EC:2.7.11.13 - FACTA Search

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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)

Gastrin and cholecystokinin (CCK) have proven trophic effects on the gut. We have previously demonstrated that these peptides stimulate an early event in cellular proliferation, namely ornithine decarboxylase activity (ODC), in a rat exocrine pancreatic cell line AR4-2J. Furthermore, this effect is mediated through a G/CCKB receptor. Thus, in the present study we sought to examine the signal transduction mechanisms linked to the G/CCKB receptor occupancy. Both gastrin and CCK induced a rapid (maximum at 40 s) increase in inositol triphosphates (InsP3) and diacylglycerol (DAG) formation in a dose-dependent manner (EC50 = 5.6 nM) that quickly returned to baseline. Although InsP3 levels remained at baseline, DAG levels demonstrated a second gradual increase that was maximal at 15 min. CCK/gastrin efficiency to stimulate DAG and InsP3 formation (EC50 = 5.6 nM) could be correlated to the G/CCKB receptor occupancy, suggesting a coupling of this receptor to phospholipase C. To examine the involvement of protein kinase C (PKC) activation in the increase in ODC activity, we stimulated the AR4-2J cells with the phorbol ester TPA and observed an increase in ODC activity with a maximal effect at 100 nM. TPA stimulation of ODC activity was completely abolished by the PKC inhibitor staurosporine (50 nM). However, 50 nM staurosporine inhibited only 65% of the gastrin and CCK induced increase in ODC activity suggesting that a portion of the G/CCKB receptor-mediated increase in ODC activity is PKC independent.
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PMID:Coupling of pancreatic gastrin/cholecystokinin-B (G/CCKB) receptors to phospholipase C and protein kinase C in AR4-2J tumoral cells. 797 29

In previous studies we have reported that gastrin exerts a trophic effect on rat colonic epithelial cells in vitro. The effect of gastrin appeared to be mediated through a protein kinase C mechanism. In this study, we have characterized the role of protein kinase C in the gastrin-induced stimulation. Gastrin, in a time- and dose-dependent manner, increased protein kinase C translocation from the cytosol to the membrane, an index of enzyme activation. Maximum translocation occurred in 1 to 2 min following exposure to gastrin (10(-8) M), before declining back to baseline level within 5 min. Gastrin did not change total protein kinase C activity in the colonic cells. Staurosporine, an inhibitor of protein kinase C, totally abolished the basal as well as the gastrin-stimulated activity of protein kinase C. The tumor promoter phorbol 12-myristate 13-acetate also stimulated colonic epithelial protein kinase C. However, prolonged treatment of cells with phorbol inhibited their subsequent response to gastrin stimulation. The response to gastrin was also prevented by the gastrin receptor antagonist proglumide. These observations suggest that protein kinase C mediates the stimulatory effect of gastrin on colonic epithelial cells, possibly through a receptor mechanism.
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PMID:Gastrin's trophic effect in the colon: identification of a signaling pathway mediated by protein kinase C. 813 92

The effects of cyclic adenosine monophosphate-dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) modulators on secretagogue-stimulated gastric acid secretion were studied in the continuously perfused stomach of the anesthetized rat. Intravenous histamine (0.25 mg/kg/h) and pentagastrin (2 micrograms/kg/h) increased secretion above baseline by three- and fourfold, respectively. Parenteral administration of a PKC activator, 12-o-tetradecanoylphorbol-13-acetate (TPA; 0.1 nmol/h), decreased histamine- and pentagastrin-stimulated secretion by 64 and 40%, respectively. Administration of PKC inhibitors, calphostin C and 1-(5-isoquinolinyl sulfonyl)-2 methylpiperazine (H-7; 10 nmol/h, each), increased histamine- and pentagastrin-stimulated secretion by 115 and 74% and 42 and 79%, respectively, while equimolar concentrations (10 nmol/h) of three other isoquinoline sulfonamides (HA-1004, H-8, and H-89) had no effect, except for H-89 (100 nmol/h) which inhibited the histamine- and penta-gastrin-stimulated acid secretion by 44%. Basal secretion was not significantly altered by the aforementioned drugs. The TPA-induced inhibition of pentagastrin-stimulated secretion was partially reversed by treatment with H-7. These findings support a role of PKA and PKC in the modulation of stimulated gastric acid secretion in vivo.
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PMID:Effects of cyclic adenosine monophosphate-dependent protein kinase and calcium-dependent protein kinase modulators on stimulated gastric acid secretion in the perfused rat stomach. 857 20

This work aimed to investigate the molecular role of gastrin in histamine synthesis in isolated rabbit fundic mucosal cells enriched in enterochromaffin-like (ECL) cells (37%). Gastrin stimulated histidine decarboxylase (HDC) activity by increasing the maximal velocity (Vmax) from 0.240 +/- 0.017 (basal value) to 0.332 +/- 0.012 pmol/mg protein/h and by decreasing the Michaelis-Menten constant value -Km; 73.90 +/- 2.2 vs. 93.42 +/- 4.32 microM (basal value)]. Pertussis toxin (PTX) (200 ng/ml) reduced the stimulation of HDC induced by 10 nM gastrin from 41.8 to 15.9%, whereas cholera toxin (CTX) (100 ng/ml) was without effect. Staurosporine and polymyxin B inhibited in a dose dependent manner the HDC activity stimulated by 10 nM gastrin. Phorbol 12-myristate 13-acetate (PMA; 100 nM) decreased Vmax (0.558 +/- 0.021 pmol/ mg protein/h) but did not change the Km. Furthermore, cycloheximide (0.1-10 microM) inhibited the gastrin-induced stimulation of HDC activity, whereas actinomycin D (up to 10 microM) was without effect. Finally, incubation of cells with gastrin (10 microM) left the expression of HDC mRNA unchanged. We concluded that gastrin, acting through "gastrin/CCK-B type" receptors coupled to PTX-sensitive G protein, exerts a short-term regulation of histamine synthesis in gastric ECL cells by increasing both the affinity of HDC for L-histidine and the number of active enzyme molecules. This last event, related to protein kinase C activation, could be due to a translational or posttranslational mechanism.
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PMID:Gastrin stimulation of histamine synthesis in enterochromaffin-like cells from rabbit fundic mucosa. 863 12

The rat pancreatic carcinoma cell line AR4-2J was screened for growth-associated genes linked to the mitogenic effect of the novel gut brain hormone, pituitary adenylate cyclase activating polypeptide (PACAP). Using the mRNA differential display technique, we identified and sequenced an unknown rat gene, PACAP-responsive gene 1 (PRG1), which is highly homologous to gly96, a novel murine gene of unknown function. The PRG1 cDNA sequence of 1.1 kb encodes a 160-amino acid protein. Using targeted PCR, the gene structure of PRG1, constituting 0.6 kb of the promotor region, and the DNA coding region, including a single 107-bp intron, were established from rat genomic DNA. In AR4-2J cells, PACAP(1-38) increased PRG1 mRNA levels up to 10-fold in a rapid (30 min), transient (3-6 h), and dose-dependent (ED50, <1 nM) fashion. The growth-stimulating gastrointestinal hormones cholecystokinin and gastrin showed a similar degree of PRG1 induction, and the PACAP-related peptides vasoactive intestinal peptide and secretin were without effect. The transcriptional inhibitor actinomycin D, various protein kinase C inhibitors, and the calmodulin inhibitor W-7 strongly reduced PRG1 induction by PACAP, whereas the translational inhibitor cycloheximide potently increased PRG1 mRNA levels in unstimulated and PACAP-stimulated cells. Feedback-mediated hyperplasia of the rat exocrine pancreas induced by oral treatment of rats with the protease inhibitor camostate (FOY-305) was preceded by a 15-fold transient elevation of PRG1 mRNA levels. These data suggest that PRG1 is an early-response gene linked to PACAP-induced growth of AR4-2J cells as well as to hyperplasia of the rat exocrine pancreas in vivo.
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PMID:PRG1: a novel early-response gene transcriptionally induced by pituitary adenylate cyclase activating polypeptide in a pancreatic carcinoma cell line. 865 10

Transcriptional regulation of the human histidine decarboxylase (HDC) gene by gastrin and the phorbol ester phorbol 12-myristate 13-acetate (PMA) was studied using transient transfection of human HDC promoter-luciferase constructs in a human gastric carcinoma cell line (AGS-B) that expresses the human cholecystokinin-B/gastrin receptor. The transcriptional activity of the human HDC promoter was stimulated 3-4-fold by gastrin and 13-fold by PMA, effects that could be blocked by down-regulation or antagonism of protein kinase C. 5'- and 3'-deletion analysis demonstrated that the sequence responsible for gastrin- and PMA-stimulated transactivation (gastrin response element (GAS-RE)) was located in a region (+2 to +24) downstream of the transcriptional start site (+1) in the human HDC promoter and contained a palindrome (5'-CCCTTTAAATAAAGGG-3'). When ligated upstream of the herpes simplex virus 1 thymidine kinase promoter, a single copy of the GAS-RE was sufficient to confer responsiveness to gastrin and PMA. Electrophoretic mobility shift assays with specific competitors and factor-specific antibody supershifts showed that the labeled GAS-RE bound a novel nuclear factor(s). In addition, both gastrin and PMA increased binding of this factor to the GAS-RE. Hence, the palindromic GAS-RE site is sufficient to explain the gastrin/PMA responsiveness of the human HDC promoter and appears to bind a novel transcription factor.
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PMID:The human histidine decarboxylase promoter is regulated by gastrin and phorbol 12-myristate 13-acetate through a downstream cis-acting element. 866 34

The mechanisms underlying the insulinotropic action of gastrin releasing peptide (GRP) were examined in normal mouse islets. GRP (100 nM) enhanced insulin secretion at glucose concentrations of > or = 11.1 mM (p < 0.05) but only in the presence of extracellular Ca2+. The insulinotropic effect of the peptide studied during perifusion at 16.7 mM glucose was transient and vanished in time. GRP stimulated, transiently, 45Ca2+ efflux from 45Ca(2+)-prelabeled islets, both in the presence and in the absence of extracellular Ca2+ (p < 0.05), suggesting that GRP releases Ca2+ from intracellular stores. Similarly, GRP increased 86Rb+ efflux from 86Rb(+)-prelabeled islets both in the presence and in the absence of extracellular Ca2+ (p < 0.001). In contrast to GRP-induced insulin secretion, the GRP-induced 86Rb+ efflux was sustained throughout the stimulation period, suggesting that increased K+ conductance may be involved in the vanishing effect of GRP on insulin secretion. Furthermore, both inhibition of protein kinase C (PKC) by staurosporine (1-10 microM) and down-regulation of PKC activity by long-term incubation with the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate inhibited GRP-stimulated insulin secretion (p < 0.05). These results indicate that GRP activates PKC by an action involving liberation of Ca2+ from Ca2+ stores. Therefore, also the influence of GRP on phosphoinositide hydrolysis was studied by means of 3H efflux from myo-[2-3H]inositol prelabeled islets. However, GRP did not stimulate the 3H efflux. In contrast, GRP-stimulated insulin secretion was abolished by an inhibitor of phospholipase D, wortmannin (1 microM). The results suggest that GRP transiently potentiates glucose-induced insulin secretion by an action mediated by PKC activated by diacylglycerol formed through activation of phospholipase D. Simultaneously, an as yet unknown mechanism liberating Ca2+ from intracellular stores is activated.
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PMID:Studies on the mechanisms by which gastrin releasing peptide potentiates glucose-induced insulin secretion from mouse islets. 892 19

The enzyme L-histidine decarboxylase (HDC; EC 4.1.1.22), which converts L-histidine to histamine, plays a key role in the regulation of acid secretion. In the rat and human stomach, the peptide hormone gastrin appears to be one of the main regulators of HDC expression. In rats, marked elevation of gastric HDC mRNA abundance was observed within 12 h after induction of hypergastrinemia by a single injection of the proton-pump blocker omeprazole. In situ hybridization revealed that HDC expression occurred in the basal third of gastric glands where enterochromaffin-like cells are localized. To study the regulation of HDC gene transcription, 1,291 nucleotides of the 5'-flanking region of the rat HDC gene and the noncoding portion of exon 1 were cloned and sequenced. Gastrin and cholecystokinin (CCK) octapeptide equipotently stimulated the transcriptional activity of the rat HDC promoter three- to fourfold, and deletion analysis revealed the presence of a gastrin response element within 201 nucleotides upstream of the translational start site. Time-course studies revealed maximal activation of the HDC promoter after 12-36 h. Direct stimulation of protein kinase C (PKC) with the phorbol ester phorbol 12-myristate 13-acetate (PMA) substantially elevated rat HDC promoter activity, whereas induction of Ca2+ -dependent signaling pathways with thapsigargin was without effect. Downregulation or blockade of PKC abolished the effects of gastrin and PMA on the HDC promoter. These data indicate that stimulation of the CCK-B/gastrin receptor activates the rat HDC promoter in a time- and dose-dependent fashion and that this effect is primarily mediated via a PKC-dependent signaling pathway. Use of HDC as a model gene will allow further investigation of the intracellular pathways that are involved in gastrin-dependent gene regulation.
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PMID:Rat histidine decarboxylase promoter is regulated by gastrin through a protein kinase C pathway. 892 92

Pituitary adenylate-cyclase-activating polypeptide (PACAP) has been shown to possess mitogenic activity in various tumor cells. The present study was designed to investigate signal transduction mechanisms and expression of the proto-oncogenes c-fos and c-jun linked to the mitogenic effect of PACAP in the pancreatic carcinoma cell line AR4-2J. PACAP-(1-27)-peptide and PACAP-(1-38)-peptide, but not the structurally related vasoactive intestinal polypeptide (VIP), potently stimulated [3H]thymidine incorporation and cell number at doses of 0.1-10 nM. Both molecular forms of PACAP strongly increased formation of cAMP and inositol trisphosphate, elevated cytosolic Ca2+ levels and induced mitogen-activated protein (MAP) kinase activity. Quantitative reverse-transcription PCR revealed that PACAP-(1-27)-peptide and PACAP-(1-38)-peptide elevated c-fos mRNA levels 50-100-fold, whereas c-jun mRNA levels increased only moderately (2-3-fold). The effect of PACAP on c-fos and c-jun expression in AR4-2J cells was rapid (20 min), transient (1-2 h), dose-dependent IC50, 0.5 nM) and was abolished by the specific PACAP receptor antagonist PACAP-(6-38)-peptide or inhibitors of protein kinase C or tyrosine kinases. Compared with PACAP, epidermal growth factor and gastrin equipotently stimulated c-fos transcription whereas VIP, secretin, forskolin or phorbolester showed only marginal effects. Both PACAP (1-27)-peptide and PACAP-(1-38)-peptide strongly increased the DNA binding activity of the c-fos/ c-jun heterodimer transcription factor AP-1 at 10 nM and also stimulated AP-1 transcriptional activity up to 20-fold in AR4-2J cells. These findings indicate that the mitogenic effect of PACAP mediated via activation of the GTP-binding protein coupled PACAP/VIP-1 (PV1) receptor is linked to the MAP kinase cascade, increased expression of the proto-oncogenes c-fos and c-jun and activation of the heterodimeric transcription factor AP-1.
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PMID:Pituitary adenylate-cyclase-activating polypeptide stimulates proto-oncogene expression and activates the AP-1 (c-Fos/c-Jun) transcription factor in AR4-2J pancreatic carcinoma cells. 902 70

In this study we investigated the short-term effect of somatostatin on histamine synthesis in a cell population isolated from rabbit gastric mucosa and enriched in enterochromaffin-like cells. Somatostatin inhibited basal and gastrin-stimulated histamine synthesis through a dual mechanism involving a decrease in the affinity of histidine decarboxylase (HDC) for its substrate (L-histidine) and a reduction in the number of functional HDC molecules. H-89 (an inhibitor of cAMP-dependent protein kinase) mimicked somatostatin-induced reduction of HDC affinity, which, on the contrary, was selectively reversed by pertussis toxin (PTX). Furthermore, forskolin was shown to reverse the inhibitory effect of H-89 and to prevent the somatostatin-induced reduction in HDC affinity for L-histidine. Thus, the somatostatin-induced reduction in affinity seems to involve a PTX-sensitive G protein and an inhibition of the cAMP-dependent pathway. On the other hand, the somatostatin-induced decrease in the number of functional HDC molecules seems to be PTX insensitive and independent from a modulation of the cAMP pathway, and does not seem to involve a significant change in HDC messenger RNA expression or a regulation of protein kinase C. The exact nature of this second mechanism will need further studies to be elucidated.
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PMID:Short-term inhibitory effect of somatostatin on gastric histamine synthesis. 904 95

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