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 effects of long term treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) on estrogen receptor (ER) expression in the human breast cancer cell line, MCF-7, were studied. This study demonstrates that treatment of cells with the phorbol ester blocked estrogen receptor activity. Treatment of cells with 100 nM TPA resulted in an 80% decrease in the level of ER protein and a parallel decrease in ER mRNA and binding capacity. Following removal of TPA from the medium, the level of ER protein and mRNA returned to control values; however, the receptor failed to bind estradiol. These cells also failed to induce progesterone receptor in response to estradiol. In addition, TPA treatment blocked transcription from an estrogen response element in transient transfection assays and inhibited ER binding to its response element in a DNA mobility shift assay. The estrogen receptor in treated cells was recognized by two monoclonal anti-ER antibodies and was not quantitatively different from ER in control cells. RNase protection analysis failed to detect any qualitative changes in the ER mRNA transcript. Mixing experiments suggest that TPA induces/activates a factor which interacts with the ER to block binding of estradiol. The effects of TPA on ER levels and binding capacity were concentration-dependent. Low concentrations of TPA inhibited estradiol binding without a decrease in the level of protein, whereas higher concentrations were required to decrease the level of ER protein. The effects of TPA appear to be mediated by activation of protein kinase C since the protein kinase C inhibitors, H-7 and bryostatin, block the effects of TPA on estradiol induction of progesterone receptor. TPA treatment had no effect on the level or binding capacity of the glucocorticoid receptor, indicating that the effects are not universal for steroid receptors. These data demonstrate that activation of the protein kinase C signal transduction pathway modulates the estrogen receptor pathway. The long term effect of protein kinase C activation is to inhibit estrogen receptor function through induction/activation of a factor which interacts with the receptor.
 ...
PMID:Effects of 12-O-tetradecanoylphorbol-13-acetate on estrogen receptor activity in MCF-7 cells. 755 63

Tumor necrosis factor-alpha (TNF-alpha) demonstrated antimitogenic activity in MCF-7 cells (estrogen receptor-positive human breast cancer cells) in a dose- and time-dependent manner (EC-50 of 2.5 ng/ml). This antimitogenic effect of TNF-alpha was accompanied by a decreased number of cells in S phase in a dose- and time-dependent manner. Based on growth arrest experiments using aphidicolin, it is apparent that TNF-alpha acted in early G1 phase. It did not show antimitogenic effects once cells reentered the S phase based on [3H]thymidine incorporation into DNA and cell cycle analysis. Specificity of TNF-alpha was established by using monoclonal anti-human TNF-alpha antibody. On the basis of Western immunoblot analysis of Rb, p53 and cell cycle inhibitory protein (Cip1) (p21) proteins, TNF-alpha decreased Rb protein expression in a dose- and time-dependent manner whereas it increased the expression level of tumor suppressor p53 protein. TNF-alpha also increased the expression level of Cip1 (p21) protein in a dose-dependent manner. This induction of Cip1 (p21) protein was preceded by the induction of p53 protein in MCF-7 cells. Cip1 (p21) protein associated with cyclin D was also increased. Tumor suppressor Rb protein expression was increased during G1 to S phase progression. Cyclin D protein expression levels were not changed in response to TNF-alpha treatment, although serine/threonine kinase inhibitors such as H7 and the protein kinase C inhibitor staurosporine decreased cyclin D expression levels in MCF-7 cells. Based on experiments with staurosporine, it appears that TNF-alpha does not utilize a protein kinase C pathway in MCF-7 cells. Other cell cycle-related proteins such as Cdk2, Cdc2, and Cdk4 did not show any change in response to TNF-alpha. TNF-alpha did not affect complexes between cyclin D and Cdk2, Cdk4, and Rb proteins in MCF-7 cells. Taken together these results suggest that Rb, p53, and Cip1 (p21) proteins mediate TNF-alpha antimitogenic activity, and TNF-alpha induces growth arrest in the G1 phase in MCF-7 cells.
 ...
PMID:Effects of tumor necrosis factor-alpha on antimitogenicity and cell cycle-related proteins in MCF-7 cells. 762 60

Increased protein kinase C (PKC) activity in malignant breast tissue and positive correlations between PKC activity and expression of a more aggressive phenotype in breast cancer cell lines suggest a role for this signal transduction pathway in the pathogenesis and/or progression of breast cancer. To examine the role of PKC in the progression of breast cancer, human MCF-7 breast cancer cells were transfected with PKC-alpha, and a group of heterogenous cells stably overexpressing PKC-alpha were isolated (MCF-7-PKC-alpha). MCF-7-PKC-alpha cells expressed fivefold higher levels of PKC-alpha as compared to parental or vector-transfected MCF-7 cells. MCF-7-PKC-alpha cells also displayed a substantial increase in endogenous expression of PKC-beta and decreases in expression of the novel delta- and eta-PKC isoforms. MCF-7-PKC-alpha cells displayed an enhanced proliferative rate, anchorage-independent growth, dramatic morphologic alterations including loss of an epithelioid appearance, and increased tumorigenicity in nude mice. MCF-7-PKC-alpha cells exhibited a significant reduction in estrogen receptor expression and decreases in estrogen-dependent gene expression. These findings suggest that the PKC pathway may modulate progression of breast cancer to a more aggressive neoplastic process.
 ...
PMID:MCF-7 breast cancer cells transfected with protein kinase C-alpha exhibit altered expression of other protein kinase C isoforms and display a more aggressive neoplastic phenotype. 770 98

All members of the steroid hormone receptor family are phosphoproteins. Additional phosphorylation occurs in the presence of hormone. This hormone-induced phosphorylation, which is 2- to 7-fold more than the basal phosphorylation, is a rapid process. All steroid receptors are phosphorylated at more than one single site. Most phosphorylation sites are located in the N-terminal domain, and phosphorylation occurs mainly on serine residues. Phosphorylation on threonine residues occurs in only a few cases. Phosphorylation on tyrosine residues has been found only for the estrogen receptor. Six different protein kinases are possibly involved in steroid receptor phosphorylation (estrogen receptor kinase; protein kinase A; protein kinase C; casein kinase II; DNA-dependent kinase; Ser-Pro kinases). Steroid receptor phosphorylation has been directly implicated in: activation of hormone binding, nuclear import of steroid receptors, modulation of binding to hormone response elements, and consequently in transcription activation.
 ...
PMID:Steroid hormone receptor phosphorylation: is there a physiological role? 805 42

In this paper we demonstrate the existence of specific, high affinity 17-beta estradiol binding in MDBK cells (a normal non-transformed renal cell line). Scatchard analysis revealed binding characteristics typical of the estrogen receptor (ER). Only unlabelled 17-beta estradiol, diethyl stilbestrol and estrone effectively competed with [3H] 17-beta estradiol for binding, other steroids did not compete. Short term TPA treatment of MDBK cells with TPA increased PKC activity and immunoreactivity and caused a transient increase in 17-beta estradiol binding, while longer term treatment with TPA decreased PKC activity and immunoreactivity. The inactive phorbol ester 4 alpha PDD was without effect on PKC activity and the ER. TPA did not affect the affinity of the ER for the nucleus nor did it increase degradation of the receptor. We hypothesize that the renal ER may be a substrate for PKC and its properties can be modified by PKC similarly to the vitamin D receptor.
 ...
PMID:Modulation of a renal estrogen receptor by protein kinase C. 808 31

The tumor cell growth inhibitory activity of tamoxifen was enhanced significantly by verapamil treatment in an estrogen receptor positive human breast cancer cell line, MCF-7. Treatment of MCF-7 cells with 5 and 10 micrograms/mL verapamil produced a 1.8- and 2.8-fold increase, respectively, in tamoxifen activity. Unlike reversal of multi-drug resistance, the verapamil-mediated increase in tamoxifen activity was not associated with enhanced drug accumulation. Tamoxifen treatment alone or in combination with verapamil did not affect the activity of protein kinase C, an enzyme implicated in the anti-tumor activity of tamoxifen. Addition of 17 beta-estradiol in the cell survival assay system partially abrogated the modulatory effect of verapamil. These data suggest that potentiation of tamoxifen activity by verapamil may involve interaction of this agent with the estrogen receptor. In conclusion, potentiation of tamoxifen activity by calcium channel blockers represents a novel approach for improving the therapeutic results with tamoxifen in women with breast cancer.
 ...
PMID:Potentiation of tamoxifen activity by verapamil in a human breast cancer cell line. 818 86

In this study, we examined antiproliferative effect of clomiphene and tamoxifen alone and their combined effect on cis-diamminedichloroplatinum(II) (CDDP) by using human ovarian cancer cells (KF, KK, and MH cells) with different sensitivity to CDDP and MCF-7 cells derived from human breast cancer. KF, KK, and MH cells did not have estrogen receptor while MCF-7 cells had it. The KF cells were most sensitive to CDDP followed by KK, MCF-7, and MH cells. Similarly, the KF cells among three human ovarian cancer cell lines were most sensitive to clomiphene and tamoxifen alone. The MCF-7 cells had similar high sensitivity to both clomiphene and tamoxifen. When effects of clomiphene and tamoxifen on the protein kinase C (PKC) activity in the cancer cells were examined, the degree of inhibition of the PKC activity in the KF cells by clomiphene and tamoxifen was most marked and that by clomiphene was followed by those by KK, MH, and MCF-7 cells, while that by tamoxifen was, in increasing order, MH, MCF-7, and KK cells. Analyses of effects of clomiphene or tamoxifen on concentrations of CDDP required for 50% inhibition of cell proliferation (IC50) revealed that although the combined effects, in the KF and KK cells were only marginal, marked enhancement of antiproliferative effects of CDDP on the MH cells resistant to CDDP was obtained. When 5 x 10(6) cells were incubated with 100 microM CDDP for 3 hr, uptake of CDDP by MCF-7 cells was lowest, followed by MH, KK, and KF cells. The CDDP uptake by KF and KK cells was increased about 30-40% in the presence of clomiphene or tamoxifen. The CDDP uptake by the MH cells in which most marked enhancement of antiproliferative effect of CDDP was observed by a combination with clomiphene or tamoxifen was increased about 80-90% in the presence of clomiphene or tamoxifen. These results suggest that not only tamoxifen but also clomiphene can potentiate antiproliferative effect of CDDP in the ER-negative CDDP-resistant cancer cells by enhancing the CDDP uptake.
 ...
PMID:Enhancement of antiproliferative effect of cis-diamminedichloroplatinum(II) by clomiphene and tamoxifen in human ovarian cancer cells. 831 39

Modulator is a novel low-molecular-weight organic compound that regulates activities of glucocorticoid and mineralocorticoid receptors as well as protein kinase C. In this study we show that male rat liver cytosolic estrogen receptor activation is inhibited by modulator in a dose-dependent manner. Fifty percent inhibition is obtained with 1 unit/ml modulator purified from bovine liver which is within the physiological concentration for modulator. However, sheep uterine cytosolic estrogen and androgen receptors are insensitive to regulation by modulator. Exogenous sodium molybdate treatment inhibits activation of all of these receptors of liver or uterus origin in an identical manner, further differentiating the effects of modulator and the molybdate anion.
 ...
PMID:Specific regulation of male rat liver cytosolic estrogen receptor by the modulator of the glucocorticoid receptor. 836 96

Tamoxifen (TAM) markedly increases the response rate of malignant melanoma to treatment with cisplatin (DDP), carmustine, and dacarbazine, and we have previously reported that there is a highly synergistic interaction between TAM and DDP with respect to the cytotoxic effect against the human melanoma cell line T-289 (E. F. Mc Clay et al., Cancer Res., 52: 6790-6796, 1992). The mechanism underlying synergy was investigated by examining the effect of selection for either DDP or TAM resistance on the magnitude of the synergy quantitated by median effect analysis. The combination index at 50% cell kill was 0.26 +/- 0.02 (SD) for parental T-289 cells (indicating marked synergy), 0.54 +/- 0.14 for cells selected for low-level DDP resistance (indicating moderate synergy), and 1.39 +/- 0.20 for cells selected for low-level TAM resistance (indicating antagonism). Thus, factors that regulate DDP sensitivity have a moderate effect on reducing the DDP/TAM synergy, but determinants of TAM sensitivity have a major effect. The known biochemical effects of TAM include antagonism of estrogen at the estrogen receptor (ER) and inhibition of calmodulin and protein kinase C activity. T-289 cells contained undetectable amounts of ER by the dextran-coated charcoal assay and expressed only trace amounts of ER mRNA, and another more avid ER antagonist, droloxifene, failed to interact synergistically with DDP. N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7), a potent calmodulin antagonist, failed to demonstrate synergy with DDP, and activation of protein kinase C, instead of interacting antagonistically with DDP, yielded synergy. TAM did not alter the cell cycle phase perturbation produced by exposure to DDP alone. We conclude that the synergy between TAM and DDP is not mediated by the effects of TAM on the ER, calmodulin, protein kinase C, or cell cycle regulation. However, the factors that determine cellular sensitivity to TAM also determine whether TAM interacts synergistically with DDP.
 ...
PMID:Tamoxifen modulation of cisplatin sensitivity in human malignant melanoma cells. 845 25

A multivariate statistical method, correspondence factorial (CF) analysis, was used to examine the correlations among the protein binding and cell proliferation effects of a series of 36 di- and triphenylethylenes (DPEs and TPEs). The analysis was applied to a study which measured their competition for estradiol binding to cytosol estrogen receptor (ER), their influence on protein kinase C (PKC) activity under different conditions of enzyme activation, their ability to promote the growth of a breast cancer cell line and to inhibit growth at high concentrations (cytotoxicity). The CF analysis revealed several levels of correlation. First, it distinguished those molecules within the population that stimulated rather than inhibited PKC activity. Second, it made apparent a strong correlation between cytotoxicity and inhibition of Ca++ and phosphatidylserine-dependent PKC activity, which was most marked when the enzyme had been activated by diacylglycerol indicating that PKC inhibition under physiological conditions might contribute to the overall cytotoxicity of these compounds. Third, a lower level of correlation was established between competition for ER binding and cytotoxicity. Taken together, the results suggest that MCF7 cells might be most sensitive to a cytotoxic effect of TPEs (via PKC and other targets) when they at the same time decrease estrogen-stimulated proliferation via an ER-mediated antiestrogenic effect.
 ...
PMID:Relative involvement of protein kinase C and of the estrogen receptor in the cytotoxic action of a population of triphenylethylenes on MCF7 cells as revealed by correspondence factorial (CF) analysis. 846 Dec 57


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>