Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Interactive regulation of gene expression by retinoic acid (RA) and adenosine monophosphate (cAMP) in mammary tumor cells was explored using Shionogi mouse mammary carcinoma cells (SC115) as a model and urokinase-type plasminogen activator (uPA) as a target gene product. Twenty-four hour treatment of SC115 cells with 100 nM RA, 1 mM 8-bromo-cAMP (BrcAMP), and 100 nM RA + 1 mM BrcAMP resulted in extracellular uPA activity increases of 1.4-fold, sevenfold, and 20-fold, respectively. These effects were dose-dependent with regard to both interacting members. Similar responses were obtained if 1 nM cholera toxin or 10 microM forskolin was used instead of the cAMP analog. Retinoids lacking the carboxylic acid function were inactive. The changes in uPA activity were accompanied by similar changes in uPA antigen concentration, as seen via Western blot analysis, and uPA mRNA abundance, as seen via Northern blot analysis. Actinomycin D, an inhibitor of RNA synthesis, blocked uPA stimulation by BrcAMP, suggesting that mRNA levels were transcriptionally regulated. The effect of BrcAMP on extracellular uPA activity was first evident at 2 h and peaked at approximately 6 h; the effect of RA alone and the synergistic response to joint treatment, however, followed a slower time course, requiring at least 12 h for initial expression and increasing gradually with time up to at least 48 h. Priming with RA for 48 h followed by extensive washing of the cells resulted in a threefold enhancement of the stimulatory effect of BrcAMP on uPA. Experiments utilizing the casein/plasminogen overlay method for the detection of uPA secretion by increased rate of uPA secretion per cell rather than to an increased fraction of uPA-secreting cells. Initial investigation of the mechanism of RA potentiation of cAMP responsiveness showed that RA did not alter cellular cAMP levels or total cAMP-dependent protein kinase A activity. Finally, the tumor promoter phorbol myristate acetate, an activator of protein kinase C, also increased SC115 cell uPA activity and synergized with RA. This raised the possibility that the enhancement of cAMP responsiveness by RA was indirectly mediated via an effect on protein kinase C. Experiments with protein kinase C-depleted cells, however, showed that this was not the case. In conclusion, RA treatment of SC115 cells potentiates the effect of cAMP on uPA expression at the single cell level via a partially irreversible mechanism independent of protein kinase C. The molecular target of RA and whether SC115 cell differentiation underlies the effect of RA remain to be established.
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PMID:Retinoic acid priming potentiates the induction of urokinase-type plasminogen activator by cyclic adenosine monophosphate in mouse mammary carcinoma cells. 164 61

(+-)-2-[Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2- yl]methoxyl]phosphinyloxy-N,N,N-trimethylethaniminium hydroxide, inner salt (SRI 62-834) is a tetrahydrofuran analogue of platelet activating factor (PAF) that is currently entering clinical trial. Like other ether lipids it is of interest as a membrane-active antitumor agent. Here, we have used two-color multiparameter flow cytometry to study simultaneously its effects on cell membrane permeability, intracellular pH, and cell size/structure of EMT6 mouse mammary tumor cells and HL-60 human promyelocytic leukemia cells in vitro. Concentrations as low as 1 microM up to 100 microM SRI 62-834 caused a rapid, dose-dependent increase in membrane permeability, initially towards outward efflux of the preloaded fluorescein probe bis(carboxyethyl)carboxyfluorescein (green fluorescence) and then towards influx of extracellular propidium (red fluorescence). At the same time, median cell size from light scatter was reduced with an increased coefficient of variation, and the proportion of cell debris was elevated. In vitro antitumor activity was seen over the same concentration range, as measured by tetrazolium dye reduction and cell growth curves. Neither low concentrations of PAF (50 nM) nor the potent PAF antagonist 3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]tria- zolo[4,3a][1,4]diazepin-2-yl]-1-(4-morpholinyl)-1-propanone (0.5-100 microM) had any influence on the membrane effects of SRI 62-834, and at higher concentrations (1-200 microM) PAF mimicked the behavior of SRI 62-834. In addition, the PAF antagonist did not modulate the cytotoxicity of SRI 62-834 or PAF. HL-60 cells were more sensitive to SRI 62-834 than were EMT6 cells in terms of both cytotoxicity and membrane permeability. However, PAF was more potent than SRI 62-834 in causing membrane permeabilization with both cell lines, whereas PAF was less active than SRI 62-834 in cytotoxicity assays. The results support a membrane-damaging role in the cytotoxicity of SRI 62-834 but suggest that additional factors are also involved. Membrane permeabilization may be related to its reported effects on protein kinase C-dependent intracellular calcium signaling but apparently does not involve a conventional PAF receptor in HL-60 or EMT6 cells.
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PMID:Multiparametric flow cytometry of the modulation of tumor cell membrane permeability by developmental antitumor ether lipid SRI 62-834 in EMT6 mouse mammary tumor and HL-60 human promyelocytic leukemia cells. 198 20

We used a dominant inhibitory mutation of c-Ha-ras which changes Ser-17 to Asn-17 in the gene product p21 [p21(Asn-17)Ha-ras] to investigate ras function in mitogenic signal transduction. An NIH 3T3 cell line [NIH(M17)] was isolated that displayed inducible expression of the mutant Ha-ras gene (Ha-ras Asn-17) via the mouse mammary tumor virus long terminal repeat and was growth inhibited by dexamethasone. The effect of dexamethasone induction on response of quiescent NIH(M17) cells to mitogens was then analyzed. Stimulation of DNA synthesis by epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) was completely blocked by p21(Asn-17) expression, and stimulation by serum, fibroblast growth factor, and platelet-derived growth factor was partially inhibited. However, the induction of fos, jun, and myc by EGF and TPA was not significantly inhibited in this cell line. An effect of p21(Asn-17) on fos induction was, however, demonstrated in transient expression assays in which quiescent NIH 3T3 cells were cotransfected with a fos-cat receptor plasmid plus a Ha-ras Asn-17 expression vector. In this assay, p21(Asn-17) inhibited chloramphenicol acetyltransferase expression induced by EGF and other growth factors. In contrast to its effect on DNA synthesis, however, Ha-ras Asn-17 expression did not inhibit fos-cat expression induced by TPA. Conversely, downregulation of protein kinase C did not inhibit fos-cat induction by activated ras or other oncogenes. These results suggest that ras proteins are involved in at least two parallel mitogenic signal transduction pathways, one of which is independent of protein kinase C. Although either pathway alone appears to be sufficient to induce fos, both appear to be necessary to induce the full mitogenic response.
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PMID:Effect of a dominant inhibitory Ha-ras mutation on mitogenic signal transduction in NIH 3T3 cells. 211 93

Dexamethasone treatment of the Jurkat T77 cell clone inhibited the enhancing effect of 12-O-tetradecanoylporbol-13-acetate (TPA) and the calcium ionophore A23187 on the interleukin 2 (IL2) mRNA levels and gene transcription from intact nuclei. Dexamethasone treatment of Jurkat T77 cells inhibited the TPA/A23187-dependent activation of the transcription from the transfected pIL2CAT, containing 600 base pairs of the genomic sequences upstream of the coding region of IL2 gene, including the TPA/calcium responsive cis-regulatory elements and promoter sequences, driving the expression of the chloramphenicol acetyltransferase (CAT) gene. Transfection of either Jurkat T77 cell clone or glucocorticoid-resistant Jurkat cells with a human glucocorticoid receptor cDNA under the transcriptional control of the Rous sarcoma virus long terminal repeat (LTR) (pRShGR alpha) significantly increased or induced, respectively, the dexamethasone-mediated inhibition of the TPA/A23187-dependent expression of pIL2-CAT as well as the enhancing effect on the expression of the cotransfected CAT gene under the control of the mouse mammary tumor virus LTR, as a marker of glucocorticoid receptor action. This suggests a role for the glucocorticoid receptor in mediating the dexamethasone action on IL2 gene expression. To study the cis-regulatory sequence specificity of the dexamethasone-induced interference with the TPA/A23187-mediated T cell activating signals, we studied the effect of the hormone on the regulatory elements contained in the Rous sarcoma virus and human T lymphotropic virus 1 long terminal repeats and the SV40 promoter, which are known to be transcriptionally enhanced by those activating agents. Dexamethasone was unable to interfere with the TPA/A23187-mediated enhancement of these cis-regulatory elements, suggesting that the hormone effect is specific for IL-2 gene sequences. Our data suggest that the dexamethasone-mediated transcriptional inhibition of the IL2 gene is mediated by an interference with the protein kinase C and calcium-mediated trans-activation of the antigen-responsive and T cell-specific elements lying in the 5'-flanking region of the gene.
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PMID:Transcriptional regulation of the interleukin 2 gene by glucocorticoid hormones. Role of steroid receptor and antigen-responsive 5'-flanking sequences. 215 67

A recombinant N-ras oncogene, under the transcriptional control of a corticosteroid-inducible mouse mammary tumor virus (MMTV) promoter, has been stably transfected into a PC12 rat pheochromocytoma subline. This cell line, designated UR61, undergoes N-ras-induced neurite outgrowth and cessation of division when treated with dexamethasone (Guerrero et al.: Biochemical and Biophysical Research Communications 150:1185-1192, 1988). We have employed the UR61 cell line as a model for ras oncogene-induced neuronal differentiation. In UR61 cells, dexamethasone-induced expression of the recombinant N-ras gene resulted in time-dependent expression of ornithine decarboxylase enzyme (ODC) activity. Prompted by recent reports of possible functional (Lacal et al.: Molecular and Cellular Biology 7:4146-4149, 1987; Wolfman and Macara: Nature 325: 359-361, 1987) and direct (Jeng et al.: Biochemical and Biophysical Research Communications 145:782-788, 1987) interactions between oncogene ras-coded p21 and protein kinase C (PK-C; Ca++/phospholipid-dependent protein kinase), we employed the protein kinase inhibitor H-8 (N-[2-(methylamino)ethyl]-5-isoquinoline sulfonamide dihydrochloride) and phorbol 12,13-dibutyrate (PDBu) to investigate this putative interaction in the UR61 cells, where ODC activity and neurite outgrowth were used as indicators of oncogenic N-ras action. Treatment of UR61 cells with PDBu depleted cells of PK-C and failed to promote neurite outgrowth but enhanced N-ras-induced neurite outgrowth and ODC activity. H-8, which suppressed ODC induction by forskolin and phorbol myristate acetate, enhanced both N-ras-induced ODC activity and neurite outgrowth. Inhibition of ODC activity by difluoromethylornithine (DFMO) did not suppress oncogenic ras-induced neurite outgrowth, suggesting that these two ras-triggered events are mechanistically independent. These findings suggest that certain actions of N-ras can occur in cells depleted of PK-C, and thus, the role of PK-C in ras-induced differentiation differs from its role in ras-induced mitogenesis and transformation.
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PMID:Potentiation of oncogenic N-ras-induced neurite outgrowth and ornithine decarboxylase activity by phorbol dibutyrate and protein kinase inhibitor H-8. 218 Sep 65

Quantitative polyacrylamide gel electrophoresis analysis of Ca2+, phospholipid-dependent protein kinase (PKC) of human mammary tumor cell lines (MCF-7, ZR-75, T-47-D, MDA-MB-231, BT-20, and HBL-100) revealed that 80% of the total cellular PKC resided in the cytosol. The tumor cells with no detectable levels of estrogen receptors (MDA-MB-231, HBL-100, and BT-20 cells) exhibited significantly larger (P less than 0.001) cytosolic PKC activities than those cells that contained estrogen receptors (MCF-7, T-47-D, and ZR-75 cells). In addition, in estrogen receptor-negative cell lines, relatively high levels of specific low-affinity (apparent Kd = 700 pM) epidermal growth factor (EGF) binding activities were found as compared with estrogen receptor-positive cells with significantly (P less than 0.001) lower levels of specific high-affinity (apparent Kd = 90 pM) EGT binding. A significant positive correlation (P less than 0.01) was observed between the number of EGF receptor (Rs = 0.50) and/or the EGF receptor dissociation constants (Rs = 0.78) with the cytosolic PKC activity levels. These data indicate that, in human breast cancer cells, a positive relationship may exist between PKC activity, estrogen, and EGF receptors.
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PMID:Epidermal growth factor binding and protein kinase C activities in human breast cancer cell lines: possible quantitative relationship. 300 98

The exposure of serum-deprived mammary tumor cells MCF-7 and T-47D to insulin, thrombin, and epidermal growth factor (EGF) resulted in dramatic modifications in the activity and in the translocation capacity of protein kinase C from cytosol to membrane fractions. Insulin induces a 600% activation of the enzyme after 5 h of exposure to the hormone in MCF-7 cells; thrombin either activates (200% in MCF-7) or down-regulates (in T-47D), and EGF exerts only a moderate effect. Thus, the growth factors studied modulate differentially the protein kinase C activity in human mammary tumor cells. The physiological significance of the results obtained are discussed in terms of the growth response elicited by insulin, thrombin, and EGF.
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PMID:Protein kinase C is differentially regulated by thrombin, insulin, and epidermal growth factor in human mammary tumor cells. 327 15

Growth of human mammary tumor cells ZR-75-1 is stimulated by estradiol (E2), epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I). In these cells ribosomal protein S6 kinase is activated by EGF, IGF-I, insulin and phorbol 12-myristate 13-acetate (TPA) but not by E2. The human mammary tumor cell line MDA-MB 231, which is E2-receptor negative, has receptors for EGF, IGF-I and insulin but is unresponsive to these factors in terms of growth and S6 kinase activation. The role of protein kinase C (PKC) in the activation of S6 kinase by growth factors and TPA was investigated in ZR-75-1 cells. Down regulation of PKC activity by treatment with TPA for 48-h blocks the stimulation of S6 kinase by TPA but leaves the activation by EGF, IGF-I and insulin unaffected. In intact ZR-75-1 cells staurosporine blocks activation of S6 kinase by EGF and TPA, however with different IC50. The results show that S6 kinase is not activated by estradiol, that its activation by EGF, IGE-I and insulin does not depend on the presence of PKC activity and that its activation by TPA is mediated by a different (PKC-dependent) pathway.
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PMID:Regulation of ribosomal protein S6 kinase in human mammary tumor cells: effect of estrogen, growth factors and phorbol ester. 327 21

Active phorbol esters such as TPA (12-0-tetra-decanoylphorbol-13-acetate) inhibited growth of mammary carcinoma cells (MCF-7 greater than BT-20 greater than MDA-MB-231 greater than = ZR-75-1 greater than HBL-100) with the exception of T-47-D cells presumably by interacting with the phospholipid/Ca2+-dependent protein kinase (PKC). The nonresponsive T-47-D cells exhibited the lowest PKC activity. A rapid (30 min) TPA-dependent translocation of cytosolic PKC to membranes was found in the five TPA-sensitive cell without affecting cell growth. However, TPA-treatment of more than 10 hours inhibited reversibly the growth of TPA-responsive cells. This effect coincided with the complete loss of cellular PKC activity due to the proteolysis of the translocated membrane-bound PKC holoenzyme (75K) into 60K and 50K PKC fragments. Resumption of cell growth after TPA-removal was closely related to the specific reappearance of the PKC holoenzyme activity (75K) in the TPA-responsive human mammary tumor cell lines suggesting an involvement of PKC in growth regulation.
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PMID:Protein kinase C desensitization by phorbol esters and its impact on growth of human breast cancer cells. 351 65

The amounts of phospholipid- and Ca2+-dependent protein kinase (PKC) of various human mammary tumor cells containing (ER+) or lacking (ER-) estrogen receptors were estimated by quantitative immunoblotting. According to several criteria the polyclonal anti-PKC antibody raised in rabbits against porcine brain PKC specifically recognizes an 80-kDa polypeptide on immunoblots. This 80-kDa PKC presumably represents the autophosphorylated form of the holoenzyme. Immunological quantitation of PKC revealed that the levels of immunodetectable PKC varied widely among the various human mammary carcinoma cell lines but closely matched the amounts determined by enzyme activity and phorbol ester binding in the respective cell line. The largest amounts of immunodetectable PKC were found in the ER- human mammary tumor cells (0.5 to 1.5 micrograms PKC/mg of cytosolic protein). These data indicate that ER- human mammary carcinoma cell lines express significantly higher levels of PKC than their estrogen-receptor-containing counterparts.
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PMID:Immunological quantitation of phospholipid/Ca2+-dependent protein kinase of human mammary carcinoma cells: inverse relationship to estrogen receptors. 362 17


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