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)

In human breast carcinoma MCF-7 cells, phorbol diesters inhibit proliferation and induce cell maturation. We have recently reported that exogenous TGF-beta 1 reverses the resistance of a breast adenocarcinoma MCF-7 subline (MCF-7:RPh-4) to these phorbol ester effects. Here, we investigated the involvement of TGF-beta 1 in the PKC-mediated inhibition of breast-cancer cell proliferation. Parental MCF-7-conditioned medium contained a 20-fold higher transforming activity on NRK-49F fibroblasts than the TPA-resistant subline. TPA increased TGF-beta activity in MCF-7 conditioned medium. MCF-7 cells also expressed more TGF-beta 1 mRNA than the resistant subline. TPA induced a dose-dependent increase in TGF-beta 1 mRNA levels that paralleled the inhibitory effect on MCF-7 proliferation. The lower level of TGF-beta mRNA expression in TPA resistant subline was not modified after addition of TPA, but was significantly increased in the presence of exogenous TGF-beta 1. These data argue in favor of a role of endogenous TGF-beta 1 in the maturation process induced by protein kinase C activation.
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PMID:Antiproliferative effect of phorbol esters on MCF-7 human breast adenocarcinoma cells: relationship with enhanced expression of transforming growth-factor-beta 1. 139 Aug 99

A single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse skin decreased 125I-labeled epidermal growth factor (EGF) binding in epidermal membrane preparations within 1 h while 1,8-dihydroxy-3-methyl-9-anthrone (chrysarobin) gradually reduced binding with maximum inhibition at 15 h. Subsequently, 125I-EGF binding increased to approximately 200% of control in epidermal membrane preparations from both TPA- and chrysarobin-treated mice. A single application of TPA but not chrysarobin resulted in a rapid translocation of protein kinase C (PKC) to the membrane; however, treatment with both promoters ultimately led to a time-dependent loss of PKC activity in both membrane and cytosol fractions. The initial inhibition of 125I-EGF binding was sustained for at least 24 h after single and multiple treatments with both promoting agents. Acid washing restored EGF binding to control levels in membrane preparations obtained 24 h after a single application, whereas acid washing of membrane preparations obtained 24 h after a second application of TPA or chrysarobin increased binding (2.5-fold and 1.5-fold that of the control, respectively). The presence of increased amounts of ligands for the EGF receptor in tumor promoter-treated epidermis was initially confirmed in 125I-EGF binding competition experiments using NRK-49F cells. A single topical application of TPA or chrysarobin induced elevated levels of transforming growth factor-alpha (TGF-alpha) mRNA at 6 h or 15-24 h, respectively. Elevated levels of a TGF-alpha precursor (21 kDa) were subsequently observed in cytosol and membrane preparations after single and multiple applications of TPA or chrysarobin. These results suggest that repeated topical application of tumor promoters may lead to sustained loss of a negative-feedback mechanism involving phosphorylation at Thr-654 of the EGF receptor by PKC. The concomitant elevation of ligands, such as TGF-alpha, may provide a mechanism for sustained cell proliferation essential for skin tumor promotion.
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PMID:Evidence for autocrine/paracrine growth stimulation by transforming growth factor-alpha during the process of skin tumor promotion. 200 35

The viral src protein kinase, pp60v-src, is a powerful intracellular mitogen which can initiate and maintain the proliferation of quiescent cells in the absence of any exogenous growth factors. In an attempt to understand how pp60v-src induces proliferation, we examined the early events in the G0 to G1 transition caused by the activation of a thermolabile v-src protein in quiescent, serum-starved tsRSV-transformed NRK cells. The reactivation of pp60v-src, in the absence of exogenous growth factors, triggered a rapid biphasic surge of membrane-associated protein kinase C (PKC) activity. Unlike TPA-stimulated PKC activity, the pp60v-src-induced increase in PKC was readily extracted from membranes by EGTA. The down-regulation of PKC activity in these quiescent cells by prolonged exposure to TPA strongly inhibited the ability of the reactivated v-src protein to stimulate DNA replication in serum-deficient medium, suggesting that PKC plays a role in the initial signal by which the viral enzyme induces the G0 to G1 transition in NRK cells.
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PMID:Membrane protein kinase C activity rapidly increases in quiescent tsRSV-infected NRK cells upon reactivation of the mitogenic v-src protein kinase. 208 Oct 97

Protein kinases are known to undergo phosphorylation to regulate their activity. To determine whether the protein kinase activity of p37v-mos was similarly regulated, we investigated the influence of two well known protein kinases, namely protein kinase C and protein kinase A, on the activity of p37v-mos in vivo. NIH3T3 cells chronically transformed with Moloney murine sarcoma virus 124 were treated with high concentrations (200-400 nM) of phorbol 12-myristate 13-acetate (PMA) for 24-48 h, concentrations known to result in the total loss of protein kinase C by causing its translocation from the cytosol to cell membranes where it is downregulated. PMA treatment caused a drastic decrease in the protein kinase activity of p37v-mos without affecting its steady state level. Similar results were obtained with p85gag-mos expressed in ts110 Mo-MuSV transformed NRK cells. Control treatment with an inactive analogue of PMA, 4-alpha phorbol 12,13-didecanoate, had no effect on the p37v-mos protein kinase activity. Treatment of cells with a direct chemical inhibitor of protein kinase C, H-7 (1-(5-isoquinoline sulfonyl)-2-methylpiperazine dihydrochloride), approximately halved p37v-mos kinase activity, although the drug did not inhibit p37v-mos kinase activity directly in vitro. In contrast to the PMA effect, in vivo activation of protein kinase A by 8-(4-chlorophenylthio)-adenosine 3',5' cyclic monophosphate did not affect p37v-mos protein kinase activity levels. These findings indicate that the protein kinase C pathway but not the protein kinase A pathway modulates v-mos protein kinase activity.
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PMID:Evidence for involvement of the protein kinase C pathway in the activation of p37v-mos protein kinase. 216 30

Activated oncogenic ras proteins are powerful mitogenic agents which by themselves can initiate and maintain the proliferation of quiescent cells in the absence of any exogenous growth factors. In an attempt to understand how ras proteins induce proliferation we examined the early events in the G0 to G1 transition caused by the activation of a thermolabile K-ras protein in quiescent, serum-starved tsKSV-transformed NRK cells. We show that ras reactivation, in the absence of exogenous growth factors, triggered a rapid surge in free cytosolic Ca2+ and diacylglycerol production, which led to a transient increase in membrane-associated protein kinase C (PKC) activity which was necessary for G1 transit. Unlike TPA-stimulated PKC activity, the ras-induced increase in PKC was readily extracted from membranes by EGTA. These signal transducing events occurred despite the fact that ras activation did not induce the tyrosine phosphorylation of any known surface receptor. The results indicate that the K-ras protein triggers the G0 to G1 transition by an intracellular mechanism and not indirectly via autocrine stimulation.
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PMID:The role of signal-transducing events in the proliferative response of cells to a mitogenic viral K-ras protein. 220 64

The protein kinase C stimulator TPA (12-O-tetradecanoyl phorbol-13-acetate) enhanced the responsiveness of adenylate cyclase to IPR (isoproterenol) and PGE1 (prostaglandin E1) in quiescent tsKSV-NRK cells at the nonpermissive 41 degrees C. Reactivating the thermolabile mitogenic/oncogenic K-ras protein in tsKSV-NRK cells by dropping the temperature to 36 degrees C also enhanced the responsiveness of adenylate cyclase to IPR and PGE1. The enhancement was transient and peaked at 6 hours after the temperature shift. This enhanced responsiveness was specifically due to the reactivated viral K-ras protein rather than the temperature shift because the same temperature shift did not affect adenylate cyclase responsiveness in uninfected NRK cells, nor was it a result of the mitogenic stimulus since reacting the mitogenic pp60v-src protein in tsASV-NRK cells did not affect adenylate cyclase responsiveness. The increased responsiveness of adenylate cyclase at 6 hours after the temperature shift was not a result of elevated membrane-associated PKC activity. However, the reactivated viral K-ras protein strongly increased the stimulability of membrane-associated PKC by TPA and it further increased TPA's ability to enhance the responsiveness of adenylate cyclase to IPR and PGE1. Thus, a viral K-ras protein and membrane-associated protein kinase C can cooperate to increase the responsiveness of adenylate cyclase to agonists.
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PMID:Protein kinase C and a viral K-RAS protein cooperatively enhance the response of adenylate cyclase to stimulators. 255 Apr 70

The conditioned medium of Simian sarcoma virus (SSV)-transformed NRK cells contains at least two activities that down regulate the epidermal growth factor receptor. To identify these activities, we analyzed the medium for the presence of factors both related to and distinct from the v-sis oncogene product. Fractionation of the conditioned medium from SSV-transformed NRK cells by chromatography on heparin-Sepharose yielded two active fractions capable of inhibiting EGF binding. The first component, which eluted at 0.8 M NaCl, is able to induce autophosphorylation of the platelet-derived growth factor (PDGF) receptor, is a mitogen for Swiss 3T3 cells and corresponds to the PDGF B chain product of the v-sis oncogene. The second component requires 2 M NaCl for elution, is mitogenic for Swiss 3T3 cells and inhibits high affinity EGF binding through a protein kinase C-independent pathway, all properties of basic FGF. These results suggest that the conditioned medium of v-sis-transformed cells contains at least two factors that can act in an autocrine capacity, one derived from v-sis and one corresponding to basic FGF.
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PMID:Basic fibroblast-like growth factor is present in the conditioned medium of simian sarcoma virus transformed NRK cells. 255 26

Wild-type or cellular RAS proteins function at the end of the G1 phase of the cell cycle, but they cannot signal quiescent cells to start cycling. By contrast, the oncogenic or "activated" RAS proteins produced by certain mutant ras genes can start quiescent cells cycling and appear to be involved in a large fraction of human cancers. One of these "activated" RAS proteins is the temperature-sensitive viral K-RAS protein produced by tsKSV-NRK rat kidney fibroblasts. Reactivating this viral K-RAS protein in serum-starved quiescent cells by lowering the temperature from a non-permissive 41 degrees C to a permissive 36 degrees C is a powerful mitogenic signal which starts the progression of cells through the various stages of the cell cycle even in the absence of serum growth factors. This first signal is associated with transient surges of cytosolic Ca2+ and membrane-associated protein kinase C activity, but is not mediated by signals from the protein-tyrosine kinase receptors of known K-RAS-induced autocrine mitogens such as TGF alpha and PDGF. While the importance of the Ca2+ transient is uncertain, the transient surge of membrane-associated protein kinase C activity appears to be involved in the process by which the viral RAS protein triggers the G0 to G1 transition. The need for the viral K-RAS protein does not end with this first signal. The protein also operates briefly at the end of the G1 phase and then, after chromosome replication, it also stimulates events necessary for the initiation of mitosis.
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PMID:Characterization of the mitogenic signal from an oncogene ras protein. 268 32

Stimulation of prostaglandin production in C-9 rat liver cells by transforming growth factor (TGF)-alpha was synergistic with that of the tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA). TGF-alpha and TPA synergized the release of radiolabelled compounds from [3H]arachidonic acid prelabelled C-9 cells. 1-Oleoyl-2-acetyl-glycerol (OAG) and TGF-alpha also synergized prostaglandin production in the C-9 cells suggesting that the tumor promoter was mimicking the physiological activator of protein kinase C, 1,2-diacylglycerol. TGF-alpha and TPA also synergistically stimulated arachidonic acid metabolism by NRK-49F rat kidney cells. In A-549 human lung carcinoma cells, TGF-beta, but not TGF-alpha, stimulated arachidonic acid metabolism synergistically with TPA.
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PMID:The stimulation of prostaglandin production by transforming growth factor-alpha and 12-O-tetradecanoyl-phorbol-13-acetate or 1-oleoyl-2-acetyl-glycerol is synergistic. 392

We have investigated the levels of calmodulin protein and calmodulin mRNA species during proliferative activation of NRK cells. Cells activated to proliferate from quiescence started to replicate DNA at 15 h, reaching a maximum at 20 h after serum addition. The maximum of mitosis was observed at 24 h. Quiescent cells showed a calmodulin concentration of 1.5 ng/micrograms of protein. At 10 h after serum addition the amount of calmodulin started to increase, reaching values of 3.0 ng/micrograms of protein at 24 h. NRK cells expressed predominantly 3 species of calmodulin transcripts: the 1.7 kb from CaM I, the 1.4 kb from CaM II and the 2.3 kb from CaM III. The amount of all the 3 transcripts was low in quiescent cells and 10 h after activation the levels were already high, reaching a maximum around 20 h. At the latter time the amount of the 3 calmodulin mRNAs was 5-10-fold higher than in serum starved cells. Run-on experiments showed that at 20 h after activation the transcription rates of the 3 calmodulin genes were higher than in quiescent cells. The addition of protein kinase C inhibitors to the cultures blocked the increase of the calmodulin transcripts while inhibitors of protein kinase A did not have any effect. Moreover, the addition of submitogenic doses of phorbol 12-tetradecanoate induced the increase of all 3 calmodulin transcripts. These results indicate that protein kinase C regulates calmodulin expression when NRK cells are activated to proliferate.
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PMID:Protein kinase C regulates calmodulin expression in NRK cells activated to proliferate from quiescence. 771 38


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