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)

It has been suggested that the c-myc gene may play an important role in the regulation of cell proliferation. We have investigated the transmembrane signaling mechanisms of various growth factors and tumor promoters in Swiss 3T3 fibroblasts and have examined the causal relationship between these mechanisms and c-myc gene activation. Platelet-derived growth factor and FGF (fibroblast growth factor) induced the activation of diglyceride-protein kinase C and Ca2+ systems through phosphoinositide turnover, resulting in the activation of the c-myc gene. Epidermal growth factor did not activate these two systems but stimulated gene activation. Prostaglandin E1 elicited Ca2+ mobilization and cyclic AMP generation followed by c-myc gene activation. In contrast to these growth factors, tumor-promoting phorbol esters induced the direct activation of protein kinase C which led to c-myc gene expression. Bile acids, which are known to be colon tumor promoters, were inactive by themselves but enhanced FGF-induced diglyceride formation and thereby potentiated protein kinase C activation. It has not yet been examined whether bile acids potentiate FGF-induced activation of the c-myc gene. The growth factors described above and the phorbol esters stimulated DNA synthesis in the presence of insulin, whereas the bile acids potentiated FGF-induced DNA synthesis. These results strongly suggest that three messenger systems, diglyceride, Ca2+ and cyclic AMP, may be involved in c-myc gene activation which may be implicated in DNA synthesis in Swiss 3T3 cells.
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PMID:[Possible modes of action of growth factors and tumor promoters in the activation of the c-myc gene in Swiss 3T3 fibroblasts]. 300 65

Epidermal growth factor (EGF) causes rapid increases in free intracellular Ca2+ and stimulates the phosphorylation of 11 cytosolic proteins in hepatocytes. Ten of the 11 cytosolic proteins altered by EGF are identical to those affected by angiotensin II, a hormone that stimulates the breakdown of phosphatidylinositol 4,5-bisphosphate. An increase in the phosphorylation of the other protein, spot c (Mr = 36,000, pI = 5.5), is observed only with EGF. Treatment of intact rats with pertussis toxin to ADP-ribosylate Ni, the inhibitory GTP-binding protein of the adenylate cyclase complex, abolished the effect of EGF on Ca2+ mobilization and on the phosphorylation of the 10 proteins affected in common with angiotensin II. This treatment had minimal effects on the ability of EGF to stimulate the phosphorylation of its unique substrate, spot c. In marked contrast, modification of Ni did not block the ability of angiotensin II to stimulate Ca2+ mobilization or protein phosphorylation. Pretreatment of normal hepatocytes with 4 beta-phorbol 12-myristate 13-acetate blocked all responses to EGF, including the increased phosphorylation of spot c, but had no effect on the responses to angiotensin II. These results imply that Ni or a similar pertussis toxin substrate may mediate the apparent effects of EGF on phosphatidylinositol breakdown and that protein kinase C may regulate a site in the transduction pathway. Angiotensin II appears to use a different signal transduction mechanism to stimulate phosphatidylinositol metabolism in hepatocytes.
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PMID:Pertussis toxin or phorbol 12-myristate 13-acetate can distinguish between epidermal growth factor- and angiotensin-stimulated signals in hepatocytes. 308 11

Down-modulation of Ca2+-activated, phospholipid-dependent protein kinase (protein binase C), which was accomplished by pretreatment with phorbol-12,13-dibutyrate for 24 h, resulted in the loss of a phorbol ester-induced stimulation of hexose transport activity in Swiss 3T3 cells. In these cells, however, platelet-derived growth factor as well as Ca2+ ionophore A23187 were still able to induce stimulation of hexose transport activity accompanied by the elevation of intracellular free Ca2+ concentration. Since chelation of extracellular Ca2+ inhibited this stimulation, inflow of extracellular Ca2+ into cytoplasm seemed to be essential for the stimulatory effect of platelet-derived growth factor and A23187 on hexose transport. Epidermal growth factor and insulin also stimulated hexose transport activity regardless of the absence of protein kinase C. However, in the case of epidermal growth factor, intracellular Ca2+, but not extracellular Ca2+, was found to be necessary for the stimulation. On the other hand, insulin stimulated the hexose transport independent of both intra- and extracellular Ca2+.
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PMID:Effect of protein kinase C activation and Ca2+ mobilization on hexose transport in Swiss 3T3 cells. 308 30

Cell cultures derived from human neonatal foreskins (HF cells) are susceptible to phorbol-12,13-didecanoate- (PDD) induced inhibition of queuine uptake, but this inhibition is pronounced only in early passage HF cells. The present analysis of five different primary cultures demonstrated that, between 10 and 30 population doublings beyond the primary cultures, HF cells gradually became refractile to PDD-induced inhibition of queuine uptake, after which PDD begins to stimulate queuine uptake. Treating late passage HF cells with conditioned medium from early passage HF cells partially restored the PDD-induced inhibition of queuine uptake. This indicates the existence of a factor produced by early passage HF cells that permits PDD to inhibit queuine uptake. The tumor promoter, teleocidin, mimics the effects of PDD on queuine uptake. Both PDD and teleocidin are known to activate protein kinase C; therefore, this kinase may be an intermediary in tumor promoter-induced effects on queuine uptake. Epidermal growth factor, platelet-derived growth factor, and transforming growth factor beta stimulated queuine uptake in both early and late passage HF cells. Growth factor stimulation of uptake was enhanced by PDD in late passage cells but inhibited by PDD in early passage cells. Polyinosinic polycytidylic acid treatment of late passage HF cells partially restored PDD-induced inhibition of queuine uptake. Human recombinant beta-interferon, plus or minus PDD, had no effect on queuine uptake. PDD did not inhibit queuine uptake in the immortal human and non-human cell lines examined.
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PMID:Inhibition of queuine uptake in diploid human fibroblasts by phorbol-12,13-didecanoate. Requirement for a factor derived from early passage cells. 309 76

The link between the biochemical and morphological differentiation of granulosa cells was studied by investigating the organization and the expression of cytoskeletal proteins which determine cell shape and contacts. In cells treated with follicle-stimulating hormone (FSH), in a serum- and growth factor-free medium, or with other compounds which elevate cellular cAMP levels, the synthesis of the adherens junction proteins, vinculin, alpha-actinin, and actin was reduced significantly when compared to unstimulated cells (7-fold for vinculin, 5-fold for alpha-actinin, and 3-fold for actin). The in vitro translatability of the mRNAs coding for these proteins and the level of actin mRNA determined by RNA blot hybridization were generally reduced in differentiating cells. The synthesis and the organization of vimentin and tubulin was unaffected during this process, whereas the organization of actin and vinculin was dramatically affected, with FSH-treated cells displaying a diffuse pattern of actin and vinculin, with very little vinculin in adhesion plaques. Gonadotropin-releasing hormone agonist and the phorbol ester 12-O-tetradecanoylphorbol-13-acetate which are known to antagonize the cAMP-mediated biochemical differentiation of granulosa cells by reducing cAMP levels or by activating protein kinase C and phospholipid turnover, blocked to a large extent the FSH-induced effect on the adherens junction proteins. Epidermal growth factor, which blocked the FSH-induced cAMP increase, but not the FSH-induced progesterone production, failed to block the synthesis of vinculin, alpha-actinin, and actin. Cytochalasin B could induce steroidogenesis and similar changes in the synthesis of these cytoskeletal proteins, whereas fibronectin, which causes cell spreading, blocked in part the FSH-induced effect on the expression of cytoskeletal proteins. The modulation of cytoskeletal proteins may therefore be an essential feature of programmed differentiation events leading to the final phenotype of granulosa cells.
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PMID:In vitro regulation of granulosa cell differentiation. Involvement of cytoskeletal protein expression. 310 32

Epidermal growth factor (EGF) binds with high affinity and specificity to a single site on the external domain of its transmembrane receptor to activate the tyrosine protein kinase activity of its cytoplasmic portion. The EGF receptor gene is amplified and over-expressed in several human tumors, suggesting that increased concentrations of the proto-oncogene leads to constitutive activity similar to that seen with oncogene erb B. Synthesis and degradation of the EGF receptor are regulated, in addition, covalent modification by phosphorylation regulates activity of the receptor protein. Intramolecular self-phosphorylation of Tyr1173 removes a competitive inhibitory constraint to enhance phosphorylation of substrates. Phosphorylation of Thr654 by protein kinase C decreases high affinity EGF binding and EGF-stimulated tyrosine protein kinase activity, providing a mechanism for heterologous regulation of the EGF receptor by tumor promoters and other ligand X receptor complexes. Extensive regulation contributes to normal growth control, abrogation of regulatory controls contributes to uncontrolled growth as seen with erb B transformation and EGF receptor gene amplification in human tumors.
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PMID:Epidermal growth factor and its receptor. 310 78

Inhibin production by cultured granulosa cells from immature diethylstilbestrol (DES)-primed rats was studied in relation to estradiol and progesterone production. The inhibin content in culture media was assayed with a specific radioimmunoassay (RIA) using an antibody to porcine 32 kDa inhibin that recognizes rat inhibin as well. Inhibin production was about 10 ng/ml/2 X 10(4) cells/72 h at the basal levels and was maximally stimulated with 25 ng/ml of follicle stimulating hormone (FSH) to 45 ng/ml which was 4.5 times the basal levels, with an ED50 value of 2.0 ng/ml. A cyclic AMP analog (dibutyryl cyclic AMP) or reagents that promote cAMP production were also effective in inhibin production, indicating that FSH stimulates inhibin production through a cAMP-dependent pathway. Luteinizing hormone (LH) was not effective in producing inhibin from freshly prepared granulosa cells, whereas granulosa cells pre-incubated with FSH for 48 h because responsive to LH regarding inhibin production. Testosterone sensitized the granulosa cells to the FSH stimulation, whereas hydrocortisone (4 ng/ml) decreased the sensitivity of granulosa cells by increasing the ED50 value for inhibin production by FSH about 10 times. A similar effect was observed regarding estradiol production, while progesterone production due to stimulation by FSH was enhanced by the hydrocortisone treatment. Insulin and platelet extract both stimulated inhibin production and enhanced the maximal response of inhibin production due to stimulation by FSH without altering, or even increasing the ED50 values. Epidermal growth factor (EGF), (D-Leu6)Des-Gly10-LHRH N-ethylamide (GnRH agonist) and 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent protein kinase C activator, inhibited both inhibin production and estradiol or progesterone production. Consequently, the regulation of inhibin production was similar to that of estradiol production, but markedly different from that of progesterone. However, inhibin and estradiol production were modulated differently by various growth factors and hormones. These phenomena might account for possible discrete changes in the plasma levels of inhibin and estradiol in vivo.
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PMID:Regulation of inhibin production by rat granulosa cells. 312 10

Epidermal growth factor (EGF) is produced in large quantities by the kidney. We identified EGF-binding sites on cultured rat renal glomerular mesangial cells. These cells serve as a model system for the investigation of renal prostaglandin biosynthesis. Since EGF has been shown to modulate phospholipase activity in other cell lines, we studied the ability of EGF to increase arachidonate release and prostaglandin E2 (PGE2) production in mesangial cells. We found that EGF stimulated arachidonate release and PGE2 production in the presence of the Ca2+ ionophore A23187. This stimulation was markedly potentiated by the addition of phorbol myristate acetate (PMA), which activates protein kinase C. However, down-regulation of protein kinase C by prolonged PMA treatment did not block the ability of EGF to stimulate PGE2 production in the presence of A23187. EGF also markedly potentiated the stimulation of PGE2 production by vasopressin, which increases intracellular Ca2+ and activates protein kinase C in these cells. The stimulatory effects of EGF were not the result of prolongation or enhancement of an increase in intracellular Ca2+ produced by ionophore or vasopressin. Furthermore, the synergistic interaction of EGF with PMA and vasopressin occurred despite the fact that these agents markedly decreased EGF binding in mesangial cells, presumably owing to protein-kinase-C-mediated phosphorylation of the EGF receptor. We conclude that there exists a distinct pathway for EGF-stimulated arachidonate release and PGE2 production in rat renal glomerular mesangial cells, which is synergistic with, but not dependent on, activation of protein kinase C. In contrast with long-term mitogenic responses to EGF, this rapid response may allow delineation of the membrane phospholipid changes and signalling steps involved in this aspect of EGF action.
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PMID:Epidermal growth factor is synergistic with phorbol esters and vasopressin in stimulating arachidonate release and prostaglandin production in renal glomerular mesangial cells. 312 30

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

Epidermal growth factor (EGF) and transforming growth factor alpha bind to a common receptor at the cell surface. Both the affinity and the tyrosine protein kinase activity of the receptor are regulated by exogenous factors, such as platelet-derived growth factor. A protein kinase C-dependent (Ca2+/phospholipid-dependent enzyme) and independent regulatory mechanism have been described. The protein kinase C-dependent mechanism results in the inhibition of the affinity and tyrosine kinase activity of the EGF receptor. We describe in this report an alternative mechanism of regulation of the receptor that is mediated by sphingosine. Treatment of WI-38 human fetal lung fibroblasts with 5 microM sphingosine for 2 min at 37 degrees C caused a marked increase in the affinity of the EGF receptor. Similar results were obtained when isolated plasma membranes prepared from these cells were incubated with sphingosine. A stimulation of the EGF receptor tyrosine protein kinase activity was also observed after sphingosine-treatment of plasma membranes. Sphingosine caused a decrease in the Km for ATP and an increase in the Vmax for the tyrosine phosphorylation of a synthetic peptide substrate. Control experiments demonstrated that these actions of sphingosine were not secondary to the inhibition of protein kinase C. These data indicate that sphingosine causes the functional conversion of the EGF receptor into an activated state that expresses both a high affinity for EGF and an increased tyrosine kinase activity. We conclude that sphingosine is a bioactive molecule in human fibroblasts.
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PMID:Two alternative mechanisms control the interconversion of functional states of the epidermal growth factor receptor. 325 97


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