rinsed and incubated in the absence or presence of 1.25-40 microM LPC 18:0 (stearoyl) for 6 h, and IL-6 concentrations determined using the 7-TD1 cell bioassay. LPC 18:0 significantly (P < 0.01) stimulated IL-6 release up to 10-fold in a concentration-related manner. In contrast, LPC 18:0 did not affect PRL release. LPC species substituted with progressively shorter saturated 1-acyl chains (16:0-10:0) were less effective for IL-6 induction. Examination of structurally related glycerophospholipid species revealed the specificity of the LPC stimulation of IL-6 release. Thus, 1.25-40 microM lysophosphatidylethanolamine (LPE; 18:0) and lysophosphatidic acid (LPA; 18:0) were without significant effect on AP IL-6 release, demonstrating the specific functional requirement for the phosphorylcholine headgroup. Hydrolysis of the structurally related choline-linked phospholipid sphingomyelin (SM) has been implicated in IL-1 beta action in certain cell types. Similarly, 1.25-20 microM lysosphingomyelin (sphingosylphosphorylcholine; SPC) also significantly (P < or = 0.01) stimulated IL-6 release from AP cells, although SPC exhibited discernibly lower potency and efficacy than LPC. An acyl analog of platelet-activation factor (PAF), i.e. 18:0-2:0 PC (1-stearoyl-2-acetoyl-sn-glycero-3-phosphorylcholine), differs from LPC by an acetyl group in the sn-2 position; PAF was at least as effective as LPC for the stimulation of IL-6 release from AP cells in vitro. Stimulation of IL-6 release by LPC 18:0 was completely suppressed by pharmacological inhibitors of protein kinase C such as H7 (20 microM) and chelerythrine (5 microM). In addition, H7 (20 microM) abolished the stimulation of IL-6 release by IL-1 beta (0.16-100 ng/mL). These findings demonstrate that LPC, acyl PAF, or SPC (but not other lysophospholipids) stimulate IL-6 release from AP cells in vitro. We conclude that LPC-mediated activation of protein kinase C is involved in the stimulatory actions of IL-1 beta in AP cells.
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PMID:Lysophosphatidylcholine stimulates interleukin-6 release from rat anterior pituitary cells in vitro. 882 3

Evidence from use of pertussis and cholera toxins and from NaF suggested the involvement of G proteins in GnRH regulation of gonadotrope function. We have used three different methods to assess GnRH receptor regulation of G(q/11)alpha subunits (G(q/11)alpha). First, we used GnRH-stimulated palmitoylation of G(q/11)alpha to identify their involvement in GnRH receptor-mediated signal transduction. Dispersed rat pituitary cell cultures were labeled with [9,10-(3)H(N)]-palmitic acid and immunoprecipitated with rabbit polyclonal antiserum made against the C-terminal sequence of G(q/11)alpha. The immunoprecipitates were resolved by 10% SDS-PAGE and quantified. Treatment with GnRH resulted in time-dependent (0-120 min) labeling of G(q/11)alpha. GnRH (10(-12), 10(-10), 10(-8), or 10(-6) g/ml) for 40 min resulted in dose-dependent labeling of G(q/11)alpha compared with controls. Cholera toxin (5 microg/ml; activator of G(i)alpha), pertussis toxin (100 ng/ml; inhibitor of G(i)alpha actions) and Antide (50 nM; GnRH antagonist) did not stimulate palmitoylation of G(q/11)alpha above basal levels. However, phorbol myristic acid (100 ng/ml; protein kinase C activator) stimulated the palmitoylation of G(q/11)alpha above basal levels, but not to the same extent as 10(-6) g/ml GnRH. Second, we used the ability of the third intracellular loop (3i) of other seven-transmembrane segment receptors that couple to specific G proteins to antagonize GnRH receptor-stimulated signal transduction and therefore act as an intracellular inhibitor. Because the third intracellular loop of alpha1B-adrenergic receptor (alpha1B 3i) couples to G(q/11)alpha, it can inhibit G(q/11)alpha-mediated stimulation of inositol phosphate (IP) turnover by interfering with receptor coupling to G(q/11)alpha. Transfection (efficiency 5-7%) with alpha1B 3i cDNA, but not the third intracellular loop of M1-acetylcholine receptor (which also couples to G(q/11)alpha), resulted in 10-12% inhibition of maximal GnRH-evoked IP turnover, as compared with vector-transfected GnRH-stimulated IP turnover. The third intracellular loop of alpha2A adrenergic receptor, M2-acetylcholine receptor (both couple to G(i)alpha), and D1A-receptor (couples to G(s)alpha) did not inhibit IP turnover significantly compared with control values. GnRH-stimulated LH release was not affected by the expression of these peptides. Third, we assessed GnRH receptor regulation of G(q/11)alpha in a PRL-secreting adenoma cell line (GGH(3)1') expressing the GnRH receptor. Stimulation of GGH(3)1' cells with 0.1 microg/ml Buserelin (a metabolically stable GnRH agonist) resulted in a 15-20% decrease in total G(q/11)alpha at 24 h following agonist treatment compared with control levels; this action of the agonist was blocked by GnRH antagonist, Antide (10(-6) g/ml). Neither Antide (10(-6) g/ml, 24 h) alone nor phorbol myristic acid (0.33-100 ng/ml, 24 h) mimicked the action of GnRH agonist on the loss of G(q/11)alpha immunoreactivity. The loss of G(q/11)alpha immunoreactivity was not due to an effect of Buserelin on cell-doubling times. These studies provide the first direct evidence for regulation of G(q/11)alpha by the GnRH receptor in primary pituitary cultures and in GGH3 cells.
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PMID:Regulation of G(q/11)alpha by the gonadotropin-releasing hormone receptor. 917 Dec 37

PRL is an anterior pituitary hormone that, along with GH and PLs, forms a family of hormones that probably resulted from the duplication of an ancestral gene. The PRLR is also a member of a larger family, known as the cytokine class-1 receptor superfamily, which currently has more than 20 different members. PRLRs or binding sites are widely distributed throughout the body. In fact, it is difficult to find a tissue that does not express any PRLR mRNA or protein. In agreement with this wide distribution of receptors is the fact that now more than 300 separate actions of PRL have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection. Clearly, a large proportion of these actions are directly or indirectly associated with the process of reproduction, including many behavioral effects. PRL is also becoming well known as an important regulator of immune function. A number of disease states, including the growth of different forms of cancer as well as various autoimmune diseases, appear to be related to an overproduction of PRL, which may act in an endocrine, autocrine, or paracrine manner, or via an increased sensitivity to the hormone. The first step in the mechanism of action of PRL is the binding to a cell surface receptor. The ligand binds in a two-step process in which site 1 on PRL binds to one receptor molecule, after which a second receptor molecule binds to site 2 on the hormone, forming a homodimer consisting of one molecule of PRL and two molecules of receptor. The PRLR contains no intrinsic tyrosine kinase cytoplasmic domain but associates with a cytoplasmic tyrosine kinase, JAK2. Dimerization of the receptor induces tyrosine phosphorylation and activation of the JAK kinase followed by phosphorylation of the receptor. Other receptor-associated kinases of the Src family have also been shown to be activated by PRL. One major pathway of signaling involves phosphorylation of cytoplasmic State proteins, which themselves dimerize and translocate to nucleus and bind to specific promoter elements on PRL-responsive genes. In addition, the Ras/Raf/MAP kinase pathway is also activated by PRL and may be involved in the proliferative effects of the hormone. Finally, a number of other potential mediators have been identified, including IRS-1, PI-3 kinase, SHP-2, PLC gamma, PKC, and intracellular Ca2+. The technique of gene targeting in mice has been used to develop the first experimental model in which the effect of the complete absence of any lactogen or PRL-mediated effects can be studied. Heterozygous (+/-) females show almost complete failure to lactate after the first, but not subsequent, pregnancies. Homozygous (-/-) females are infertile due to multiple reproductive abnormalities, including ovulation of premeiotic oocytes, reduced fertilization of oocytes, reduced preimplantation oocyte development, lack of embryo implantation, and the absence of pseudopregnancy. Twenty per cent of the homozygous males showed delayed fertility. Other phenotypes, including effects on the immune system and bone, are currently being examined. It is clear that there are multiple actions associated with PRL. It will be important to correlate known effects with local production of PRL to differentiate classic endocrine from autocrine/paracrine effects. The fact that extrapituitary PRL can, under some circumstances, compensate for pituitary PRL raises the interesting possibility that there may be effects of PRL other than those originally observed in hypophysectomized rats. The PRLR knockout mouse model should be an interesting system by which to look for effects activated only by PRL or other lactogenic hormones. On the other hand, many of the effects reported in this review may be shared with other hormones, cytokines, or growth factors and thus will be more difficult to study. (ABSTRACT TRUNCATED)
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PMID:Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. 962 54

The hypothalamic hormone, TRH, stimulates PRL secretion and gene transcription. We have examined the possibility that the mitogen-activated protein kinase (MAPK) may play a role in mediating TRH effects on the PRL gene. TRH was found to stimulate sustained activation of MAPK in PRL-producing, GH3 cells, consistent with a possible role in transcriptional regulation. A kinase-defective, interfering MAPK kinase (MAPKK) mutant reduced TRH induction of the PRL promoter. Treatment with the MAPKK inhibitor, PD98059, blocked TRH-induced activation of MAPK and also reduced TRH induction of a PRL-luciferase reporter gene, confirming that MAPK activation is necessary for TRH effects on PRL gene expression. Previous studies have demonstrated that the PRL promoter contains binding sites for members of the Ets family of transcription factors, which are important for mediating MAPK responsiveness of the PRL promoter. Mutation of specific Ets sites within the PRL promoter reduced responsiveness to both TRH and MAPK. The finding that DNA elements required for MAPK responsiveness of the PRL gene colocalize with DNA elements required for TRH responsiveness further supports a role for MAPK in mediating TRH effects on the PRL gene. We also explored the signaling mechanisms that link the TRH receptor to MAPK induction. Occupancy of the TRH receptor results in activation of protein kinase C (PKC) as well as increases in the concentration of Ca2+ due to release from intracellular stores and entry of Ca2+ through Ca2+ channels. A PKC inhibitor, GF109203X, and an L-type Ca2+ channel blocker, nimodipine, both partially reduced TRH-induced MAPK activation and PRL promoter activity. The effects of the two inhibitors were additive. These studies are consistent with a signaling pathway involving PKC- and Ca2+-dependent activation of MAPK, which leads to phosphorylation of an Ets transcription factor and activation of the PRL promoter.
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PMID:A role for the mitogen-activated protein kinase in mediating the ability of thyrotropin-releasing hormone to stimulate the prolactin promoter. 1040 61

The ability of PRL or rat placental lactogen (rPL)-1 to induce relaxin mRNA expression was analyzed in a luteinized rat granulosa cell culture model. PRL receptor activation induced relaxin mRNA expression in a concentration- and time-dependent manner. High concentrations of PRL receptor agonist, equivalent to those of the second half of pregnancy in rats, were required to elicit relaxin mRNA expression. A 40-fold induction of relaxin mRNA was observed in cells treated 24 h with 1 microg/ml of rPL-1. Estrogen enhanced relaxin expression induced by PRL but did not affect relaxin expression on its own. PRL/rPL-1 induction of relaxin expression was independent of the extracellular regulated kinase (ERK) members of the mitogen-activated protein kinase (MAPK) pathway, based on the inability of the ERK kinase inhibitor PD98059 to block induction of relaxin expression. PRL/rPL-1 induction of relaxin expression required protein kinase C (PKC) delta, based on the ability of the preferential PKC delta inhibitor rottlerin to abolish induction of relaxin expression. Direct activation of PKC by phorbol myristate acetate, however, was not sufficient to promote induction of relaxin mRNA expression. Stats (signal transducers and activators of transcription) 3 and 5 DNA binding activities were induced by PRL/rPL-1 treatment of luteinized granulosa cells but only Stat 3 DNA binding was reduced by rottlerin. PRL/rPL-1 treatment of luteinized granulosa cells resulted in increased phosphorylation on tyrosine-705 and serine-727 of Stat 3, and these responses were reduced and blocked, respectively, by rottlerin. Tyrosine and serine phosphorylations of Stat 3 in the corpus luteum were also increased in the second half of pregnancy when PL levels are highest. Stat 3, but not Stat 1 or 5, coimmunoprecipitated with luteal PKC delta during pregnancy; Stat 3 transiently coimmunoprecipitated with PKC delta from luteinized granulosa cells in response to PRL receptor activation; and Stat 3/PKC delta complex formation required PKC delta kinase activity. Taken together, these results show that PKC delta is obligatory for PRL/rPL-1-dependent relaxin expression, that PKC delta complexes with Stat 3 in response to PRL receptor activation, and that PKC delta is involved in the regulation of Stat 3 phosphorylation downstream of the PRL receptor. These results demonstrate that PRL/rPL-1 promotes relaxin expression in luteal cells and that this event is mediated, at least in part, via PKC delta.
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PMID:Induction of relaxin messenger RNA expression in response to prolactin receptor activation requires protein kinase C delta signaling. 1077 Apr 94

Rapid, nongenomic effects of testosterone on PRL release in vitro were investigated. Anterior pituitary tissue from adult male rats was stimulated in vitro for 5 or 20 min with testosterone (T; 1 or 100 nM) or testosterone-BSA (T-BSA; 1 or 100 nM) with or without 1.2 mM tannic acid, which enables visualization of secretory granule exocytosis. Within 5 min, both concentrations of T and T-BSA stimulated exocytosis from type 2 lactotrophs (characterized by small spherical granules), but not from type 1 lactotrophs (characterized by large polymorphic granules). The effects of T on type 2 lactotrophs could be blocked by preincubation with dopamine (500 nM), but were not time or concentration dependent, and could not be inhibited by 1) removal of extracellular Ca2+, 2) the L-type Ca2+ channel blocker nifedipine (100 nM), 3) the Ca2+-adenosine triphosphatase inhibitor thapsigargin (150 nM), 4) the PKC inhibitor retinal (10 microM), or 5) the gamma-aminobutyric acidA chloride channel blocker picrotoxin (100 microM). T-BSA (0.1 nM to 1 microM) for 5 or 20 min also caused an increased release of immunoreactive PRL into the medium compared with control incubations. T and T-BSA did not stimulate exocytosis from gonadotrophs or cause LH release. In conclusion, we report for the first time a rapid, nongenomic effect of T on PRL secretion.
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PMID:Nongenomic actions of testosterone on a subset of lactotrophs in the male rat pituitary. 1096 81

GH and PRL stimulate proliferation and insulin production of pancreatic beta-cells. Whereas GH- and PRL-regulated transcription of the insulin gene in insulinoma cells has been shown to depend on STAT5 (signal transducer and activator of transcription 5), the signaling pathways involved in GH/PRL-induced beta-cell replication are unknown. The roles of various signaling pathways in human GH (hGH)-induced DNA synthesis were studied by analysis of the effect of specific inhibitors in both the insulin-producing cell line, INS-1, and in primary beta-cells. The mitogen-activated protein kinase kinase (MEK)-inhibitor, PD98059, as well as the mitogen-activated protein kinase p38 (MAPKp38) inhibitor, SB203580, partially inhibited hGH- induced proliferation in INS-1 cells but had no significant effect in primary beta-cells. Staurosporine, a protein kinase C (PKC) and protein kinase A (PKA) inhibitor, blocked both basal and hGH-induced proliferation in INS-1 cells, but had no inhibitory effect in primary beta-cells. Wortmannin, a phosphatidylinositol 3-kinase (PI3K) inhibitor, inhibited hGH-induced proliferation neither in INS-1 cells nor in primary beta-cells, whereas the tyrosine kinase inhibitor, genistein, completely inhibited hGH- induced proliferation in both primary beta-cells and INS-1 cells. To analyze the possible role of STAT5 in hGH-induced proliferation, a dominant negative STAT5 mutant, STAT5Delta749, was expressed in INS-1 cells under the control of a doxycycline- inducible promoter by stable transfection. Two clones were found to exhibit dose-dependent, doxycycline-inducible expression of STAT5Delta749 and suppression of hGH-stimulated transcriptional activation of a STAT5-regulated PRL receptor (PRLR) promoter-reporter construct. Furthermore, induction of STAT5Delta749 expression completely inhibited hGH-induced DNA synthesis. Analysis of endogenous gene expression revealed a doxycycline-dependent inhibition of hGH-stimulated PRLR and cyclin D2 mRNA levels. Our results suggest that GH/PRL-induced beta-cell proliferation is dependent on the Janus Kinase2 (JAK2)/STAT5 signaling pathway but not the MAPK, PI3K, and PKC signaling pathways. Furthermore, the cell cycle regulator cyclin D2 may be a crucial target gene for STAT5 in this process.
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PMID:Growth hormone- and prolactin-induced proliferation of insulinoma cells, INS-1, depends on activation of STAT5 (signal transducer and activator of transcription 5). 1114 45


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