EC:2.7.11.13 - FACTA Search

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)

Based on the unique susceptibility of the neonatal pulmonary circulation to hypoxia-induced structural alteration in vivo, we hypothesized that pulmonary artery (PA) smooth muscle cells (SMC) from the neonate would demonstrate enhanced growth capacity in vitro compared to adult cells. To test this hypothesis, matched neonatal and adult bovine SMC were tested for differences in size, serum-stimulated proliferation, susceptibility to senescence, resistance to serum withdrawal, autocrine growth capacity, and responsiveness to a locally important growth factor (insulin-like growth factor I; IGF-I) and an activator of protein kinase C (PKC) (phorbol 12-myristate 13-acetate; PMA). Neonatal PA SMC were smaller, grew faster, reached a higher plateau density, and were less susceptible to senescence. They were more resistant to serum withdrawal, had spontaneous autocrine growth capacity, and were more responsive to IGF-I, PMA, and the combination. Acquisition of increased growth factor responsiveness occurred between d5 and d14 after birth. Increased neonatal growth to IGF-I was associated with reduced IGF-I binding activity, implicating a post-receptor mechanism in enhanced responsiveness. Increased membrane-bound PKC catalytic activity was found in serum-deprived neonatal SMC. This basal increase was equal to that stimulated by 1 nM PMA in adult SMC, a pretreatment that caused these cells to become as responsive to IGF-I as untreated neonatal ones. We conclude that neonatal bovine PA SMC have marked enhancement of growth capacity in vitro, the acquisition of which is dependent on time from birth and is associated with auto-activation of PKC, These increased growth properties detected in vitro may contribute to the striking hyperplasia of neonatal PA SMC found in vivo following hypoxic exposure.
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PMID:Enhanced growth capacity of neonatal pulmonary artery smooth muscle cells in vitro: dependence on cell size, time from birth, insulin-like growth factor I, and auto-activation of protein kinase C. 807 85

High levels of extracellular K+ ensure proper development and prolong survival of cerebellar granule neurons in culture. We find that when switched from a culture medium containing high K+ (25 mM) to one containing a low but more physiological K+ concentration (5 mM), differentiated granule neurons degenerate and die. Death induced by low K+ is due to apoptosis (programmed cell death), a form of cell death observed extensively in the developing nervous system and believed to be necessary for proper neurogenesis. The death process is accompanied by cleavage of genomic DNA into internucleosome-sized fragments, a hallmark of apoptosis. Inhibitors of transcription and translation suppress apoptosis induced by low K+, suggesting the necessity for newly synthesized gene products for activation of the process. Death can be prevented by insulin-like growth factor I but not by several other growth/neurotrophic factors. cAMP but not the protein kinase C activator phorbol 12-myristate 13-acetate can also support survival in low K+. In view of the large numbers of granule neurons that can be homogeneously cultured, our results offer the prospect of an excellent model system to study the mechanisms underlying apoptosis in the central nervous system and the suppression of this process by survival factors such as insulin-like growth factor I.
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PMID:Induction of apoptosis in cerebellar granule neurons by low potassium: inhibition of death by insulin-like growth factor I and cAMP. 824 1

In rat thecal-interstitial cells (TIC), treatment with the synthetic androgen mibolerone has led to the documentation of an autoregulatory process for androgen production. In the present study, accumulated evidence has provided insight into the mechanisms of mibolerone action that control this process. Investigations using the nonsteroidal antiandrogen hydroxyflutamide were conducted to characterize mibolerone's mode of action. Hydroxyflutamide had differential effects on hCG action, the 1-microM dose stimulating hCG-induced androsterone synthesis by 27% and the 10-microM concentration decreasing the androgen levels by 84%. In addition, treatment with 1 microM hydroxyflutamide was effective in partially reversing the inhibitory action of mibolerone on hCG-stimulated androsterone production. Thus, the data indicated that mibolerone's mode of action may be mediated, at least in part, via the androgen receptor. The possibility that mibolerone had multiple sites of action prompted studies on the effectiveness of this androgen to alter various signaling pathways. Treatment with increasing concentrations (0.01-100 nM) of the phorbol ester 12-0-tetradecanoylphorbol 13-acetate (TPA), which activates protein kinase C, resulted in a 75% decrease in hCG-stimulated androgen production at a dose of 100 nM TPA. Treatment with mibolerone (100 nM) was unable to alter the action of TPA on androgen synthesis when doses of 1 and 10 nM TPA were employed. It was also found that Ca2+ can serve as a mediator of mibolerone action. Treatment with a 0.01-microM dose of A23187, a Ca2+ ionophore known to increase intracellular Ca2+, was ineffective in altering hCG-stimulated androsterone synthesis. The concurrent treatment of mibolerone (100 nM) and A23187 (0.01 microM) resulted in the potentiation of mibolerone's inhibitory effects on hCG-stimulated androgen production, thereby suggesting that mibolerone can stimulate Ca2+ influx. Additional studies revealed that the administration of a 1-microM dose of the L-type Ca2+ channel blocker verapamil to TIC cultures was able to partially block the inhibitory effect of mibolerone on androgen synthesis. Evidence for an additional site of mibolerone action was revealed through an analysis of the mRNA levels of P450scc and P450(17) alpha enzymes. Although hCG and insulin-like growth factor I treatment resulted in 20- and 32-fold increases in the amount of P450scc and P450(17) alpha mRNA, respectively, the addition of mibolerone (100 nM) reduced only P450(17) alpha mRNA levels by 91%. Overall, the evidence indicates that mibolerone has multiple sites of action in exerting its regulatory effect on androgen synthesis.
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PMID:Mechanisms of action for an androgen-mediated autoregulatory process in rat thecal-interstitial cells. 828 1

Recent studies indicate that insulin and insulin-like growth factors regulate development of the nervous system. The signal transduction pathways that mediate the neurotrophic responses to these peptides are largely unknown. The aims of this study were to examine the regulation of c-fos mRNA expression by insulin and insulin-like growth factor I (IGF-I) in postmitotic neurons derived from fetal chick forebrain and to investigate the role of protein kinase C (PKC) in c-fos induction by these growth factors. Cultured neurons were treated with growth factors or other known activators of c-fos gene expression, and then total cellular RNA was isolated and analyzed by Northern analysis using a full-length mouse c-fos cDNA probe. Fetal calf serum, insulin, IGF-I, 12-O-tetradecanoylphorbol (TPA), and cycloheximide induced a 2.2-kilobase c-fos transcript in neurons. Increased levels of c-fos mRNA were apparent as early as 15 min after the addition of insulin. Levels peaked after 60 min and then remained high up to 180 min. The onset of c-fos induction by IGF-I was similar to insulin; however, the response was more transient. Analyses of dose-response curves indicate that insulin and IGF-I stimulate c-fos expression by interacting with their own receptor type. The decay rate of c-fos mRNA was unaltered by insulin or IGF-I. Pretreatment of neurons with actinomycin D (2 microM) for 5 min prior to the addition of insulin completely blocked the induction of c-fos mRNA. TPA increased c-fos mRNA levels with similar kinetics to that of insulin and IGF-I; however, the attenuation phase more closely paralleled that of insulin. Two inhibitors of PKC, sphingosine and staurosporine, completely blocked the induction of c-fos mRNA by insulin, IGF-I, and TPA. These data indicate that insulin and IGF-I stimulate transcription of the c-fos gene in neurons by a PKC-mediated pathway. Increased AP-1 activity may mediate some of the neurotrophic responses to insulin and IGF-I.
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PMID:Insulin and insulin-like growth factor I induce c-fos expression in postmitotic neurons by a protein kinase C-dependent pathway. 832 43

As a step to elucidate a role of protein kinase C(PKC) pathways in the regulation of insulin-like growth factor I(IGF-I) gene, we sought to determine whether the IGF-I gene promoter of chicken can be a target of regulation by PKC. An initial gene transfer study showed that, in a human cell line HepG2, the IGF-I gene promoter directs accurate transcription of IGF-I-luciferase fusion gene and enhances luciferase activity. Treatment of transfected cells with 12-o-tetradecanoylphorbol 13-acetate(TPA) increased promoter activity of 2100 and 600bp 5'-flanking sequence 4.9- and 3.6-fold, respectively. Site-directed mutagenesis in the AP-1-like sequence located within the 600bp resulted in 91% loss of its TPA-induced promoter activity, and a gel mobility-shift analysis revealed that TPA-stimulation of HepG2 cells caused a dramatic increase in specific protein-binding to the AP-1-like sequence, suggesting that the sequence functions as an AP-1 enhancer. These observations support a direct role for PKC pathways in activating the IGF-I gene promoter in chicken.
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PMID:An AP-1 enhancer mediates TPA-induced transcriptional activation of the chicken insulin-like growth factor I gene. 843 27

Modulation of steroid receptor-dependent transcription by extra- cellular ligands represents a novel mechanism of steroid receptor regulation. We have assessed the effects of epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha), and insulin-like growth factor I (IGF-I) on transcription from consensus estrogen response elements (ERE) in estrogen receptor (ER)-positive BG-1 human ovarian adenocarcinoma calls. EGF, TGF alpha, IGF-I, and estradiol (E2) enhanced transcription in a dose-dependent manner using either a strong or a minimal promoter, and ICI 164,384, a specific ER antagonist, inhibited these responses. Combinations of E2 with TGF alpha or IGF-I induced synergistic activation of transcription from an ERE, whereas as additive response was observed with combinations of IGF-I and TGF alpha of EGF. Tetradecanoyl 12-phorbol 13-acetate (TPA), a protein kinase C (PKC) activator, stimulated ERE-mediated transcription, and this effect was inhibited by ICI 164,384. Bisindolylmaleimide, a relatively specific inhibitor of PKC, completely antagonized TPA-induced transcription, but did not affect the response to TGF alpha, IGF-I, or E2. The combination of TPA with E2 in transcriptional synergism was inhibited by ICI 164,384; conversely, the combination of TPA with either TGF alpha of IGF-I elicited a response only equal to the maximal TPA response. Thus, peptide growth factors elicit ER-dependent transcription independently of PFC; however, there may be a common mechanistic component, as saturation of response was observed. Finally, activation of ERE-dependent transcription in Chinese hamster ovary cells by IGF-I was observed in the presence of a mutant receptor that lacks estrogen-binding activity. The effect of both IGF-I and E2 were dependent on the ability of the ER to bind to DNA. IGF-I elicited only weak transcriptional activation in the presence of a deletion mutant that lacked the entire A/B domain; however, synergism between IGF-I and E2 was observed with this mutant. Therefore, ligand-independent activation of ER-dependent transcription by IGF-I is predominantly mediated through activation function I by a mechanism distinct from that of E2.
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PMID:Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol. 861 9

Renal nephron segments are heterogeneous, and receptors for endothelin (ET)-1, ET-3, Angiotensin II (AII), epidermal growth factor (EGF), and insulin-like growth factor I distribute differently along the nephron segments. Recently, growth factors and vasoactive substances are reported to stimulate mitogen-activated protein kinase (MAP-K). In this study, we showed that mRNA and proteins of MEK-K, Raf-1-K, MAPK-K, MAP-K (p42 and p44), and S6-K are expressed ubiquitously in intact nephron segment. We demonstrated that four tiers of a cascade composed of the Raf-1-K, MAP-K, MAP-K, and S6-K are stimulated by ET-1 and ET-3 in rat intact glomeruli (Glm) via primarily B-type ET receptors and PKC. The stimulatory effect of EGF and IGF-I to MAP-K activity is inhibited by a tyrosine kinase inhibitor in Glm. IGF-I significantly stimulates MAP-K activity and EGF and All moderately stimulate MAP-K activity in the proximal convoluted tubule (PCT). EGF significantly increased MAP-K cascades and ET-1 and ET-3 slightly increased MAP-K cascades in the medullary thick ascending limb (MTAL). EGF significantly stimulated MAP-K cascades, and ET-1 and ET-3 moderately stimulate MAP-K cascades in the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD). MAPK-K and S6-K are similarly stimulated by these agonists in each segment. This study shows that MAP-K cascades are expressed in every nephron segment. ET-1, ET-3, All, EGF, and IGF-I stimulate MAP-K cascades heterogeneously along the nephron segment. It was concluded that MAP-K cascades play an important role in the regulation of renal function.
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PMID:Presence and regulation of Raf-1-K (Kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments. 874 82

In the present study we have examined the signaling cascades involved in insulin-like growth factor I (IGF-I)-induced mitogenesis in fetal rat brown adipocyte primary cultures, a model that constitutively expresses a high number of IGF-I receptors, where IGF-I is a complete mitogen at physiological concentrations. IGF-I rapidly stimulated beta-chain IGF-I receptor autophosphorylation, which peaked at a physiological/mitogenic concentration (1.4 nM) and also stimulated tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Tyrosine-phosphorylated IRS-1 bound and subsequently activated phosphatidylinositol 3-kinase by 3.5-fold, whereas the tyrosine-phosphorylated IGF-I receptor was not directly associated with the p85 subunit of the phosphatidylinositol 3-kinase. Moreover, mitogenic concentrations of IGF-I enhanced glucose transport by 2.5-fold. In addition, tyrosine phosphorylation of the 46- and 52-kDa SHC proteins was high in the basal state and doubled after IGF-I treatment, whereas IGF-I enhanced by 4-fold tyrosine phosphorylation of the 66-kDa SHC band. Furthermore, a 2-fold increase in the Ras. GTP active form was induced upon IGF-I stimulation. Downstream from Ras, IGF-I increased both Raf kinase and protein kinase C (PKC) zeta activities by 3.5-fold. (Bu)2cAMP, an inhibitor of IGF-I-induced mitogenesis in fetal brown adipocyte primary cultures, did not block the very early steps of the IGF-I-induced mitogenic cascade, such as IGF-I receptor autophosphorylation, IRS-1 or SHC tyrosine phosphorylation, and Ras activation to its GTP active form. However, (Bu)2cAMP disrupted IGF-I-Raf and IGF-I-PKC zeta signaling pathways by preventing IGF-I-induced Raf-1 kinase and PKC zeta enzymatic activities, respectively. Our results show the first characterization in situ of an IGF-I mitogenic signaling cascade that downstream Ras diverges to the nucleus through two different serine/threonine kinases (Raf-1 kinase and PKC zeta) in mammalian fetal primary cells under physiological conditions. Both kinases represent a point of regulation primarily described for IGF-I-induced, cAMP-inhibited mitogenic pathways.
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PMID:Involvement of Raf-1 kinase and protein kinase C zeta in insulin-like growth factor I-induced brown adipocyte mitogenic signaling cascades: inhibition by cyclic adenosine 3',5'-monophosphate. 875 54

The effects of various neuropeptides on human plasma cells were studied. Of the various neuropeptides tested, vasoactive intestinal peptide (VIP) enhanced Ig production and growth in human plasma cell lines, IM-9 and AF-10, and in plasma cells generated in vivo (four out of four patients with plasma cell leukemia) and in vitro. In contrast, other neuropeptides (neuropeptide Y, somatostatin, substance P, peptide YY, neurokinin A, calcitonin gene-related peptide, chole-cystokinin octapeptide, and beta-endorphin) were ineffective. Moreover, VIP-induced enhancement was specifically blocked by VIP receptor antagonist. Among the various cytokines, IL-6, GH, and insulin-like growth factor I (IGF-I) also enhanced Ig production and thymidine uptake in plasma cells. However, VIP-induced enhancement was not mediated by IL-6, GH, or IGF-I because antibodies to these cytokines failed to block VIP-induced enhancement. Phorbol 12,13 dibutyrate enhanced Ig production and thymidine uptake in plasma cells, and the Phorbol 12,13 dibutyrate-induced enhancement was blocked by H7 (a protein kinase C inhibitor) but not by H8 (a protein kinase A inhibitor). Similarly, VIP-induced enhancement was blocked by H7 but not by H8. Collectively, VIP enhances plasma cell responses via mechanisms that may involve protein kinase C.
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PMID:Vasoactive intestinal peptide enhances immunoglobulin production and growth in human plasma cells via mechanisms that may involve protein kinase C. 876 69

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

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