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)

Two protein kinase-inhibitors, 6-dimethyl amino purine and 2-amino purine inhibited induction of beta-casein synthesis by prolactin when added to the culture medium of rabbit mammary explant and cells. The accumulation of the mRNA for alpha s1- and beta-caseins and for whey acidic protein did not take place in the presence of the inhibitors whereas beta-actin mRNA concentration was not altered. In the same experimental conditions, H7, an inhibitor of protein kinase C and, to a lower extent, of protein kinase A did not prevent prolactin from acting. These data suggest for the first time that specific protein kinases are involved in the transduction of the prolactin signal to milk protein genes.
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PMID:6-Dimethyl amino purine and 2-amino purine inhibit the induction of expression of milk protein genes by prolactin. 139 84

Insulin and the phorbol ester, phorbol 12-myristate 13-acetate, induce beta-actin gene transcription in H4 cells. This occurred rapidly, with a maximum 15-fold stimulation following 15 min of insulin (5 x 10(-9) M) or phorbol ester (1 microgram/ml) exposure. The increase in beta-actin transcription was transitory, returning to baseline within 120 min. Pretreatment of cells with phorbol ester for 24 h, reducing functional protein kinase C activity, abolished the ability of phorbol esters to increase beta-actin transcription. When insulin was added to phorbol ester-pretreated cells the insulin-induced increase in beta-actin transcription was reduced by 40-60%. These findings support our hypothesis that a common regulatory signal is utilized by both insulin and phorbol esters for the complete induction of specific genes.
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PMID:Regulation of beta-actin gene transcription by insulin and phorbol esters. 157 14

The bacterial neomycin phosphotransferase gene driven by the Moloney mouse leukemia virus long terminal repeat (LTR) or SV40 early region promoter was introduced into the human promonocyte-macrophage cell line, U937, and into the pluripotential human embryonic teratocarcinoma cell line, NT2/D1. Clonally derived cell lines capable of growing in 2-4 mg/ml of the aminoglycoside antibiotic, G418 (Geneticin), were established and transfected with pHIVCat, a plasmid expressing the bacterial chloramphenicol acetyl transferase (CAT) activity under the control of the human immunodeficiency virus (HIV-1) LTR. All of the G418 resistant (neo(r)) U937 cell lines and 10 of 14 neo(r) NT2/D1 cell lines exhibited reduced basal levels of CAT expression or impaired responses to activation of the HIV-1 LTR by phorbol 12-myristate 13-acetate (PMA) when compared to the parental lines. Other differences included inhibition of tat activation of the HIV-1 LTR and increased sensitivity of U937 cells to human tumor necrosis factor alpha. The expression of other eukaryotic promoters including the HTLV-1 LTR, SV40 ori sequences, and the human beta-actin gene promoter was similarly affected. However, differentiation of the neo(r) U937 cells into macrophages was neither delayed nor impaired. Because PMA is an activator of protein kinase C (PKC) and a potent inducer of HIV-1 directed gene expression, the amounts, sensitivity to G418, and cytosol to membrane translocation of this enzyme were determined in the wild type and neo(r) U937 cells. G418 at concentrations too low to affect cell growth (12-150 micrograms/ml) inhibited PMA-induced transactivation responses in wild type cells but did not inhibit PKC-dependent protein phosphorylation in vitro. PKC activities in the wild type and neo(r) cells were similar in absolute amounts and in the cytosol-membrane distribution of the enzyme. In contrast with wild type cells, however, all of the cytosolic Ca(2+)-phospholipid-dependent form of PKC disappeared from the neo(r) cells within 30 min after PMA induction. The results suggested that, depending upon the cell type, gene cotransfer using aminoglycoside resistance as a selectable marker may seriously perturb important cellular control mechanisms such as the PKC pathway leading to activation of gene expression.
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PMID:Gene activation mediated by protein kinase C in human macrophage and teratocarcinoma cells expressing aminoglycoside phosphotransferase activity. 166 Apr 86

Our previous work on protein kinase C (PKC) and colon cancer has shown altered levels of PKC activity in human colon tumors, as well as activation of PKC by colon tumor promoters such as bile acids. To understand further the role of PKC in colon carcinogenesis, we analyzed the expression of phorbin, a gene induced by PKC activation, in a series of different stages of human colon tumors. As shown by northern blot analyses of poly (A)+ RNA, higher levels of phorbin RNA were seen in 26 colon tumor samples than in their adjacent normal colonic mucosa. There also appeared to be a correlation between the abundance of phorbin RNA in the tumors and the extent of invasion (tumor-to-normal tissue phorbin RNA ratio = 4.2, 8.0, and 11.9 for Dukes' A, B, and C, respectively). Phorbin RNA was also abundant in a human colon cancer line (HT29). We also examined the expression of other mitogen-responsive genes (c-myc, ODC, and beta-actin) in a set of 19 colon tumor samples. All tumors displayed significant (mean 3.8-fold) increases in the level of c-myc RNA compared with their adjacent normal colonic mucosa. About 47% and 16% of these tumor samples also showed increased levels of ODC (mean 3.1-fold) and beta-actin (mean 1.6-fold) RNA, respectively. The increased levels of c-myc, ODC, and beta-actin RNA did not correlate with the extent of tumor invasion. Taken together, these results demonstrate that human colon tumors usually display increased levels of both phorbin and c-myc RNAs. The marked increases in phorbin RNA suggest that this could serve as a useful biomarker in studies on human colon cancer.
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PMID:Increased levels of phorbin, c-myc, and ornithine decarboxylase RNAs in human colon cancer. 169 76

The myeloid interleukin-3 (IL-3) dependent cell line, FDC-P1, enters the G0 stage of the cell cycle after IL-3 deprivation for 24 hr. The expression of 13 protooncogenes and immediate-early genes was compared with 4 "control" genes after the addition of either IL-3 or phorbol myristate acetate (PMA) to IL-3-deprived cells. mRNA transcripts encoding c-myc and the T-cell receptor c-gamma gene were induced to high levels only after IL-3 addition, whereas c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 were induced transiently only after PMA addition. The remaining genes (fra-1, p53, jun-D, c-Ha-ras, c-Ki-ras, c-raf, beta-actin, ornithine decarboxylase, and histone 2B) were detected after culture with either IL-3 or PMA. When cells were serum- and IL-3-deprived, c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 were detected after exposure to either serum or PMA. Moreover, culture with cycloheximide and PMA resulted in superinduction of these genes, whereas cycloheximide and IL-3 addition did not. mRNAs encoding these genes had half-lives of 10-20 min after PMA treatment, whereas that of beta-actin was longer (greater than 2 hr), suggesting that short mRNA half-lives contributed to the transient nature of these genes. Although c-fos, fos-B, c-jun, jun-B, Krox-20, and Krox-24 expression can be detected in IL-3-dependent cells after exposure to either PMA or serum, these genes were not detected after IL-3 addition, which allows cell-cycle progression. These results document the existence of IL-3 and PMA-responsive genes and demonstrate that IL-3 and protein kinase C agonists can induce distinct patterns of gene expression.
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PMID:Interleukin-3 and phorbol esters induce different patterns of immediate-early gene expression in an interleukin-3 dependent cell line. 170 18

Chronic exposure of differentiated avian skeletal muscle cells in culture to the phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (PMA), results in the selective disassembly of sarcomeric structures and loss of muscle-specific contractile proteins, leaving cytoskeletal structures and their associated proteins intact. We demonstrate here that these morphological and biochemical changes are accompanied by dramatic and selective decreases in the level of the mRNAs that encode the contractile proteins. We measured the effects of PMA on the transcriptional activity and mRNA stability of four contractile protein genes (alpha-cardiac and alpha-skeletal actin, cardiac troponin C [cTnC], and myosin light chain lf [MLClf]) and two nonmuscle genes (beta-cytoplasmic actin and the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase [GAPDH]). The transcriptional activity of the alpha-cardiac actin and cTnC genes dramatically decreased by 8 h after the addition of PMA, while other muscle and nonmuscle genes examined showed no change. Pulse-chase experiments of in vivo labeled RNA showed significant reductions in mRNA half-lifes for all the contractile protein mRNAs examined, while the half-lifes of beta-actin and GAPDH mRNA were unchanged. All of the above effects occurred under conditions in which cellular protein kinase C (PKC) levels had been reduced by greater than 90%. The fact that many of the contractile protein genes remained transcriptionally active despite the fact that the cells were unable to accumulate their mRNAs to any significant extent indicated that the treated cells were still committed to skeletal muscle differentiation. The selective changes in the stability of the contractile protein mRNAs suggest that the control of mRNA stability may be part of the normal regulatory program of skeletal muscle differentiation and that this control may be linked to the integrity of the contractile apparatus and mediated by second messenger pathways involving PKC activation.
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PMID:Phorbol esters selectively downregulate contractile protein gene expression in terminally differentiated myotubes through transcriptional repression and message destabilization. 171 91

We have examined the effect of prolactin (PRL) on growth-related gene expression, protein kinase C (PKC) activity and diacylglycerol (DAG) mass in rat liver. Hepatic levels of messenger (m)RNA for c-myc, ornithine decarboxylase (ODC) and beta-actin increased in a dose-dependent manner within 1 h after PRL administration. Prolactin also caused a transient elevation of liver DAG levels and particulate-associated PKC activity. The PRL-provoked increases in DAG mass and particulate PKC activity were coincident and maximal at 20 min and began declining toward control levels by 30 min. These results suggest a temporal relationship between PRL-stimulated DAG accumulation and PKC activation. Furthermore, the subsequent rapid induction of growth-related gene expression provides new information on the role of PRL as a hepatic mitogen.
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PMID:Prolactin activates protein kinase C and stimulates growth-related gene expression in rat liver. 171 97

Phospholipase C activity is necessary for transcriptional c-fos activation by providing diacylglycerol as an activator of protein kinase C. We found that transcriptional activation of c-fos and the phosphorylation of its major transcription factor were inhibited by tricyclodecan-9-yl xanthogenate, which blocks phospholipase C-type reactions. Transcription of the c-ras and beta-actin genes in the same cells remained unaffected.
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PMID:Inhibition of c-fos transcription and phosphorylation of the serum response factor by an inhibitor of phospholipase C-type reactions. 216 25

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) regulates the expression of c-myc protooncogene in HL-60 promyelocytic leukemia cells (Reitzma, P. H., Rothberg, P. G., Astrin, S. M., Trial, J., Barshavit, Z., Hall, A., Teitelbaum, S. U., and Kahn, A. J. (1983) Nature 306, 492-494). The regulation of c-myc expression occurs at least in part at the transcriptional level (Simpson, R. U., Hsu, T., Begley, D. A., Mitchell, B. S., and Alizadeh, B. N. (1987) J. Biol. Chem. 262, 4104-4108). Also, 1,25-(OH)2D3 stimulates an increase in protein kinase C (PKC) levels and inhibitors of PKC block 1,25-(OH)2D3-induced differentiation of HL-60 cells (Martell, R. E., Simpson, R. U., and Taylor, J. M. (1987) J. Biol. Chem. 262, 5570-5575). In this report we demonstrated that sphinganine, an inhibitor of PKC that is mechanistically and structurally distinct from 1-(5-isoquinoline sulfonyl)-2-methylpiperazine-HCl (H-7), also blocks 1,25-(OH)2D3 induction of HL-60 cell differentiation. The effect of inhibitors of PKC on 1,25-(OH)2D3 regulation of c-myc transcription was examined. H-7 (18 microM) and sphinganine (3 and 6 microM) blunted 1,25-(OH)2D3-induced reduction of c-myc transcription as assessed by nuclear run-off assays. We showed that c-myc/beta-actin ratios (cpm/cpm, % of control mean +/- S.E.) were as follows: ethanol control, 100 +/- 14%; 50 nM 1,25-(OH)2D3, 17 +/- 5%; 50 nM 1,25-(OH)2D3 and 6 microM H-7, 13 +/- 6%; 50 nM 1,25-(OH)2D3 and 18 microM H-7, 53 +/- 6% 50 nM 1,25-(OH)2D3 and 18 microM N-[2-guanidinoethyl]-5-isoquinoline sulfonamide (HA-1004), 10 +/- 8%; 50 nM 1,25-(OH)2D3 and 6 microM sphinganine, 49 +/- 8%. No significant differences in c-myc transcription between control, 18 microM H-7, 18 microM HA-1004, and 3 or 6 microM sphinganine-treated cells were observed. The block in c-myc transcription was beyond exon 1, and regulation of exon 1 transcription by 1,25-(OH)2D3 was not detected. Furthermore, we demonstrated that expression of markers for HL-60 cell differentiation was more rapidly induced by 25 nM 12-O-tetradecanoylphorbol-13-acetate than 50 nM 1,25-(OH)2D3, suggesting that direct activation of PKC by phorbol esters may make processes required for 1,25-(OH)2D3 induction of differentiation unnecessary. In summary, these data suggest that a primary effect of 1,25-(OH)2D3 on HL-60 cells is to regulate PKC levels, and regulation of c-myc transcription by 1,25-(OH)2D3 is a result of this action.
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PMID:1,25-Dihydroxyvitamin D3 regulation of c-myc protooncogene transcription. Possible involvement of protein kinase C. 268 61

The components of the renin-angiotensin system have been colocalized in many tissues suggesting that local generation of angiotensin II can regulate blood flow in specific organs or tissues. This in combination with the fact that proliferating tissues require angiogenesis and increased blood flow to develop have led us to study the relationship of angiotensinogen mRNA production to cell cycle regulation. Reuber H35 (H4IIE) cells were growth-arrested by serum deprivation. Cells were then treated with 10% fetal calf serum, depleted serum, or insulin. Insulin and serum were equally potent at increasing beta-actin mRNA levels, depressing angiotensinogen mRNA levels, and in increasing [3H]methyl thymidine incorporation. The half-maximal insulin effect occurred at 5 x 10(-9) M. Insulin-like growth factor I and II had no effect on any of the parameters measured. 12-O-tetradecanoyl phorbol 13-acetate (TPA) also induced beta-actin mRNA, decreased angiotensinogen mRNA, and caused an increase in [3H]methyl thymidine incorporation. The TPA effects were of shorter duration and of lower magnitude than those caused by insulin or serum. Inactivation of protein kinase C by preincubation with TPA did not block the insulin response. TPA has been shown to induce angiogenesis in vitro. Thus, these studies suggest that inhibition of angiotensinogen gene activity may be part of the proliferative or angiogenic process. Our experimental data may provide a model for further experimental dissection of the biochemical steps involved in angiogenesis.
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PMID:Angiotensinogen mRNA. Regulation by cell cycle and growth factors. 328 43


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