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)

The evolution of a fully malignant tumor is a multistep process resulting from the action of multiple factors, both environmental and endogenous, and involves alterations in the function of multiple cellular genes. Chemical carcinogens that initiate this process appear to do so by damaging cellular DNA. In addition to producing simple point mutations, this damage appears to induce the synthesis of a transacting factor that can induce asynchronous DNA replication. This response may result in gene amplification and/or gene rearrangement. This phenomenon may also play a role in synergistic interactions between chemicals and viruses in the causation of certain cancers. The primary target of the tumor promoters TPA, teleocidin, and aplysiatoxin appears to be cell membranes. All three of these agents act, at least in part by, enhancing the activity of the phospholipid-dependent enzyme PKC. We have proposed a stereochemical model to explain the interaction of these amphiphilic compounds with the PKC system. We have found that TPA and teleocidin markedly enhance the transformation of C3H10T1/2 mouse fibroblasts when these cells are transfected with the cloned H-ras human bladder cancer oncogene. Thus, tumor promoters can act synergistically with an activated oncogene to enhance cell transformation. Furthermore, carcinogen-transformed rodent cells display aberrations in the expression of various endogenous retrovirus-related sequences. Activation of some of these sequences may lead to insertion mutations and further aberrations in gene expression. These findings are discussed in terms of a multistep model that involves progressive changes in cellular oncogenes and aberrations in the function of DNA transcription enhancer sequences. It will be of interest to determine to what extent these concepts apply to the etiology of cancers of the respiratory tract.
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PMID:Mechanisms of multistage chemical carcinogenesis and their relevance to respiratory tract cancer. 315 53

Microinjection of purified protein kinase C (PKC) into Swiss 3T3 fibroblasts pretreated with the phorbol ester phorbol-12,13-dibutyrate restores the mitogenic response of the cells to phorbol-12,13-dibutyrate (G. Pasti, J.C. Lacal, B.S. Warren, S.A. Aaronson, and P.M. Blumberg, Nature [London] 324:375-377, 1986). Our present studies demonstrate that the mitogenic activity of the H-ras oncogene in H-ras p21-microinjected quiescent cells is markedly reduced under conditions in which PKC is downregulated by chronic phorbol ester treatment. The ability to reconstitute the mitogenic response upon microinjection of both H-ras p21 and PKC implies involvement of functional PKC in the mitogenic activity of the H-ras oncogene product.
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PMID:Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product. 332 89

2,3,7,8,-Tetrachlorodibenzo-p-dioxin (TCDD) administered in vivo causes drastic reduction in the weight of the mouse thymus at low doses (e.g., 30 micrograms/kg single i.p. injection), the reduction becoming statistically significant after 2 days. To understand the cause for such thymic involution TCDD-evoked changes in various biochemical parameters in this tissue were examined. The most noticeable change was observed in the increased activity of specific protein-tyrosine kinases and protein kinase C and an increased level of p21ras-associated binding of [3H]GTP. Since no significant change was observed with cAMP-stimulated protein kinases and cAMP levels, the above changes appear to be a selective effect on these special classes of proteins. As a result of a time sequence study it has become apparent that the rise in protein-tyrosine kinase activities becomes significant within 24 hr, whereas the rise in protein kinase C does not become significant until 48 hr. Among protein-tyrosine kinases, pp60c-src and probably pp561skT were found to be significantly elevated by TCDD treatment. In view of similarities between TCDD and thyroid hormones in causing thymic involution, the levels of c-erb-A expression were assessed in the liver by using avian 32P-labeled v-erb-A probe and RNA transfer blot hybridization technique. The results clearly indicate that TCDD has the property to elevate levels of mRNA bearing homology to v-erb-A. Such changes in c-erb-A expression and protein-tyrosine kinase occurred only in TCDD-susceptible (responsive) strains but not in tolerant (nonresponsive) strains of mice at the dose tested. Based on such observations a hypothesis has been proposed that TCDD owes its potency to its ability to stimulate the expression of one of a family of DNAs bearing homology to v-erb-A and that one of the major consequences of such an action is stimulation of various tyrosine kinases.
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PMID:2,3,7,8-Tetrachlorodibenzo-p-dioxin causes increases in expression of c-erb-A and levels of protein-tyrosine kinases in selected tissues of responsive mouse strains. 338 Jul 84

The evolution of a fully malignant tumor is a multistep process resulting from the action of multiple factors, both environmental and endogenous, and involves alterations in the function of multiple cellular genes. Chemical carcinogens that initiate this process appear to do so by damaging cellular DNA. In addition to producing simple point mutations, this damage appears to induce the synthesis of a trans acting factor that can induce asynchronous DNA replication. This response may result in gene amplification and/or gene rearrangement. This phenomenon may also play a role in synergistic interactions between chemicals and viruses in the causation of certain cancers. The primary target of the tumor promoters TPA, teleocidin, and aplysiatoxin appears to be the cell membrane. All three of these agents act, at least in part, by enhancing the activity of the phospholipid-dependent enzyme protein kinase C. We have proposed a stereochemical model to explain the interaction of these amphiphilic compounds with the PKC system. We have found that TPA and teleocidin markedly enhance the transformation of C3H 10T1/2 mouse fibroblasts when these cells are transfected with the cloned H-ras human bladder cancer oncogene. Thus, tumor promoters can act synergistically with an activated oncogene to enhance cell transformation. Furthermore, carcinogen-transformed rodent cells display aberrations in the expression of various endogenous retrovirus-related sequences. Activation of some of these sequences may lead to insertion mutations and further aberrations in gene expression. Thus, multistage carcinogenesis may involve both changes in cellular oncogenes and aberrations in the function of DNA sequences that control gene transcription.
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PMID:Cell culture studies on the mechanism of action of chemical carcinogens and tumor promoters. 406 3

Normal and activated Ras proteins are known to act as signal transducers, mediating mitogenic responses. Interactions of p21ras and protein kinase C (PKC) are required in a number of mitogenic or activation signaling pathways. The constitutive expression of activated v-Haras in Jurkat cells, a human T lymphoblastoid cell line, renders the cells susceptible to apoptosis during transient down-regulation or inhibition of PKC. Similarly, the expression of v-Ki-ras in murine fibroblasts induces apoptosis during suppression of PKC activity. This Ras-specific cell death is dependent upon suppression of cellular PKC activity, and can be blocked by the survival-promoting bcl-2 gene product. In vivo phosphorylation studies indicate that Bcl-2 is a phosphoprotein, and the phosphorylation state of Bcl-2 is modulated in the setting of activated p21Ha-ras in response to inhibition of PKC. These findings suggest an interactive regulation of growth or apoptosis in cells which involves at least three molecules: p21ras, PKC and Bcl-2.
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PMID:Direction of p21ras-generated signals towards cell growth or apoptosis is determined by protein kinase C and Bcl-2. 747 73

Ribonucleotide reductase is a highly regulated activity responsible for reducing ribonucleotides to deoxyribonucleotides, which are required for DNA synthesis and DNA repair. We have tested the hypothesis that malignant cell populations contain alterations in signal pathways important in controlling the expression of the two genes that code for ribonucleotide reductase, R1 and R2. A series of radiation and H-ras transformed mouse 10T1/2 cell lines with increasing malignant potential were exposed to stimulators of cAMP synthesis (forskolin and cholera toxin), an inhibitor of cAMP degradation (3-isobutyl-1-methylxanthine) and a biologically stable analogue of cAMP (8-bromo-cAMP). Dramatic elevations in the expression of the R1 and R2 genes at the message and protein levels were observed in malignant metastatic populations, which were not detected in the normal parental cell line or in cells capable of benign tumor formation. These changes in ribonucleotide reductase gene expression occurred without any detectable modifications in the rates of DNA synthesis, showing that they were regulated by a novel mechanism independent of the S phase of the cell cycle. Furthermore, studies with forskolin (a stimulator of the protein kinase A signal pathway) and the tumor promoter 12-0-tetradecanoylphorbol-13-acetate (a stimulator of the protein kinase C signal pathway), alone or in combination, indicated that their effects on R1 and R2 gene expression in a highly malignant cell line were greater than when they were tested individually, suggesting that the two pathways modulating R1 and R2 gene expression can cooperate to regulate ribonucleotide reduction, and interestingly this can occur in a synergistic fashion. Also, a direct relationship between H-ras expression and ribonucleotide reductase gene expression was observed; analysis of forskolin mediated elevations in R1 and R2 message levels closely correlated with the levels of H-ras expression in the various cell lines. In total, these studies demonstrate that ribonucleotide reductase expression is controlled by a complex process, and malignant ras transformed cells contain alterations in the regulation of signal transduction pathways that lead to novel modifications in ribonucleotide reductase gene expression. This signal mechanism, which is aberrantly regulated in malignant cells, may be related to regulatory pathways involved in determining ribonucleotide reductase expression in a S phase independent manner during periods of DNA repair.
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PMID:Alterations in the cyclic AMP signal transduction pathway regulating ribonucleotide reductase gene expression in malignant H-ras transformed cell lines. 750 77

Several signalling transduction modulators were used to examine their effects on the morphological changes, foci formation in soft agar and cellular growth in v-H-ras-transformed NIH 3T3 cells. The results from this study showed that specific tyrosine kinase inhibitors (genistein and tyrphostin 23) and cyclic AMP-elevating agents (forskolin and 3-isobutyl-1-methyl-xanthine) could effectively induce differential flat phenotype of v-H-ras transformant at micromolar concentrations. At the same dose range, both signalling modulators also caused a significant suppression of anchorage-independent and cellular growth in the same transformant. By contrast, compound inhibitors such as protein kinase C (staurosporin and H-7), phospholipase A2 (aristolochic acid), phospholipase C (neomycin sulfate) and cyclooxygenase (indomethacin) all did not alter the cellular morphology or foci formation in soft agar, although PKC inhibitors exhibited a slight inhibition on the cellular growth. Based on these observations, we propose that the alterations of protein kinase A or tyrosine kinase-associated signal pathways is necessary and the original cause of the transformation event, but that increase of the activities of protein kinase C, phospholipase C, phospholipase A2 or cyclooxygenase probably is an indirect result of the v-H-ras-mediated transformation.
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PMID:Effects of signalling transduction modulators on the transformed phenotypes in v-H-ras-transformed NIH 3T3 cells. 751 7

Growth factor receptor-binding protein-2 (GRB2) couples growth factor receptor activation to the p21ras nucleotide exchange factor son-of-sevenless (SOS). Son-of-sevenless can serve as a substrate for mitogen-activated protein kinases and may be subject to feed back regulation in mitogen-stimulated cells. Herein, we demonstrate phosphorylation on GRB2 in rat A10 vascular smooth muscle cells exposed to platelet-derived growth factor (PDGF). Lysates from smooth cells stimulated with PDGF revealed a shift in the electrophoretic mobility of GRB2. Further investigation confirmed that phosphorylation on GRB2 accompanied this mobility shift. Phosphorylation on GRB2 was time-dependent and correlated with PDGF receptor activation. The time-course for phosphorylation of GRB2 and subsequent decay corresponded with other events characteristic of platelet-derived growth factor signaling. GRB2 was not phosphorylated in cells treated with phorbol 12-myristate 13-acetate, and down-regulation of protein kinase C failed to attenuate phosphorylation on GRB2 in response to growth factor. Analysis of GRB2 immune complexes revealed a kinase activity capable of phosphorylating GRB2 in vitro and demonstrated that the kinase activated in response to PDGF may physically associate with GRB2 signaling complexes.
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PMID:Platelet-derived growth factor stimulates phosphorylation of growth factor receptor-binding protein-2 in vascular smooth muscle cells. 752 85

The role of ras on protein kinase C (PKC) signaling was examined in two keratinocyte cell lines. Increasing the level of extracellular calcium from 0.15 mM to 1.0 mM induces some features of differentiation in the spontaneously immortalized HaCaT line, but fails to do so in a c-H-ras-transfected subline (ras-HaCaT). Raising extracellular calcium also induced a transient increase in membrane-associated PKC activity 5 min after calcium addition, in HaCaT, but not in the ras-HaCaT cells. Partial purification of PKC from the membrane/particulate fraction revealed the major isoform expressed in HaCaT to be an 80 KD species recognized by the anti-PKC alpha antibody. In ras-HaCaT, the major expressed isoform is a 130 KD species recognized by the PKC beta antibody. The kinase activity of the partially purified high molecular weight PKC is phospholipid dependent but calcium independent. Further evaluation of PKC in the HaCaT and ras-HaCaT membrane/particulate cell fraction by immunoblotting using affinity-purified antibodies against PKC alpha, beta, delta, epsilon and zeta revealed a 130 KD band reacting with the PKC delta antibody. Increased expression of this high molecular weight protein was observed in ras-HaCaT. Immunoprecipitation of PKC in ras-HaCaT using the PKC delta antibody also revealed a 130 KD species. Analysis of the PKC delta immunoprecipitate demonstrated a phospholipid, but not calcium-dependent kinase which autophosphorylated. These results suggest that the 130 KD protein may be a novel (calcium-independent) PKC (nPKC) isoform and increased expression in the ras-transfected HaCaT may be a consequence of oncogenic ras expression. This 130 KD species may also play a role in the ras-associated inhibition of differentiation in HaCaT.
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PMID:Increased expression of a high molecular weight (130 KD) protein kinase C isoform in a differentiation-defective ras-transfected keratinocyte line. 754 54

Protein phosphorylation has evolved as the most versatile posttranslational modification widely used by cells. Signal transduction pathways mediated by activation of MAP kinases and protein kinase C trigger the exit of cells from the quiscence (Go-->G1 transition). Indeed, binding of growth factors at the cell surface triggers their receptors, usually possessing a tyrosine kinase on the cytoplasmic side, to phosphorylate other molecules passing on the information sequentially to GRB2 protein, to p21ras, to c-Raf-1, to MAP kinase kinase, to MAP kinase, to p90rsk, to transcription factors. Activated PKC, MAP kinase, and pp90src can translocate to the nucleus where they phosphorylate a number of protein transcription regulators in a cell cycle-dependent manner or in response to cell stimulation for exit from quiescence. The cell cycle is mainly regulated by p34cdc2 or otherwise called cdc2 in association with cyclins B at G2/M and by Cdk2 in association with cyclins A, D1, and E at G1/S checkpoints; phosphorylation of histone H1 and lamins by cdc2 triggers chromosome assembly and nuclear envelope breakdown, respectively, as a prelude to mitosis. Cdc2 activities functioning as a G2/M regulator are controlled by its phosphorylation and dephosphorylation at Ser/Thr residues. MAP kinases might be the missing link in the chain connecting the Go to G1 transition with the cell cycle regulation, whereas phosphorylation of replication protein factors, retinoblastoma, and p53 might link the G1 to S transition with the control of DNA synthesis. A number of transcription factors are known to stimulate DNA replication, including p53, c-Myc, AP-1, Oct-1, T-antigen; the DNA binding activities of all these proteins and their interaction with other transcription factors are controlled by phosphorylation. The nuclear import of several proteins including NF kappa B, Dorsal, glucocorticoid receptor, ISGF3, rNFIL-6, T antigen, and the kinases PKC, MAP, and p90rsk, are dependent on their phosphorylation at specific sites. Histone phosphorylation stimulated at discrete stages of the cell cycle or in response to cAMP or other stimuli might induce profound changes in chromatin organization.
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PMID:Phosphorylation of transcription factors and control of the cell cycle. 754 80


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