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)

We investigated the effects of TGF-beta on a MCF-7 subline (MCF-7:RPh-4) which is resistant to phorbol diesters with respect to growth inhibition and estrogen receptor content modulation. This biological unresponsiveness of MCF-7:RPh-4 cells to phorbol esters seems to be unrelated to activation of protein kinase C. In the presence of 80 nM PMA (12-O-tetradecanoylphorbol-13-acetate), TGF-beta induced a dose-dependent inhibition of MCF-7:RPh-4 cell proliferation. MCF-7:RPh-4 cells grown in PMA-free medium for at least 28 days remained insensitive to PMA but lost sensitivity to TGF-beta. Under these conditions, addition of 80 nM PMA restored sensitivity to TGF-beta. In the presence of a fixed concentration of TGF-beta, the dose-dependent inhibition of proliferation and the decrease in estrogen receptor content induced by PMA were comparable to those observed in PMA-treated parental MCF-7 cells. These observations indicate that TGF-beta reverses PMA resistance in MCF-7:RPh-4 cells. In addition, TGF-beta does not modify the basal or PMA-stimulated phosphorylation of Mr 28,000 endogenous protein. These results suggest that TGF-beta interferes with the protein kinase C pathway independently of enzyme activation.
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PMID:Transforming growth factor beta (TGF-beta) reverses phorbol diester resistance of a breast adenocarcinoma (MCF-7) subline. 230 34

We investigated the effects of the antiestrogen tamoxifen on MCF-7 cell protein kinase C either by using the in vitro histone kinase assay or by studying the phosphorylation of its endogenous Mr 28,000 protein substrate in intact cells. In the in vitro assay, tamoxifen inhibited the enzyme competitively with respect to phospholipid, whereas estradiol and morpholinobenzyl phenoxy ethanamine, a specific ligand for antiestrogen binding sites, were considerably less efficient. In contrast, tamoxifen did not affect phosphorylation of the Mr 28,000 protein induced by the phorbol ester 12-O-tetradecanoylphorbol 13-acetate in intact MCF-7 cells. Estradiol and morpholinobenzyl phenoxy ethanamine also had no effect. At high concentration (100 microM), tamoxifen itself stimulated specific phosphorylation of this Mr 28,000 protein. Estradiol and morpholinobenzyl phenoxy ethanamine neither mimicked nor interfered with this effect. Our data suggest that the effect of tamoxifen on protein kinase C activity depends on the phospholipid environment of the enzyme, and opposite effects may be observed in intact cells to those seen in disrupted cells. The action of tamoxifen on endogenous protein phosphorylation was thought to be due to direct interaction with the phospholipid binding domain of the enzyme rather than by interaction with the estrogen receptor or the antiestrogen binding site. Nevertheless, our results do not rule out a possible activation by tamoxifen of specific protein kinase(s) and phosphatase(s). In any case, the antiproliferative activity of tamoxifen on MCF-7 cells cannot be attributed to its effects on protein kinase C.
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PMID:Opposite effects of tamoxifen on in vitro protein kinase C activity and endogenous protein phosphorylation in intact MCF-7 cells. 239 53

The main objective of this study was to differentiate between lymph nodes infiltrated by estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast carcinoma. Lymph nodes were obtained from 40 postmenopausal cancer patients, 10 from each disease stage. Six patients from each group had estrogen receptor-positive (BCaER+) and four estrogen receptor-negative (BCaER-) tumors. Both tumor-containing (T) and uninvolved (N) lymph nodes from the same patient were examined by the following parameters: magnitude of lymph node nucleic acid hybridization with cDNA probes from breast cancer MCF-7ER+ and MCF-7ER- cells; and binding capacity of 3H-estradiol, 125I-EGF, and 125I-PDGF binding and protein kinase C activities of the lymph nodes. Concomitant with the appearance of transformed cells, several events occur: Tumor cells induce stimulation of mononuclear cells and macrophages and evoke T- and B-cell proliferation, leading to the synthesis of tumor cell membrane-associated antibodies. In estrogen receptor-positive (ER+) breast carcinoma, estrogens and host hormonal modulatory mechanisms stimulate production and release of epithelial growth (EGF) and platelet-derived growth factors (PDGF). These factors are characterized by protein kinase C activities. There is infiltration of tumor cells into the lymph node and infiltration of leukocytes into the tumor site. In the lymph node, tumor progression depends on tumor cell proliferation rate and metastatic aggressiveness. The experiments described in this study document the changes that occur in lymph nodes, with differences between nodes infiltrated with BCaER+ and BCaER- breast carcinomas. Hybridization of 32P-cDNA from MCF-7ER+ cells with cellular RNA from BCaER+ involved (T) lymph nodes is greater than with cellular RNA from uninvolved (N) lymph nodes. The magnitude of hybridization correlated (P less than 0.005) with the disease stage.
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PMID:Prognostic significance of mRNA-encoding estrogen receptor and epithelial growth factor receptor in breast carcinoma progression into lymph nodes: 1. Estrogen receptor encoding mRNA. 253 80

Tamoxifen and other structurally related nonsteroidal antiestrogens possess properties in addition to their estrogen antagonist activity including inhibition of both calmodulin and protein kinase C. The present studies were designed to test whether the estrogen-reversible (estrogen receptor mediated) and estrogen-irreversible effects of nonsteroidal antiestrogens on cell cycle progression in vitro were mediated at the same or different points within the cell cycle and if the estrogen-irreversible effects coincided temporally with that of a calmodulin antagonist, R24571. Initial experiments investigated the effects of ICI 164384, a pure estrogen antagonist, on proliferation kinetics in asynchronous cultures of MCF-7 human breast cancer cells. At concentrations greater than 1 nM ICI 164384 significantly reduced growth rate while at greater than or equal to 50 nM, ICI 164384 completely arrested growth after the first 24 h of exposure. Concentrations up to 5 microM failed either to cause more profound effects on growth or induce cytotoxicity. Growth inhibition was associated with a decrease in the proportion of S phase cells and an accumulation of cells in G1 phase, and was completely reversed by the simultaneous addition of equimolar estradiol. In order to identify the points of action within the cell cycle of ICI 164384, and the estrogen-reversible and estrogen-irreversible components of the nonsteroidal estrogen antagonist, hydroxyclomiphene, and the calmodulin antagonist, R24571, experiments were undertaken with MCF-7 cells synchronized by mitotic selection. The mean point of action was assessed by delaying addition of the drugs for increasing time periods following mitotic selection and using DNA flow cytometry to determine the proportion of the population affected by drug administration at a specific time within G1 phase. These studies showed that sensitivity to ICI 164384 was restricted to the early part of G1 phase and that the mean time of action was 4.9 h after the beginning of G1 for this pure estrogen antagonist. The mean times of action of the estrogen-reversible (4.1 h into G1 phase) and estrogen-irreversible (4.1 h) mechanisms of action of hydroxyclomiphene, and R24571 (4.0 h), all appeared to be within a similar time frame in early to mid G1 phase. It is concluded that ICI 164384 inhibits breast cancer cell proliferation by inducing a transition delay in G1 phase and that the point of action of this pure estrogen antagonist in early G1 phase is indistinguishable temporally from that of nonsteroidal antiestrogens and calmodulin antagonists.
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PMID:Points of action of estrogen antagonists and a calmodulin antagonist within the MCF-7 human breast cancer cell cycle. 270 27

These studies were undertaken to determine whether nonsteroidal antiestrogens would inhibit the calcium/lipid-dependent protein kinase (protein kinase C) activity in hormonally-responsive human reproductive tissues. Cytosol was prepared from human corpus luteum and term placenta. Protein kinase C activity was examined with various antiestrogens, estrogens, and catecholestrogens. The nonsteroidal antiestrogens tamoxifen, clomiphene and Z-4-hydroxytamoxifen inhibited protein kinase C in cytosol from human corpora lutea and placentae in a concentration-dependent manner. The IC50 values were 35-45 microM for tamoxifen, 58-66 microM for clomiphene, and 88 microM for hydroxytamoxifen. Protein kinase C purified 600-fold from human placenta was also inhibited by tamoxifen. The estrogens, estradiol and diethylstilbestrol (DES), and the catecholestrogens, 2-hydroxyestradiol and 4-hydroxyestradiol, had no effect on protein kinase C activity, nor were they able to prevent the inhibition of protein kinase C by the antiestrogens. Inhibition of the enzyme by the antiestrogens was competitive with phosphatidylserine and 1,2-diolein. In addition, tamoxifen inhibited enzyme activity stimulated by the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). The data suggest that the action of these antiestrogens on protein kinase C was a direct inhibition of the enzyme. Furthermore, the site of interaction showed markedly different structural specificity from that of the estrogen receptor.
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PMID:Nonsteroidal antiestrogen inhibition of protein kinase C in human corpus luteum and placenta. 281 41

In addition to the effects of estrogens on transcription, mediated by the estrogen receptor, and the antiestrogenic effects of triphenylethylene derivatives resulting from their competitive action at the estrogen receptor level, estrogens and antiestrogens can affect cellular processes though other mechanisms. Estrogens can bind and alter enzymatic activities in membranes isolated from target cells, can influence the activities of purified enzymes and can change cell permeability and polarization under conditions excluding transcriptional effects. Triphenylethylene antiestrogens at micromolar concentrations can affect cholinergic, histaminergic and dopaminergic systems, affect calmodulin action and influence protein kinase C activity. Tamoxifen added to suspension of human endometrial adenocarcinoma cells at concentrations greater than 10 microM both increased phosphoinositide hydrolysis and inhibited the stimulatory effect of carbachol on this system. These effects, however, may represent nonspecific actions of the antiestrogens, shared with the structurally related phenothiazines, on the plasma membrane.
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PMID:Non-genomic effects of estrogens and antiestrogens. 284 81

The effects of the tumor promoter phorbol 12-tetradecanoate 13-acetate (TPA) on the epidermal growth factor (EGF) receptor levels were investigated in hormone-dependent (MCF-7, T-47-D, and ZR-75-1) and hormone-independent (MDA-MB-231, HBL-100, and BT-20) human mammary carcinoma cell lines. In the absence of TPA, hormone-independent cell lines contained high concentrations of low-affinity EGF receptors (apparent Kd = 8 X 10(-10) M), whereas hormone-dependent cell lines exhibited low concentrations of high-affinity receptors (apparent Kd = 1 X 10(-10) M). TPA causes a change of the receptor from a high- to the low-affinity state in hormone-dependent cell lines (MCF-7, T-47-D, and ZR-75-1), as well as in the hormone-independent HBL-100, whereas the affinity remained unchanged in MDA-MB-231 and BT-20 cells. In addition, progesterone receptor levels are decreased after TPA treatment in the hormone-dependent cell lines MCF-7, T-47-D, and ZR-75-1, whereas the estrogen receptor levels remained unchanged. Tumor promoters such as TPA or teleocidin inhibited the proliferation of these cell lines at concentrations above 10 microM with the exception of the T-47-D cells. The most sensitive cell line towards growth inhibition by tumor promoter was the hormone-dependent MCF-7 cell line. Evaluation of different TPA analogs indicated a positive correlation between the growth-inhibitory effects and their ability to stimulate the subcellular redistribution of protein kinase C activity in MCF-7 cells. These data suggest a protein kinase C-mediated down-regulation of the progesterone receptor concentration and of the EGF receptor affinity, which is supposed to mediate the mitogenic response. Furthermore, these results support the hypothesis that the tumor-derived growth factors induced by estradiol act via the EGF receptor in hormone-dependent mammary carcinoma cells.
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PMID:Correlation between hormone dependency and the regulation of epidermal growth factor receptor by tumor promoters in human mammary carcinoma cells. 300 36

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 triphenylethylene antiestrogen tamoxifen has been shown previously to inhibit both calmodulin and protein kinase C activities, which are involved in the control of cell proliferation. We have studied the effect of several derivatives of the triphenylethylene antiestrogen family on the inhibition of both calmodulin-dependent cyclic adenosine 3':5'-monophosphate-phosphodiesterase activity and proliferation of breast cancer cells cultured with 0.5 microM estradiol in order to prevent interaction of these drugs with the estrogen receptor. We have observed that hydroxylation of the triphenylethylene molecule significantly decreases its ability to inhibit the calmodulin-dependent phosphodiesterase activity in vitro. Furthermore, the growth-inhibiting activity of several antiestrogens and other calmodulin antagonists [R24571, trifluoperazine, N-(6-aminohexyl)-5-chloronaphthalene-1-sulfonamide, and N-(6-aminohexyl)-1-naphthalenesulfonamide] correlated with their antagonistic effects on calmodulin activity. The level of activity was determined as follows: R24571 greater than tamoxifen = N-demethyltamoxifen = nafoxidine greater than 4-hydroxytamoxifen greater than 3,4-dihydroxytamoxifen = trifluoperazine greater than N-(6-aminohexyl)-5-chloronaphthalene-1-sulfononamide greater than metabolite A greater than N-(6-aminohexyl)-1-naphthalenesulfonamide. On the other hand both protein kinase C-activating and -inhibiting drugs (phorboltetradecanoate-13-acetate and tamoxifen, respectively) have a synergistic inhibitory effect on the growth of MCF-7 cells. Our data suggest that antiestrogen interactions with calmodulin and not protein kinase C may play a role in mediating the drug-induced estrogen-independent inhibition of breast cancer cell growth.
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PMID:Calmodulin antagonism and growth-inhibiting activity of triphenylethylene antiestrogens in MCF-7 human breast cancer cells. 302 16

Recently hormone - dependent mammary carcinoma cell lines were shown to exhibit in vitro significantly lower protein kinase C (PKC) activities and epidermal growth factor receptor (EGF-R) as compared to hormone - independent cell lines. Measurements of EGF-R levels in primary human breast cancer biopsies were determined by [125I]-EGF binding. The EGF binding correlated inversely with the estrogen (ER) (p less than 0.001), progesterone receptor (PR) (p less than 0.005) contents and with the age of the patients. In contrast, the amounts of PKC, determined by phorbol ester binding, correlated inversely only with the PR (p less than 0.001), but not with the ER (p = 0.065). There was, however, a significant inverse correlation (p less than 0.05) between phorbol ester binding and ER levels if ER positive biopsies but with a PR negative value (i.e. with a non functional estrogen receptor) were excluded from statistical analysis. These data suggest an inverse relationship between the EGF-R or the phorbol ester receptor and the steroid receptor system in human breast cancer.
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PMID:Phorbol ester and epidermal growth factor receptors in human breast cancer. 349 60


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