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)

Over-expression studies have demonstrated that RALT (receptor associated late transducer) is a feedback inhibitor of ErbB-2 mitogenic and transforming signals. In growth-arrested cells, expression of endogenous RALT is induced by mitogenic stimuli, is high throughout mid to late G1 and returns to baseline as cells move into S phase. Here, we show that physiological levels of RALT effectively suppress ErbB-2 mitogenic signals. We also investigate the regulatory mechanisms that preside to the control of RALT expression. We demonstrate that pharmacological ablation of extracellular signal-regulated kinase (ERK) activation leads to blockade of RALT expression, unlike genetic and/or pharmacological interference with the activities of PKC, Src family kinases, p38 SAPK and PI-3K. Tamoxifen-dependent activation of an inducible Raf : ER chimera was sufficient to induce RALT expression. Thus, activation of the Ras-Raf-ERK pathway is necessary and sufficient to drive RALT expression. The RALT protein is labile and was found to accumulate robustly upon pharmacological inhibition of the proteasome. We were able to detect ubiquitin-conjugated RALT species in living cells, suggesting that ubiquitinylation targets RALT for proteasome-dependent degradation. Such an integrated transcriptional and post-translational control is likely to provide RALT with the ability to fluctuate timely in order to tune ErbB signals.
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PMID:Expression of RALT, a feedback inhibitor of ErbB receptors, is subjected to an integrated transcriptional and post-translational control. 1222 56

The MDM2 oncoprotein (p90) binds to p53 and inhibits its function. Here, the expression of mdm2 mRNA subsequent to phorbol 12,13-dibutyrate (PDB) or diethylstilbestrol (DES) treatment was analyzed in human breast tumor-derived GI-101A cell line. Expression of mdm2 mRNA was detected in rapidly growing GI-101A cells and that was similar to the expression seen in HL-60 cells. On the other hand PC12 (rat adrenal pheochromocytoma cells) did not show any mdm2 expression. GI-101A cells were treated with varying concentrations of DES or PDB, and mdm2 mRNA levels were determined by RT-PCR analysis. The RT-PCR results clearly showed that mdm2 mRNA expression was increased with increasing concentrations of PDB and DES treatments. To determine the specificity of the effects produced by DES and PDB the cells were treated with estrogen receptor antagonist tamoxifen and protein kinase C (PKC) specific inhibitor chelerythrine. Tamoxifen and chelerythrine co-treatments inhibited DES and PDB stimulated increases of mdm2 transcription respectively, in GI-101A cells. In an attempt to determine the upstream signaling pathway, the effects of PDB or DES on the mitogen activated protein kinase (MAPK) levels were determined by western blot analysis in the presence and absence of PD098059, a specific inhibitor of mitogen activated protein kinase kinase (MAPKK). The phospho-MAPK (p44/42) levels, an activated form of MAPK, increased in DES and PDB stimulated cells whereas PD098059 treatment inhibited this increase. Our data implicate MAPK as an upstream regulator of mdm2 expression and help to speculate on the intracellular regulation of mdm2 expression.
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PMID:Regulation of mdm2 mRNA expression in human breast tumor-derived GI-101A cells. 1223 95

A number of studies have shown that tamoxifen increases the sensitivity of several types of solid tumours to cisplatin without increasing the associated side effects. The cellular mechanisms responsible for this increased sensitivity are currently unknown. In this study we have investigated whether tamoxifen alone or in combination with cisplatin could induce apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines. We have shown that tamoxifen treatment resulted in G(1) arrest in two cell lines, HN5 and HN6. Tamoxifen induced growth suppression was independent of p53 status but resulted in up-regulation of cyclin dependent kinase inhibitors (CDKIs) p21/Waf-1, p27/Kip1 and p15/INK4a. Furthermore, tamoxifen treatment resulted in an increased level of hypophosphorylated active RB. Cisplatin induced p53 independent apoptosis in both head and neck cancer cell lines. There was a significant sensitizing effect of tamoxifen on cisplatin-induced apoptosis in HN5 and HN6 cells, with the combined treatment being more effective in inducing apoptosis. Addition of tamoxifen did not result in significant inhibition of PKC activity in HN5 and HN6 cells. However, tamoxifen treatment resulted in increased secretion of TGF-beta1 by HN5 and HN6 cells. An anti-TGF-beta blocking antibody prevented both the blockade of cellular proliferation and the increased expression of CDKIs associated with tamoxifen treatment of HN5 and HN6 cells. These results show that tamoxifen alone induces a transient G(1) arrest that greatly sensitizes the cells to apoptosis induced by cisplatin. We have shown that the mechanism for this p53-independent G(1) arrest and apoptosis is at least partly due to the activation of TGF-beta1 resulting in the induction of p15/INK4b, p27/Kip-1, p21/Waf-1 and RB hypophosphorylation. These in vitro results suggest that combination of tamoxifen and cisplatin might be a more effective treatment for head and neck cancers than single modality therapy.
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PMID:Tamoxifen inhibits the growth of head and neck cancer cells and sensitizes these cells to cisplatin induced-apoptosis: role of TGF-beta1. 1237 63

Dideoxyforskolin, a forskolin analogue unable to stimulate adenylate cyclase, and tamoxifen, an antioestrogen widely used against breast cancer, are both known to block some Cl- channels. Their effects on Cl- responses to glycine or GABA have been tested here by using whole-cell recording from cultured spinal neurons. Dideoxyforskolin (4 or 16 microm) and tamoxifen (0.2-5 microm) both potentiate responses to low glycine concentrations. They also induce blocking effects, predominant at high glycine concentrations. At 5 microm, tamoxifen increased responses to 15 microm glycine by a factor >4.5, reaching 20 in some neurons. Potentiation by extracellular dideoxyforskolin or tamoxifen persisted after intracellular application of the modulator and was not due to Zn2+ contamination. Potentiation by tamoxifen also persisted in a Ca2+-free extracellular solution, after intracellular Ca2+ buffering and protein kinase C blockade. Thus, the critical sites of action are not intracellular. The EC50 for glycine was lowered 6.6-fold by 5 microm tamoxifen. The kinetics and voltage-dependence of the effects of tamoxifen on glycine responses support the idea that this hydrophobic drug may act from a site located within the membrane. Tamoxifen (5 micro m) also increased responses to 2 micro m GABA by a factor of 3.5, but barely affected peak responses to 20 microm GABA. The demonstration that tamoxifen affects some of the main inhibitory receptors should be useful for better evaluating its neurological effects. Furthermore, the results identify a new class of molecules that potentiate glycine receptor function.
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PMID:Potentiation of glycine responses by dideoxyforskolin and tamoxifen in rat spinal neurons. 1260 58

We examined protein kinase C (PKC) in the regulation of breast cancer cells by estrogen. Estrogen receptor (ER)- positive (+) MCF-7 and ER-negative (-) HCC38 cells were treated with 17 beta-estradiol (E(2)) or E(2)-BSA, which cannot enter the cell. E(2) and E(2)-BSA rapidly increased PKC-alpha in both cells via phosphatidylinositol-dependent phospholipase C and G protein, but not phospholipase A(2) or arachidonic acid. In MCF-7 cells, E(2) and E(2)-BSA had comparable effects, maximal at 90 min. In HCC38 cells, PKC was maximal at 9 min, with E(2)-BSA more than E(2). Tamoxifen blocked estrogen-dependent PKC in MCF-7 cells and reduced it in HCC38 cells. ER-antagonist ICI 182780, ER-agonist diethylstilbestrol, and antibodies to ER alpha and ER beta had no effect. E(2) stimulated [(3)H]thymidine incorporation in MCF-7 only; E(2)-BSA had no effect. Tamoxifen did not alter E(2)-dependent increases in MCF-7 cells, whereas ICI 182780 reduced DNA synthesis in control and E(2)-treated cultures. PKC activity was positively correlated with tumor severity in 133 breast cancer specimens and was greater in ER(-) tumors. Tamoxifen treatment reduced recurrence, and recurrent tumors had higher PKC activity. This indicates that E(2) rapidly increases PKC activity via membrane pathways not involving ER alpha or ER beta and suggests that tamoxifen works by reducing PKC activity through non-ER alpha/ER beta-dependent mechanisms.
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PMID:Estrogen-dependent rapid activation of protein kinase C in estrogen receptor-positive MCF-7 breast cancer cells and estrogen receptor-negative HCC38 cells is membrane-mediated and inhibited by tamoxifen. 1269 87

Tamoxifen (TAM) is the endocrine therapeutic agent the most widely used in the treatment of breast cancer, and it operates primarily through the induction of apoptosis. In this study, we attempted to elucidate the non-ER mediated mechanism behind TAM treatment, involving the phospholipase C-protein kinase C (PLC-PKC) mediated phospholipase D (PLD) activation pathway, using multimodality methods. In TAM treated MCF7 cells, the PLC and PLD protein and mRNA levels increased. Phosphatidylethanol (PEt) and diacylglycerol (DAG) generation also increased, showing increased activity of PLD and PLCgamma1. Translocation of PKCalpha, from cytosol to membrane, was observed in TAM treated cells. By showing that both PKC and PLC inhibitors could reduce the effects of TAM-induced PLD activation, we confirmed the role of PKC and PLC as upstream regulators of PLD. Finally, we demonstrated that TAM treatment reduced the viability of MCF7 cells and brought about rapid cell death. From these results, we confirmed the hypothesis that TAM induces apoptosis in breast cancer cells, and that the signal transduction pathway, involving PLD, PLC, and PKC, constitutes one of the possible mechanisms underlying the non-ER mediated effects associated with TAM.
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PMID:Phospholipase C-protein kinase C mediated phospholipase D activation pathway is involved in tamoxifen induced apoptosis. 1276 85

Tamoxifen at a dose of 400 microg/kg/day has been reported to reduce the fertility of adult male rats and alter the pattern of cauda sperm motility from forward progressive to circular yawing type. Since sperm motility is powered by mitochondria, the effect of tamoxifen on mitochondrial function was studied. Tamoxifen treatment significantly increased rhodamine 123 fluorescent dye uptake by sperm mitochondria, reflecting an altered mitochondrial membrane potential. ATP and DAG levels, activities of glycolytic enzymes, creatine kinase and PKC all remained unaffected by tamoxifen. This is also the first report describing the presence of PKC alpha and beta in rat sperm. Morphological and biochemical integrity of sperm membranes was determined by electron microscopy and malondialdehyde levels, which were unaltered after tamoxifen treatment. This study indicates that the altered sperm motility induced by tamoxifen is accompanied by changes in mitochondrial membrane potential, but in the absence of any detectable change in membrane integrity, lipid peroxidation, ATP levels and activities of glycolytic enzymes, creatine kinase and PKC.
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PMID:Tamoxifen, protein kinase C and rat sperm mitochondria. 1297 82

Tamoxifen inhibits bone resorption by disrupting calmodulin-dependent processes. Since tamoxifen inhibits protein kinase C in other cells, we compared the effects of tamoxifen and the PKC inhibitor, bis indolylmaleimide II (bIM), on bone resorption and acid transport activity in isolated membrane vesicles. Bis indolylmaleimide inhibited bone resorption 50% with an IC50 approximately 3 microM, as well as acid transport activity in a concentration -dependent manner with an IC50 of approximately 0.4 IM. The IC50 of bIM for inhibiting acid transport activity was similar to that of calmodulin antagonists. The potassium ionophore, valinomycin, failed to restore bIM or tamoxifen-dependent inhibition of acid transport, suggesting that bIM and tamoxifen both inhibit H(+)-ATPase activity. Half maximal inhibitory concentrations of tamoxifen and bIM were not additive in acid transport assays, suggesting different sites of action. Furthermore, exogenous calmodulin blocked tamoxifen, but not bIM, -dependent inhibition of acid transport. We also compared the effects of tamoxifen and bIM on phosphorylation of proteins in isolated membrane fractions as determined by 32P incorporation and autoradiography. Tamoxifen had no effect on protein phosphorylation in contrast to bIM, which inhibited phosphorylation of eight proteins with different apparent kinetics. The data suggest that, while tamoxifen and bIM both affect H(+)-ATPase activity, the mechanisms of action are different.
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PMID:Differential effects of calmodulin and protein kinase C antagonists on bone resorption and acid transport activity. 1466 43

Tamoxifen, a non-steroidal anti-estrogen widely used against breast cancer, is also useful for treatment of other malignancies, due to its sensitizing effect on other chemotherapeutic agents and radiation. We have investigated the advantages of combining tamoxifen with one of the commonly used cancer chemotherapeutic drug, etoposide (VP-16) in brain tumor cell lines. While tamoxifen (10 microM) increased etoposide cytotoxicity 8.3-fold in the human glioma cell line (HTB-14), it increased etoposide cytotoxicity 47.5- and 40-fold in two primary cell lines established from pediatric medulloblastoma patients (MCH-BT-31 and MCH-BT-39), respectively. Similarly, in the pediatric ependymoma cell lines (MCH-BT-30 and MCH-BT-52), tamoxifen enhanced etoposide cytotoxicity 6- and 2.68-fold, respectively. CalcuSyn analysis of cytotoxicity data showed that tamoxifen and etoposide combinations were synergistic with combination index values ranging from 0.243 to 0.369 at IC50 level among different pediatric brain tumor cell lines. Tamoxifen is also cytotoxic at higher concentrations (> 20 microM) in brain tumor cells. To understand the mechanism underlying the tamoxifen modulation of etoposide cytotoxicity, we analyzed expression of P-glycoprotein (P-gp), insulin-like growth factor-I receptor (IGF-IR), IGF-I, IGF-II and estrogen receptor as well as protein kinase C (PKC) activity. While P-gp, IGF-IR and IGF-I were not affected, enhanced inhibition of PKC, and IGF-II were observed in brain tumor cells treated with tamoxifen and etoposide combination as compared to cells treated with either drug alone. Tamoxifen at 10 microM when combined with etoposide at 0-100 microM concentrations reduced PKC activity 77% compared to only 58% without tamoxifen. IGF-II expression decreased to 48.6% of the untreated control in the combination treatment as compared to 31.2% for etoposide alone and 26.2% for tamoxifen alone treatments. These results suggest that inhibitory effect of tamoxifen on brain tumor cells manifest through different mechanisms involving inhibition of targets such as PKC and IGF-II.
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PMID:Tamoxifen modulation of etoposide cytotoxicity involves inhibition of protein kinase C activity and insulin-like growth factor II expression in brain tumor cells. 1507 44

Tamoxifen is a well-known antiestrogen used for the hormonotherapy of estrogen receptor positive breast cancer. In addition to its high affinity binding to the estrogen receptor (ER), tamoxifen binds with comparable affinity to the microsomal antiestrogen binding site (AEBS), and inhibits with a micromolar efficiency, protein kinase C (PKC), calmodulin (CaM)-dependent enzymes and Acyl CoenzymeA: Cholesterol Acyl Transferase (ACAT). Each of these tamoxifen targets might explain the genomic as well as non-genomic effects of tamoxifen. In this review, we will report current knowledge about the structural features of tamoxifen involved in this multiple targeting. These data provide a useful guide for the conception of selective ligands of ERs, AEBS, PKC, CaM or ACAT based on the chemical structure of tamoxifen.
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PMID:Multiple targeting by the antitumor drug tamoxifen: a structure-activity study. 1557 15


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