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)

Rat liver nuclei pure by enzymatic and electron microscope criteria contain protein kinase C (PKC) that can be activated several hundredfold within 3 min of addition of prolactin or phorbol 12-tetradecanoate 13-acetate. Rat prolactin stimulated PKC maximally at 10(-12) M, whereas ovine prolactin was maximally stimulatory at 10(-10) M. Activation was time and dose dependent, exhibited a biphasic pattern, and was blocked by anti-prolactin antiserum, by PKC inhibitors such as 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) and sphingosine, and by cyclosporine. Moreover, the ability of prolactin to activate nuclear PKC was inhibited totally by a monoclonal antibody to the rat liver prolactin receptor, implicating a prolactin receptor-mediated activation process. Epidermal growth factor (EGF), a liver mitogen, caused a lesser but significant activation of nuclear PKC. However, EGF and suboptimal prolactin were synergistic. Human growth hormone, which has lactogenic properties, stimulated PKC activity, whereas nonlactogenic substances such as ovine growth hormone, insulin, dexamethasone, and 8-bromo-cAMP were inactive. That this may be a general mechanism for prolactin is suggested by the ability of prolactin to stimulate PKC 140-fold in rat splenocyte nuclei. Prolactin has comitogenic properties in lymphocytes.
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PMID:Rapid activation of protein kinase C in isolated rat liver nuclei by prolactin, a known hepatic mitogen. 318 50

Hepatocytes, isolated from adult male rats and maintained in serum- and hormone-free medium, were pretreated with phorbol esters known to activate protein kinase C (4 beta-phorbol-12-myristate-13-acetate) and to be inactive in this respect (4 alpha-phorbol and its 12,13-didecanoate ester). Subsequently the cells were assayed for steroid-metabolizing capacity using androst-4-ene-3,17-dione as substrate. The active phorbol ester was seen to inhibit steroid metabolism markedly after 1 h whereas the inactive derivatives did not show this effect. The endogenous activator of protein kinase C (diacylglycerol) was also seen to inhibit steroid metabolism in a manner similar to the 4 beta-phorbol ester. Hepatic steroid metabolism is, thus, inhibited by activation of protein kinase C and this may be one of the mechanisms by which the regulatory hormones (e.g. growth hormone) affect steroid metabolism in the liver.
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PMID:Effect of phorbol esters and diacylglycerol on steroid metabolism in isolated rat hepatocytes. 341 Dec 82

Tumor-promoting phorbol esters alter binding of growth factors and hormones to their specific receptors. Action of diacylglycerols, endogenous phorbol ester analogues, on 125I-labeled insulin binding to its receptor from human cells was therefore investigated. A variety of 1,2-diacylglycerols and 1,3-diacylglycerols inhibited 125I-insulin binding to intact human monocyte-like (U-937) and lymphoblastoid (IM-9) cells in a dose-, time-, and temperature-dependent manner within 30 sec at 37 degrees C in a fashion analogous to that of the tumor-promoting phorbol diester 12-O-tetradecanoylphorbol-13-acetate (TPA). Inhibition of insulin binding by diacylglycerols, analyzed by Scatchard plot, seems to be due to altered binding affinity of the insulin receptor. Diacylglycerol effects were reversible, were seen regardless of the order of addition of 125I-insulin and diacylglycerols, and were demonstrated only with occupied insulin receptors. Corresponding fatty acids or phospholipids did not affect specific insulin binding to the intact U-937 cells. Diacylglycerols also inhibited binding of 125I-insulin-like growth factor (IGF) I but not that of 125I-human growth hormone (HGH) to the human cells. The non-tumor-promoting phorbols (phorbol, 4-alpha-phorbol, phorbol-12,13-distearate) did not affect insulin binding to intact cells. Both diacylglycerols and TPA stimulated internalization of 125I-insulin by U-937 and IM-9 cells. The ability of diacylglycerol to mimic the effects of TPA on the insulin receptor supports the concept of diacylglycerols as endogenous phorbol diester analogues even though the sole role of protein kinase C in our system is doubtful.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Diacylglycerol modulation of insulin receptor from cultured human mononuclear cells. Effects on binding and internalization. 353 83

The effect of phorbol diester tumour promoters on the release of growth hormone (GH) and prolactin (Prl) was studied in rat pituitary cells cultured in monolayer. 12-O-tetradecanoyl phorbol-13-acetate (TPA), the most potent phorbol ester, stimulated GH accumulation in the cultured medium in a dose-dependent manner. TPA also stimulated Prl accumulation. A time course study indicated that TPA mainly stimulates release of GH. The maximal stimulation of GH release by TPA (100 ng/ml) was 3-4-fold over control. Phorbol-12,13-dibutyrate (PDB), another tumour-promoting phorbol ester, stimulated GH release to an extent similar to that of TPA, while a biologically inactive compound, phorbol-12,13-diacetate (PDA), had no effect. TPA-stimulated GH release was not affected by the presence of indomethacin, an inhibitor of prostaglandin (PG) synthesis, indicating that PG is not involved in the process of TPA-stimulated GH release. Co++, a competitive antagonist of Ca++, at 2.0 mM completely suppressed the GH release induced by TPA, and this inhibition was partially reversed by the addition of 2.0 mM Ca++. Verapamil, a Ca++ channel blocker, reduced TPA-stimulated GH release, and trifluoperazine, an inhibitor of Ca-calmodulin formation, had a similar effect. Somatostatin (SRIF) also inhibited the GH release by TPA. These observations are compatible with the idea that Ca++ may be involved in the process of TPA-stimulated GH release. Since TPA has been reported to activate a Ca++- and phospholipid-dependent protein kinase (protein kinase C), it is possible that TPA stimulate GH release by activating the enzyme. Further studies are required to clarify this point.
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PMID:Effect of phorbol esters on the release of growth hormone and prolactin from rat pituitary cells cultured in monolayer. 614 63

We have investigated the ability of a constitutively active Gq-alpha mutant, Q209L-alpha q, to regulate target gene expression. Transient expression in GH3 pituitary cells of a rat proximal prolactin promoter-chloramphenicol acetyltransferase construct (-187)PRL-CAT, was stimulated by co-expression of Q209L alpha q, but not by wild-type alpha q. Q209L-alpha q stimulated expression of constructs driven by promoters for either rat prolactin or growth hormone, but not of a control construct driven by the thymidine kinase promoter. Thus, transcriptional effects of alpha q are specific both for the activated state of this G-alpha subunit and the promoter examined. Since both the prolactin and growth hormone promoters are activated by the pituitary cell-specific transcription factor Pit-1, we examined whether a Pit-1 binding site could direct a response to Q209L-alpha q. Two copies of prolactin promoter Pit-1 binding site 1P conferred upon a heterologous metallothionein promoter a response to Q209L-alpha q, implying an involvement of this site in the transcriptional action of Q209L-alpha q on the prolactin promoter. The phorbol ester activator of protein kinase C, 12-O-tetradecanoylphorbol-13-acetate, stimulated (-187)PRL-CAT activity, but opposed the action of Q209L-alpha q on activity of this PRL-CAT construct. Q209L-alpha q stimulation of (-187)PRL-CAT activity was inhibited by co-expression of a dominant negative Raf mutant, Raf-C4, but not by a point mutant of Raf-C4 with reduced inhibitory properties. These results imply that activated alpha q subunits can stimulate prolactin promoter activity via a pathway that involves a Pit-1 DNA binding site(s), is opposed by protein kinase C, and is mediated by a pathway in which Raf-1 kinase plays a role.
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PMID:Constitutively active Gq-alpha stimulates prolactin promoter activity via a pathway involving Raf activity. 748 29

In goldfish, growth hormone (GH) secretion is regulated by multiple neuroendocrine factors. Among these regulators, gonadotropin-releasing hormone (GnRH) and dopamine (DA) are effective stimulators of GH release. The stimulatory actions of GnRH and DA are mediated by GnRH and DA D1 receptors on somatotropes, respectively. In this article, results from recent in vitro pharmacological and electrophysiological studies examining the possible involvement of extracellular Ca2+, protein kinase C, voltage-sensitive Ca2+ channels (VSCC) and phospholipase A2 in mediating GnRH-induced GH release are presented. Results from experiments investigating the possible interactions of cyclic adenosine 3',5'-monophosphate (cAMP), and extracellular Ca2+ entry through VSCC in mediating the DA D1-elicited GH response are also reported. These data were discussed in conjunction with other information available in the literature on the signal transduction mechanisms mediating GH secretion in goldfish. Based on these findings, a model for the transduction pathways integrating the initiation and maintenance of the distinct GnRH-induced and DA D1-elicited GH responses was proposed. GnRH and DA stimulate GH release via separate PKC- and cAMP-dependent mechanisms, respectively. These signalling mechanisms appear to act on distinct GH pools. PKC and cAMP subsequently activate VSCC. Ca2+ entry through VSCC plays a role in the sustained GH release response by enhancing the PKC- and cAMP-induced GH release.
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PMID:Signal transduction pathways in GnRH- and dopamine D1-stimulated growth hormone secretion in the goldfish. 753 77

To investigate whether alpha (alpha)-adrenoceptor agonists have a stimulatory effect on the expression of the angiotensinogen (Ang) gene in opossum kidney (OK) cells, we used OK 27 cells with a fusion gene containing the 5'-flanking regulatory sequence of the rat angiotensinogen gene fused with a human growth hormone (hGH) gene as a reporter, pOGH (Ang N-1498/+18), permanently integrated into their genomes. The level of expression of the pOGH (Ang N-1498/+18) was quantitated by the amount of immunoreactive-human growth hormone (IR-hGH) secreted into the medium. The addition of iodoclonidine (alpha 2-adrenoceptor agonist, 10(-13) to 10(-9) M) and phorbol 12-myristate 13-acetate (PMA, 10(-13) to 10(-5) M) stimulated the expression of pOGH (Ang N-1498/+18) in a dose-dependent manner, whereas the addition of phenylephrine (alpha 1-adrenoceptor agonist, 10(-13) to 10(-5) M) had no effect. The stimulatory effect of iodoclonidine was blocked by the presence of yohimbine (alpha 2-adrenoceptor antagonist) and staurosporine (an inhibitor of protein kinase C) but not blocked by the presence of prazosin (alpha 1-adrenoceptor antagonist) or Rp-cAMP (an inhibitor of cAMP-dependent protein kinase A). The addition of iodoclonidine, phenylephrine or PMA had no effect on the expression of pTKGH in OK 13 cells, an OK cell line, into which had been stably integrated a fusion gene, pTKGH containing the promoter/enhancer DNA sequence of the viral thymidine-kinase (TK) gene fused with a human growth hormone gene as a reporter.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha-adrenoceptors and angiotensinogen gene expression in opossum kidney cells. 756 70

Following the growth hormone (GH) and GH receptor (R) interaction, the receptor and Janus tyrosine kinase 2 (JAK2) become tyrosine phosphorylated along with other intracellular proteins. Previously, we reported that GH induces tyrosine phosphorylation of intracellular proteins with molecular masses of approx 95 kDa (pp95) in mouse 3T3-F442A preadipocytes and in mouse L-cells that express recombinant GHRs. We have studied this GH-induced phosphorylation event in greater detail. Three proteins with apparent molecular masses of 93, 95, and 96 kDa showed increased tyrosine phosphorylation in a time-dependent manner following GH treatment of cells that express GH receptors. GH-induced tyrosine phosphorylation of these proteins is independent of activation of protein kinase C (PKC). Cell fractionation studies revealed that the majority of tyrosine-phosphorylated pp95/96 is located in the cytoplasm. pp95 and pp96 have pIs of approx 6.2. Immunoprecipitation and Western blot analyses revealed that pp93 and pp95/96 are not immunologically related with Stat1, Stat3, Stat4, JAK2, and GHR. Thus, pp93 and pp95/96 may be important GH signal transducers independent of PKC activation and different from the characterized members in the JAK-STAT pathway.
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PMID:Characterization of growth hormone-induced tyrosine-phosphorylated proteins in mouse cells that express GH receptors. 758 Sep 36

In numerous studies on mammary epithelial cell lines multiple factors, added to the medium or contained in the serum, were required for casein gene expression. It has been shown in these systems that the mammary gland factor (MGF) is implicated in the activation of the beta-casein gene promoter. In the present study, we determined the relationship between known agents that affect casein gene expression and MGF activity using the properties of rabbit primary mammary epithelial cells to respond to PRL alone, when cultured in chemically defined medium. We demonstrate that MGF is rapidly activated by PRL alone or by human growth hormone, a natural ligand of many PRL receptors (PRL-Rs), in the cytoplasm and accumulated in the nucleus. The MGF activation by PRL occurred in the absence of endogenous extracellular matrix, a condition where casein synthesis is known to be markedly reduced. Different inhibitors of protein-tyrosine kinases, which have been shown to reduce casein mRNA synthesis, but not of protein kinase C, decrease the MGF activity. A tyrosine phosphatase inhibitor, sodium pervanadate, induced two GAS-binding complexes related to MGF and STAT1. Our data show that MGF is a latent cytoplasmic factor rapidly activated in mammary epithelial cells, by a mechanism involving a tyrosine kinase and a tyrosine phosphatase.
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PMID:Activation of STAT factors by prolactin, interferon-gamma, growth hormones, and a tyrosine phosphatase inhibitor in rabbit primary mammary epithelial cells. 767 19

The role of protein kinase C (PKC) in the regulation of basal steroidogenesis and steroid hydroxylase gene expression in Y1 adrenocortical cells was investigated. Treatment of Y1 cells with either staurosporine or calphostin C, inhibitors of PKC, increases steroid hormone production up to 7-fold. Induction of P450-cholesterol side chain cleavage enzyme (SCC) mRNA expression parallels induction of steroidogenesis by the PKC inhibitors. Staurosporine increases expression of a transiently transfected SCC promoter--human growth hormone construct in Y1 cells, indicating that PKC regulates expression of SCC mRNA at the level of transcription. Treatment with staurosporine increases expression of mRNA for two additional steroid synthetic enzymes, P450-11 beta-hydroxylase and 3 beta-hydroxysteroid dehydrogenase. These data indicate that PKC acts as a tonic negative regulator of basal steroidogenesis in Y1 cells by suppressing expression of mRNA encoding the steroid synthetic enzymes. Protein kinase A (PKA) and PKC have reciprocal effects on steroidogenesis and expression of the steroid synthetic enzymes in Y1 cells. However, the results of this study demonstrate that these signaling pathways are not interdependent. Steroid production by Y1 cells treated with (Bu)2cAMP and calphostin C together is equal to the sum of steroid production after treatment with either agent alone. Pretreatment of Y1 cells with Rp-8-Bromo-cAMP, a specific inhibitor of PKA, prevents induction of steroidogenesis by (Bu)2cAMP, but not by staurosporine, indicating that PKC is not dependent on PKA activity. In addition, induction of SCC mRNA expression by staurosporine, in Y1 cells which are defective in activation of PKA (Y1 kin-8), is equivalent to induction in Y1 cells. These data indicate that PKA and PKC regulate basal steroidogenesis through independent effects on expression of the steroid synthetic enzymes.
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PMID:Protein kinase C is a tonic negative regulator of steroidogenesis and steroid hydroxylase gene expression in Y1 adrenal cells and functions independently of protein kinase A. 769 83


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