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)

Human promyelocytic leukaemia (HL-60) cells were employed to study the induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme in controlling prostaglandin inactivation. Phorbol 12-myristate 13-acetate (PMA) stimulated 15-PGDH activity in a time- and concentration-dependent manner. Dimethyl sulphoxide (DMSO) also stimulated the enzyme activity, although a much delayed stimulation was observed. Western blot studies indicated that PMA increased significantly a 28 kDa immunoreactive protein characteristic of 15-PGDH. L-[35S]Methionine labelling of the PMA-treated cells showed a similar enhancement over the control cells. These studies indicate that PMA induced synthesis of 15-PGDH. Stimulation of 15-PGDH activity by PMA or DMSO appears to be mediated by protein kinase C activation, since an inactive analogue of PMA failed to induce the effect, and both staurosporine and H-7 blocked the stimulation. Stimulation by PMA was optimal at 10 nM and less effective at higher concentrations. Western blot studies indicated that a similar, if not greater, amount of enzyme protein was induced at high concentrations of PMA, suggesting that enzyme inactivation might be occurring. Possible enzyme inactivation by protein kinase C activation was further examined by incubating DMSO-treated cells with a high concentration of PMA (50 nM). Time-dependent inactivation of 15-PGDH within the first 1 h was observed and this inactivation was partially blocked by staurosporine and H-7. Pulse-chase experiments indicated that 15-PGDH had a rapid turnover rate (t 1/2 = 47 min), and PMA shortened the half-life of the enzyme (t 1/2 = 33 min), suggesting that PMA might have an additional effect on 15-PGDH degradation. The rapid turnover of 15-PGDH indicates that the enzyme activity depends on continued enzyme synthesis, and this could be susceptible to hormone and drug control mechanisms.
 ...
PMID:Stimulation of synthesis de novo of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase in human promyelocytic leukaemia (HL-60) cells by phorbol ester. 195 49

Pro-inflammatory prostaglandins are known to be first catabolized by NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) to inactive metabolites. This enzyme is under regulatory control by various inflammation-related agents. Regulation of this enzyme was investigated in human promonocytic U937 cells. 15-PGDH activity was found to be optimally induced by phorbol 12-myristate 13-acetate (PMA) at 10 nM after 24 h of treatment. The induction was blocked by staurosporine or GF 109203X indicating that the induction was mediated by protein kinase C. The induction by PMA was inhibited by the concurrent addition of dexamethasone. Nearly complete inhibition was observed at 50 nM. Other glucocorticoids, such as hydrocortisone and corticosterone, but not sex hormones, were also inhibitory. Inhibition by dexamethasone could be reversed by the concurrent addition of antagonist mifepristone (RU-486) indicating that the inhibition was a receptor-mediated event. Either induction by PMA or inhibition by dexamethasone the 15-PGDH activity correlated well with the enzyme protein expression as shown by the Western blot analysis. These results provide the first evidence that prostaglandin catabolism is regulated by glucocorticoids at the therapeutic level.
 ...
PMID:Dexamethasone inhibits the induction of NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase by phorbol ester in human promonocytic U937 cells. 1083 59

The hypotheses that PKC epsilon is necessary for: 1) PGF2 alpha to inhibit LH-stimulated progesterone (P4) secretion, and 2) for the expression of key prostaglandin synthesizing/metabolizing enzymes were tested in bovine luteal cells in which PKC epsilon expression had been ablated using a validated siRNA protocol. Steroidogenic cells from Day -6 bovine corpus luteum (CL) were isolated and transfected to reduce PKC epsilon expression after 48, 72 and 96 h. A third tested hypothesis was that an increase in intracellular calcium concentration ([Ca(2+)]i) is the cellular mechanism through which PGF2 alpha inhibits luteal progesterone. The hypothesis was tested with two pharmacological agents. In the first test, the dose-dependent effects on raising the [Ca(2+)]i with the ionophore, A23187, on basal and LH-stimulated P4 secretion in cells collected from early (Day -4) and mid-cycle (Day -10) bovine CL was examined. In the second test, the ability of PGF2 alpha to inhibit LH-stimulated P4 secretion in Day-10 luteal cells was examined under conditions in which an elevation in [Ca(2+)]i had been buffered by means of the intracellular calcium chelator, Bapta-AM.PKC epsilon expression was reduced 65 and 75% by 72 and 96 h after transfection, respectively. In cells in which PKC epsilon expression was ablated by 75%, the inhibitory effect of PGF2 alpha on LH-stimulated P4 secretion was only 29% lower than in the LH-stimulated group. In contrast, it was reduced by 75% in the group where PKC epsilon expression had not been reduced (P < 0.05). Real time PCR analysis indicated that there were no differences in the expression of cyclooxygenase-2 (COX-2), aldoketoreductase 1B5 (AKR1B5), prostaglandin E synthase (PGES), hydroxyprostaglandin-15 dehydrogenase (PGDH) and PGE2 -9-reductase as a function of PKC epsilon down-regulation. Finally, LH stimulated secretion of P4 at each luteal stage (Day -4 and -10), and PGF2 alpha inhibited this only in Day -10 cells (P < 0.05). When A23187 was used at concentrations greater than 0.1 mumol, the induced elevation in [Ca(2+)]i inhibited the effect of LH on secretion of P4 in Day -4 and -10 cells (P < 0.05, Fig. 5). The inhibitory effect of PGF2 alpha on LH-stimulated P4 in Day -10 cells was reduced if an increase in [Ca(2+)]i was prevented with Bapta-AM. These results support the hypothesis that differential expression of PKC epsilon and an elevation of [Ca(2+)]i are important for acquisition of luteolytic response to PGF2 alpha.
 ...
PMID:PKC epsilon and an increase in intracellular calcium concentration are necessary for PGF2 alpha to inhibit LH-stimulated progesterone secretion in cultured bovine steroidogenic luteal cells. 1776 Sep 87

Prostaglandins (PGs) induce the mechanism of labor in humans. The enzymes responsible for PG synthesis and metabolism are prostaglandin-endoperoxide synthase 2 (PTGS2) and 15-hydroxyprostaglandin dehydrogenase (PGDH). In human chorion trophoblast cells, calcium ionophore A23187 upregulates PTGS2 and downregulates PGDH protein and mRNA. The authors hypothesize that this regulation requires activation of protein kinase C (PKC) and mitogen-activated protein kinases (MAPKs). Human chorion trophoblasts were incubated with A23187 or phorbol 12-myristate 13-acetate (PMA) in the absence or presence of inhibitors of PKC, c-Jun N-terminal kinase, p38, and MEK1/2. PTGS2 and PGDH mRNA were measured by real-time reverse-transcription polymerase chain reaction. PMA upregulated PTGS2 and downregulated PGDH. The PMA effect was reversed by the inhibition of PKC. The p38 inhibitor reduced the stimulatory effect of PMA and A23187 on PTGS2. MEK1/2 inhibitor reduced the effect of PMA on PTGS2. All MAPK inhibitors failed to reverse the effect of either A23187 or PMA on PGDH. The authors conclude that upon stimulation with the same upstream signals, different downstream intracellular pathways regulate PTGS2 and PGDH mRNA expression.
 ...
PMID:Opposite effect of phorbol ester PMA on PTGS2 and PGDH mRNA expression in human chorion trophoblast cells. 1821 53

Multiple lines of evidence have suggested a role for both bile acids and prostaglandins (PG) in gastrointestinal carcinogenesis. Levels of PGE(2) are determined by both synthesis and catabolism. Previously, bile acid-mediated induction of cyclooxygenase-2 (COX-2) was found to stimulate PGE(2) synthesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the catabolism of PGE(2), has been linked to colorectal carcinogenesis. In this study, we determined whether bile acids altered the expression of 15-PGDH in human colon cancer cell lines. Treatment with unconjugated bile acids (chenodeoxycholate and deoxycholate) suppressed the transcription of 15-PGDH, resulting in reduced amounts of 15-PGDH mRNA, protein, and enzyme activity. Conjugated bile acids were less potent suppressors of 15-PGDH expression than unconjugated bile acids. Treatment with chenodeoxycholate activated protein kinase C (PKC), leading in turn to increased extracellular signal-regulated kinase (ERK) 1/2 activity. Small molecules that inhibited bile acid-mediated activation of PKC and ERK1/2 also blocked the downregulation of 15-PGDH. Bile acids induced early growth response factor-1 (Egr-1) and Snail, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Egr-1 or Snail blocked chenodeoxycholate-mediated downregulation of 15-PGDH. Together, these data indicate that bile acids activate the signal transduction pathway PKC --> ERK1/2 --> Egr-1 --> Snail and thereby suppress 15-PGDH transcription. Bile acids appear to increase the release of PGs from cells by downregulating catabolism in addition to stimulating synthesis. These results provide new mechanistic insights into the link between bile acids and gastrointestinal carcinogenesis.
 ...
PMID:Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes. 1960 33

The ovulatory gonadotropin surge increases granulosa cell prostaglandin synthesis as well as prostaglandin dehydrogenase (PGDH), the key enzyme responsible for prostaglandin metabolism. To investigate gonadotropin regulation of PGDH in the primate follicle, monkey granulosa cells were obtained across the 40-h periovulatory interval. PGDH activity was low before the ovulatory hCG stimulus, peaked 12-24 h after hCG, and was low again 36 h after hCG administration. Granulosa cells maintained in vitro with hCG showed a similar temporal pattern of PGDH. The LH/CG receptor can utilize multiple signaling pathways to regulate intracellular events. Gonadotropin-stimulated cAMP appears to act primarily via the Epacs to increase PGDH mRNA, protein, and activity. In contrast, PLC activation of PKC likely decreases PGDH mRNA, protein, and activity late in the periovulatory interval. Increased, then decreased PGDH activity may delay accumulation of prostaglandins in the follicle until late in the periovulatory interval, contributing to timely ovulation in primates.
 ...
PMID:Prostaglandin dehydrogenase (PGDH) in granulosa cells of primate periovulatory follicles is regulated by the ovulatory gonadotropin surge via multiple G proteins. 2116 5