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)

Growth hormone promotes the differentiation of 3T3-F442A preadipocytes via unknown mechanisms. The ability of growth hormone to enhance the phosphorylation of ribosomal protein S6 through the activation of S6 kinases in this cell line was investigated. Growth hormone rapidly stimulated an S6 phosphotransferase activity measured in unpurified extracts. Using specific antisera, this activity was resolved into two components, comprising the p90rsk and p70s6k S6 kinases. Activation of these enzymes occurred simultaneously within minutes but proceeded with distinct time courses. p90rsk activation was transient, down-regulating within 60 min, whereas p70s6k activation was sustained beyond this time. The degree of activation of both S6 kinases by growth hormone closely paralleled their apparent phosphorylation status, with multi-site phosphorylation associated with full activation. Pretreatment of cells with a selective inhibitor of protein kinase C prevented activation of both S6 kinases by growth hormone but not by epidermal growth factor.
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PMID:Simultaneous activation of p90rsk and p70s6k S6 kinases by growth hormone in 3T3-F442A preadipocytes. 838 47

The mechanism of action of growth hormone (GH) is not known, although indirect evidence suggests that protein kinase C (PKC) might play an important role in the insulin-like actions of GH. In this investigation, we directly examined the effects of GH relative to those of insulin on PKC activity in isolated rat hepatocytes. Human GH (10(-7) mol/L) significantly increased the activity of PKC in both cytosolic and particulate fractions. The effect was maximal at 1 minute, disappeared at 5 minutes, and then increased again at 30 minutes in both fractions. At 1 minute, maximal and half-maximal stimulation of PKC activity occurred at hGH concentrations of 10(-7) and 5 x 10(-9) mol/L, respectively. Insulin (10(-7) mol/L) also induced a significant and transient increase in enzyme activity at 2 minutes in cytosolic and particulate fractions; at 30 minutes, PKC activity was decreased in the soluble fraction (-17%) and increased in the particulate fraction (+65%). Measurement of specific [3H]-phorbol dibutyrate (PDBu) binding suggested translocation of PKC from the cytosol to the membrane fraction after 30 minutes of incubation, only after insulin treatment. The early effects of GH and insulin on PKC activity were additive in both the particulate and cytosolic fractions. Although the later effects of GH and insulin on PKC were quite different, both hormones rapidly activated PKC in isolated hepatocytes, suggesting that PKC might be involved in triggering the insulin-like actions of GH.
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PMID:Evidence that growth hormone stimulates protein kinase C activity in isolated rat hepatocytes. 841 41

A clonal hepatocyte line (FMH-202-2), derived from livers of fetal transgenic mice harbouring human growth hormone (hGH) and SV40 T antigen as transgenes, was used in the investigation of protooncogene expression involved in liver-specific growth control and/or in hepatocellular transformation. In this model system, representing an immortalized, yet untransformed phenotype, the transgenes hGH and SV40 T antigen were expressed constitutively. The c-fos protooncogene was induced by incubation with insulin, epidermal growth factor (EGF) and insulin-like growth factor (IGF-I) in a transient manner comparable to its expression in primary murine hepatocytes. Elucidation of second messenger mechanisms demonstrated that c-fos induction by hepatotrophic growth factors was not mediated by protein kinase C. In contrast to primary hepatocytes, the c-myc protooncogene exhibited a constitutive expression pattern which was independent of growth factor stimulation. These results indicate that apart from hGH and SV40 T antigen, c-myc may play a role in cellular immortalization, but that constitutive expression of these genes, even in combined coexpression, does not suffice to induce the transformed phenotype.
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PMID:Expression of c-fos and c-myc protooncogenes in an immortalized hepatocyte line harbouring SV40 T antigen and hGH as transgenes. 851 38

We examined the effect of phorbol ester on growth hormone (GH)-releasing hormone (GRH)-induced GH secretion and cyclic adenosine monophosphate (cAMP) production in three pituitary adenomas and thyrotropin-releasing hormone (TRH)- and corticotropin-releasing hormone (CRH)-induced redistribution of protein kinase C (PKC) from cytosol to membrane in a pituitary adenoma resected from patients with acromegaly. GRH stimulated GH secretion in accordance with cAMP production in three cases, whereas 12-O-tetradecanoyl phorbol-13 acetate (TPA) stimulated GH secretion with cAMP production in one case. Simultaneous addition of GRH and TPA enhanced cAMP production in three pituitary adenomas. Moreover, addition of TPA with GRH resulted in additive secretion of GH in vitro. In one case, we were able to measure PKC activity and prove translocation of PKC stimulated by TRH and CRH in accordance with GH secretion in vitro and in vivo. These results suggest that TPA, an activator of PKC, has a stimulatory effect on GRH-induced cAMP production and that, finally, TRH- and CRH-induced PKC activation may cause greater secretion of GH by enhancement of cAMP production in human GH-hypersecreting adenoma cells.
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PMID:Growth hormone secretion in human acromegalic pituitary adenomas: cyclic adenosine monophosphate and protein kinase C responses. 859 91

The term "nonfunctioning" pituitary adenomas (NFPA) implies heterogeneity, since it relies on a clinical definition that is mainly related to tumor mass. The first complaint is often of impaired visual function, and despite the secretion of gonadotropins, hypogonadism is frequent. NFPA must be differentiated from prolactinomas, because of the therapeutic implications, but although prolactin (PRL) levels greater than 200 ng/mL indicate prolactinoma, PRL levels of 100 to 150 ng/mL are equivocal. An assessment of gonadotropin response to gonadotropin-releasing hormone (GnRH) is of no use, but the thyrotropin-releasing hormone (TRH) test is invaluable. NFPA are monoclonal in origin, but genetic mutations data have not clarified their etiology, which remains largely unknown. Proliferating cell nuclear antigen expression is increased in recurrent adenomas, as is abnormality and overexpression of the protein kinase C family in aggressive tumors. Mutations of tumor-suppressor genes, such as the p53 and Rb genes, and of the metastasizing suppressor gene nm23, have been found in invasive tumors. Immunohistochemistry data confirm that most NFPA originate from gonadotroph cells; many NFPA are negative for all anterior pituitary hormones tested, although isolated or clustered cells are often positive for glycoprotein hormones or their subunits. Silent gonadotroph and also silent growth hormone (GH) or corticotroph tumors can constitute the anatomical basis for clinical NFPA. The heterogeneity of the immunohistochemistry data is reflected in the receptor complex of these tumors. Dopaminergic receptors have recently been visualized in vivo and there are also receptors for TRH or GnRH, since levels of alpha or beta subunits and intact gonadotropins increase after TRH or GnRH stimulation. As a result, three second-line pharmacological approaches have been tried: dopamine agonists, octreotide, and GnRH superagonists or antagonists, with tumor shrinkage of up to 11% to 20%. However, surgery should be tried first.
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PMID:Nonfunctioning adenomas of the pituitary. 876 90

The regulation of clonal rat insulinoma (RINm5F) cell proliferation and hormone accumulation was investigated with the aim of identifying putative compounds capable of inducing differentiation, i.e. decreased growth and increased insulin accumulation, by the tumor cells. In particular, interest was focused on the role of a number of peptides as well as pharmacological probes modulating various signal transduction systems and which have been shown to regulate normal beta-cell proliferation and insulin accumulation. Growth hormone stimulated insulin accumulation and inhibited DNA synthesis, whereas galanin and insulin-like growth factor I caused a moderate suppression of insulin accumulation but did not affect proliferation, while epidermal growth factor, transforming growth factor beta, platelet-derived growth factor, acidic and basic fibroblast growth factor, bradykinin and somatostatin were virtually inactive on all parameters tested. Exogenous prostaglandins E2 and F1 alpha were inactive, while the cycloxygenase inhibitor indomethacin slightly suppressed insulin accumulation. The cytokine IL-1 beta caused a significant decrease in both beta-cell mitogenesis and insulin accumulation, effects that were mediated through nitric oxide generation. The vitamin A derivative retinyl acetate slightly inhibited serum-stimulated DNA synthesis, but did not affect insulin accumulation. The vitamin E alpha-tocopherol significantly enhanced insulin release but did not affect mitogenesis. By contrast, gamma-tocopherol was inactive on both these parameters. The alpha-adrenergic agonist clonidine evoked a slight inhibition of serum-stimulated DNA synthesis, without influencing insulin accumulation, whereas phenylephrine did not affect any of these parameters. Carbamylcholine increased insulin accumulation, but not cell proliferation, whereas the adenylyl cyclase activator forskolin suppressed mitogenesis but did not affect insulin accumulation. Inhibition of protein kinase C with staurosporine or prolonged treatment with phorbol ester suppressed DNA synthesis, as did the tyrosine kinase inhibitor genistein. Stimulating Ca2+ influx by closing ATP-dependent K+ channels with glibenclamide enhanced DNA synthesis, while opening of these channels with diazoxide suppressed cell growth. Conversely, preventing Ca2+ influx by the Ca2+ channel antagonist D-600, chelating intracellular Ca2+ by fura-2 AM or inhibiting the Ca2+/calmodulin-dependent protein kinase by calmidazol resulted in a decreased DNA synthesis. On the other hand, uncontrolled influx or mobilization of Ca2+ by ionomycin or thapsigargin resulted in an arrested DNA synthesis. The present paper shows that RINm5F insulinoma cell proliferation and insulin accumulation can be modulated by various peptidergic and pharmacological agents regulating certain signal transduction pathways. However, mitogenesis in the insulinoma cells seemingly is controlled in a vastly different manner in comparison to that in normal beta-cells. The most spectacular finding in this screening study, i.e. that growth hormone, contrarily to its effect on normal beta-cells, suppresses insulinoma cell growth, merits further elucidation of the underlying mechanisms. Possibly the hormone might become of utility in a clinical setting in the treatment of patients with insulin-producing tumors.
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PMID:Regulation of insulinoma cell proliferation and insulin accumulation by peptides and second messengers. 880 83

Although the ability of growth hormone (GH) to stimulate body growth and regulate metabolism has been recognized for many years, only recently has insight been gained into the molecular mechanisms by which binding of GH to its receptor (GHR) elicits its diverse effects. This review provides an overview of what is currently known about the molecular mechanisms of GH action. The model presented is one in which GH binding to two GHRs causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3' phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.
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PMID:Molecular mechanism of growth hormone action. 881 91

In goldfish, maturational gonadotropin (GTH) and growth hormone (GH) release are stimulated by two native GTH-releasing hormones (sGnRH and cGnRH-II). Both GnRHs stimulate GTH and GH release via activation of phospholipase C, protein kinase C, Ca2+ entry through voltage-sensitive channels and calmodulin. However, sGnRH-induced GTH release also involves arachidonic acid and intracellular Ca2+ components absent from its action on GH, as well as from cGnRH-II action on GTH and GH secretion. The relative roles and interactions of these signaling pathways in mediating sGnRH and cGnRH-II action on acute and prolonged GTH and GH release are compared. How two GnRHs bind to similar receptors but induce similar and dissimilar transduction mechanisms in two cell types and within one cell type is unknown.
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PMID:GnRH signaling in goldfish pituitary cells. 883 90

To investigate whether expression of the renal angiotensinogen gene is regulated by dopaminergic receptors, we used opossum kidney (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, angiotensinogen nucleotide (N) -1498/+18], permanently integrated into their genomes. The level of expression of pOGH (angiotensinogen N-1498/+18) in OK 27 was evaluated by the amount of immunoreactive hGH (ir-hGH) secreted into the culture medium. In the absence of 3-isobutyl-1-methylxanthine (IBMX), addition of dopamine (10(-13) to 10(-5)M) had minimal effect on the expression of the pOGH (angiotensinogen N-1498/+18) in OK 27 cells. In the presence of IBMX, addition of low concentrations (10(-13) and 10(-7) M) of dopamine stimulated the expression of pOGH angiotensinogen N-1498/+18) in OK 27 cells in a dose-dependent manner, whereas high concentrations (i.e., > 10(-7) M) had minimal effect. The stimulatory effect of dopamine on the expression of pOGH (angiotensinogen N-1498/+18) was inhibited by the presence of SCH-23390 (D1-dopaminergic receptor antagonist) and spiperone (D2-dopaminergic receptor antagonist), but not by ketanserin (5 HT2/5HT1c-serotonergic receptor antagonist). Moreover, the stimulatory effect of dopamine was inhibited by the presence of U-73122 (an inhibitor of phospholipase C and phospholipase A2) or staurosporine (an inhibitor of protein kinase C) or (R)-p-adenosine 3',5'-cyclic monophosphorothioate (Rp-cAMP[S]; an inhibitor of cAMP-dependent protein kinase AI and II). Addition of low concentrations (10(-13) to 10(-9)M) of SKF-82958 (D1-dopaminergic receptor agonist) or PPHT (D2-dopaminergic receptor agonist) also stimulated the expression of pOGH (angiotensinogen N-1498/+18). The stimulatory effect of SKF-82958 was inhibited by the presence of SCH-23390 or Rp-cAMP[S], whereas the effect of PPHT was inhibited by the presence of spiperone or staurosporine. These studies demonstrate that the expression of pOGH (angiotensinogen N-1498/+18) in OK 27 cells is modulated by dopaminergic receptor agonists.
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PMID:Dopaminergic receptors and angiotensinogen gene expression in opossum kidney cells. 885 71

In goldfish, growth hormone (GH) release is stimulated by dopamine via D1 receptors and cAMP-dependent mechanisms and by gonadotropin-releasing hormone (GnRH) through a protein kinase C (PKC) pathway; in addition, both D1 and GnRH actions require extracellular Ca2+. In this study, the involvement of arachidonic acid (AA) and calmodulin (CaM) in mediating the GH responses to D1 and GnRH stimulation was examined using primary cultures of dispersed goldfish pituitary cells. In 2-hr static incubation experiments, the phospholipase A2 inhibitor bromophenacylbromide (BPB; 50 microM) decreased the GH responses to the D1 agonist SKF38393 (1 microM), the adenylate cyclase activator forskolin (10 microM), and the cAMP analog 8Br-cAMP (1 mM), but not the responses to salmon (s)GnRH (100 nM), chicken (c)GnRH-II (100 nM), and AA (50 microM). Similarly, the phospholipase A2 inhibitor quinacrine (50 microM) and an inhibitor of AA metabolism, nordihydroguaiaretic acid (NDGA; 50 microM), reduced the GH responses to SKF38393, forskolin, and 8Br-cAMP. The response to the dopamine agonist apomorphine (1 microM) was also decreased by NDGA. The GH responses to AA did not add to those of forskolin or SKF38393, but were additive to responses to sGnRH and the PKC activator tetradecanoyl phorbol acetate (TPA; 100 nM). In perifusion experiments, treatment with BPB reduced the acute GH response to 1 microM SKF38393, 10 microM forskolin, or 1 mM 8Br-cAMP. Taken together, these results suggest that mobilization and metabolism of AA mediate both acute and prolonged GH responses to D1, but not GnRH. The involvement of AA probably occurs distal to D1-induced cAMP generation. Two-hour static incubation with 10 nM to 10 microM KN62, a CaM-dependent kinase II inhibitor, decreased the GH response to 100 nM sGnRH or cGnRH-II. KN62 (1 microM) similarly decreased the GH response to 1 mu M SKF38393, 10 microM forskolin, 1 mM 8Br-cAMP, or 100 nM TPA. In perifusion studies, KN62 (1 microM) also reduced the acute GH response to 5 min pulses of 100 nM sGnRH, 100 nM cGnRH-II, or 1 microM SKF38393. These results indicate that CaM mediates the acute, as well as the prolonged, GH responses to GnRH and dopamine. The involvement of CaM likely occurs distal to cAMP and PKC.
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PMID:Role of arachidonic acid and calmodulin in mediating dopamine D1- and GnRH-stimulated growth hormone release in goldfish pituitary cells. 886 Mar 13


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