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 cleavage activity, stability, and efficacy of 2'-amino pyrimidine modified ribozymes on malignant glioma growth. A synthetic protein kinase C alpha (PKC alpha) ribozyme with complete pyrimidine nucleotide substitution retained a comparable cleavage activity compared with the unmodified ribozyme. The half-life of the modified ribozyme in serum was increased 14,000-fold compared with the unmodified version. The PKC alpha modified ribozyme inhibited glioma cell growth in vitro as a result of the inhibition of PKC alpha gene expression. A single injection of cationic liposome ribozyme complexes into glioma tumors inhibited tumor growth, demonstrating both the efficacy of the ribozyme and a major role of PKC alpha in tumor growth.
 ...
PMID:A nuclease-resistant protein kinase C alpha ribozyme blocks glioma cell growth. 962 87

Through direct synthetic efforts, we discovered a small molecule that is a nanomolar inhibitor of the human fibroblast growth factor-1 receptor (FGFR) tyrosine kinase. PD 166866, a member of a new structural class of tyrosine kinase inhibitors, the 6-aryl-pyrido[2,3-d]pyrimidines, was identified by screening a compound library with assays that measure protein tyrosine kinase activity. PD 166866 inhibited human full-length FGFR-1 tyrosine kinase with an IC50 value of 52.4 +/- 0.1 nM and was further characterized as an ATP competitive inhibitor of the FGFR-1. In contrast, PD 166866 had no effect on c-Src, platelet-derived growth factor receptor-beta, epidermal growth factor receptor or insulin receptor tyrosine kinases or on mitogen-activated protein kinase, protein kinase C and CDK4 at concentrations as high as 50 microM. PD 166866 was a potent inhibitor of basic fibroblast growth factor (bFGF)-mediated receptor autophosphorylation in NIH 3T3 cells expressing endogenous FGFR-1 and in L6 cells overexpressing the human FGFR-1 tyrosine kinase, confirming a tyrosine kinase-mediated mechanism. PD 166866 also inhibited bFGF-induced tyrosine phosphorylation of the 44- and 42-kDa (ERK 1/2) mitogen-activated protein kinase isoforms in L6 cells, presumably via inhibition of bFGF-stimulated FGFR-1 tyrosine kinase activation. PD 166866 did not inhibit platelet-derived growth factor, epidermal growth factor or insulin-stimulated receptor autophosphorylation in vascular smooth muscle, A431 or NIHIR cells, respectively, further supporting its specificity for the FGFR-1. In addition, daily exposure of PD 166866 to L6 cells at concentrations from 1 to 100 nM resulted in a concentration-related inhibition of bFGF-stimulated cell growth for 8 consecutive days with an IC50 value of 24 nM. In contrast, PD 166866 had little effect on platelet-derived growth factor-BB-stimulated growth of L6 cells or serum-stimulated vascular smooth muscle cell proliferation. Finally, PD 166866 was found to be a potent inhibitor of microvessel outgrowth (angiogenesis) from cultured artery fragments of human placenta. These results highlight the discovery of PD 166866, a new nanomolar potent and selective small molecule inhibitor of the FGFR-1 tyrosine kinase with potential use as antiproliferative/antiangiogenic agent for such therapeutic targets as tumor growth and neovascularization of atherosclerotic plaques.
 ...
PMID:In vitro biological characterization and antiangiogenic effects of PD 166866, a selective inhibitor of the FGF-1 receptor tyrosine kinase. 965 4

Thrombospondin 1 (TSP1) is an angiogenesis inhibitor that decreases tumor growth. We now report that TSP1 directly inhibits the proliferation of human melanoma cells. TSP1, peptides, and a recombinant fragment from the type I repeats, but not peptides that bind CD36 or CD47, inhibit the proliferation of A2058 melanoma cells. In contrast, chemotaxis is mediated by peptides or recombinant fragments from the procollagen, type I, type II, and cell-binding domains. The antiproliferative activity of TSP1 is mediated by a different signal transduction pathway than those mediating motility responses to the same protein. Activators of protein kinase A and protein kinase C inhibit chemotaxis but not the antiproliferative activity of TSP1, whereas the antiproliferative activity is reversed by inhibiting the tyrosine kinase or phosphatase activities. TSP1-mediated chemotaxis is partially dependent on a pertussis toxin (PT)-sensitive G-binding protein, whereas haptotaxis is not. Chemotaxis stimulated by the procollagen domain and the CD47-binding sequences from the COOH-terminal domain are also sensitive to PT, but responses to the type I and type III domains are not sensitive to PT. Residual chemotaxis to TSP1 in the presence of PT may therefore be mediated by the activities of the type I or type III repeats. Thus, TSP1 elicits several intracellular signals in melanoma cells that result from interactions with several domains of this protein and differentially affect growth and motility.
 ...
PMID:Differential roles of protein kinase C and pertussis toxin-sensitive G-binding proteins in modulation of melanoma cell proliferation and motility by thrombospondin 1. 967 84

The new antiestrogen toremifene (TOR) is currently on the market for the treatment of advanced breast cancer in postmenopausal women. TOR is known to exhibit a similar efficacy profile as tamoxifen (TAM) in the treatment of advanced breast cancer and there are studies to suggest that the beneficial side effects of TAM on bone and blood lipids are also achieved with TOR. However, the data concerning the action of TOR on the endometrium is sorely lacking. In light of the estrogenic effect of TAM on the uterus and the 2-3-fold increased incidence in endometrial carcinoma detected in patients receiving TAM therapy, it is imperative to investigate the effect of TOR on endometrial carcinoma. We compared the actions of TAM and TOR on the EnCa101 human endometrial tumor model and find that both antiestrogens have similar growth stimulatory effects. To investigate a potential mechanism of antiestrogen-stimulated endometrial tumor growth, we have examined known activators of the AP-1 signal transduction pathway, the protein kinase C (PKC) family of isozymes, in the EnCa101 human endometrial tumor model. We find that increased PKC isozyme expression correlates with hormone-independent breast cancer as well as antiestrogen-stimulated endometrial cancer.
 ...
PMID:Antiestrogen stimulated human endometrial cancer growth: laboratory and clinical considerations. 969 72

Suppressor macrophages induced by the continuous invasion of tumor cells and parasites, which can acquire an ability in vitro to kill or inhibit tumor cells and inhibit the activity of T, B lymphocytes and NK cells, have been indicated. We have developed a procedure previously to modulate the suppressor macrophages by bacterial lipopolysaccharide (LPS). The modulated macrophages remained and even enhanced the ability to inhibit tumor growth and to up-regulate or enhance the activities of T, B lymphocytes and NK cells in vitro. However, the mechanisms of macrophage modulation by LPS are unknown. This investigation was designed to analyze the regulation of PKC activity and to characterize the isoforms of PKC during macrophage modulation by using Western blot and endogenous substrate phosphorylation (PKC-DESP). In rest cells, PKC-beta was found to be the most abundant isoform in macrophages; and PKC-alpha, beta was found predominantly in the cytosol. Using PMA as a positive control, we found that the immuno-modulator agent--LPS triggered the physical translocation from the cytosol onto the membrane of PKC-alpha and PKC-epsilon, but PKC-beta (beta I or beta II) was difficult to detect. The analysis of PKC-DESP showed a pattern with a time course similar to that observed with Western blot. We observed that LPS and PMA increase the level of phosphorylation of 55 kDa and 74 kDa proteins with a corresponding decrease in the cytosolic proteins. It suggests that the translocation of PKC-alpha and PKC-epsilon, may be important events involving in the PKC-pathway by LPS-mediated modulation in suppressor macrophages.
 ...
PMID:[LPS and PMA induced PKC-alpha and PKC-epsilon activation and translocation in murine peritoneal macrophages]. 977 87

We have evaluated the effects of bryostatin 1 on growth of a highly malignant p53-null mouse mammary tumor line, 4T1, and the mechanism by which bryostatin 1 inhibits in vitro growth and in vivo development of tumor and metastases from the orthotopic site. Bryostatin 1 at 20-400 nM concentrations inhibits growth of 4T1 cells by approximately 60% in two-day cultures. Inhibition of growth is associated with an increase in the number of cells undergoing apoptosis with concomitant elevation in the steady state levels of bax protein and drop in bcl-2 levels. The cytotoxic effect of bryostatin 1 on 4T1 cells occurs independently of p53, since there was no evidence of p53-mediated transcriptional activity in 4T1 cells following treatment with bryostatin 1.4T1 cells respond in vivo to bryostatin 1 therapy (75 microg/kg body weight). Intraperitoneal administration of bryostatin 1 inhibits both primary and secondary tumor growth by approximately 50%. However, although bryostatin 1 has a remarkable capacity to slow tumor growth and progression, it is unable to completely eradicate tumor growth and progression due to in vivo development of tumor resistance to bryostatin 1. Levels and cellular distribution of PKCalpha and delta do not correlate with the growth inhibitory effects of bryostatin 1 on 4T1 cells; however, reduction in cytosolic PKCalpha and delta without associated increase in membrane compartment appear to correlate with bryostatin-resistance. Our results suggest that the therapeutic effects of bryostatin 1 in our system do not involve alterations in levels and distribution of PKC but rather a direct upregulation of bax/ bcl-2 ratios that is independent of p53.
 ...
PMID:p53 and protein kinase C independent induction of growth arrest and apoptosis by bryostatin 1 in a highly metastatic mammary epithelial cell line: In vitro versus in vivo activity. 985 25

MCF-7 breast cancer cells stably transfected with protein kinase C-alpha (MCF-7-PKC-alpha cells) show anchorage-independent growth and exhibit increased tumorigenicity in nude mice. Since integrins are involved in tumor growth and metastatic spread, we investigated whether integrin expression is differentially regulated in MCF-7-PKC-alpha cells. Fluorescence-activated cell sorting revealed that alphavbeta3 is highly expressed on MCF-7-PKC-alpha cells, but is undetectable on MCF-7V cells (MCF-7 cells transfected with vector only). In contrast, MCF-7-PKC-alpha cells have reduced expression of alphavbeta5. Blocking experiments with antibodies to alphavbeta3 and alphavbeta5 revealed that these receptors are used by MCF-7-PKC-alpha cells to adhere primarily to vitronectin and osteopontin. Consistent with heterodimer expression, MCF-7-PKC-alpha cells express increased beta3 and decreased beta5 on their surface. Surface expression of alphav on MCF-7-PKC-alpha cells is unchanged. Western blotting, Northern analysis, and nuclear run-on assays indicated that post-translational mechanisms increase the surface expression of beta3 on MCF-7-PKC-alpha cells. In contrast, reduced beta5 transcription diminishes beta5 surface expression on MCF-7-PKC-alpha cells. These results indicate that overexpression of PKC-alpha in MCF-7 cells alters beta5 and beta3 expression by transcriptional and post-translational mechanisms, respectively, resulting in altered heterodimer expression. These findings suggest that the increased metastatic capacity of tumor cells with elevated protein kinase C levels may result, in part, from modulation of integrin expression.
 ...
PMID:Overexpression of protein kinase C-alpha in MCF-7 breast cancer cells results in differential regulation and expression of alphavbeta3 and alphavbeta5. 1037 5

The orphan receptor tyrosine kinase Tie-1 is expressed predominantly in endothelial cells. Expression of this receptor is increased in physiologic angiogenesis and pathologic situations including tumor growth and arteriovenous malformations. Tie-1 is essential for vascular development where it acts in later stages of angiogenesis to suppress endothelial activation and stabilize the newly formed vessel. Stimulation of protein kinase C in endothelial cells results in endoproteolytic cleavage of Tie-1, releasing the extracellular ligand-binding domain of the receptor. We show that this is mediated by a metalloprotease. Immunoprecipitation and immunoblotting of lysates prepared from human placentas confirm that Tie-1 truncation occurs in vivo. We propose cleavage of this receptor may be a mechanism for inducing vessel destabilization by preventing ligand-activated signaling through Tie-1. Using an antibody that recognizes the carboxy terminus of the intracellular domain, we show that the Tie-1 endodomain formed on cleavage persists as a cell-associated fragment for several hours. Subcellular fractionation reveals this tyrosine kinase containing receptor fragment to be localized in the membrane fraction of the cell. Immunoprecipitation with antibodies recognizing phosphotyrosine demonstrates that cleavage of Tie-1 stimulates association of newly generated endodomain with cellular phosphoproteins. Furthermore, there was a marked induction of tyrosine phosphorylation of several proteins after PMA-induced endodomain generation. These data indicate that ectodomain cleavage may be a mechanism for down-regulating ligand-induced signaling through Tie-1 while activating an alternative ligand-independent signaling pathway in endothelial cells. Ectodomain cleavage occurs in some other receptor tyrosine kinases. We suggest that rather than solely being a means of down-regulating receptor activity, ectodomain cleavage may be a novel way for a receptor to switch between two alternative signaling pathways.
 ...
PMID:Potential roles of metalloprotease mediated ectodomain cleavage in signaling by the endothelial receptor tyrosine kinase Tie-1. 1041 29

CGP 41251 was originally identified as an inhibitor of protein kinase C (PKC), inhibiting mainly the conventional PKC subtypes, and subsequently shown to inhibit the vascular endothelial growth factor (VEGF) receptor kinase insert domain-containing receptor, which is involved in angiogenesis. CGP 41251 inhibits reversibly intracellular PKC activity, induction of c-fos and the corresponding activation of the mitogen-activated protein kinase induced by either tumor promoting phorbol esters, platelet-derived growth factor, or basic fibroblast growth factor, but not by the epidermal growth factor. CGP 41251 inhibited the ligand-induced autophosphorylation of the receptors for platelet-derived growth factor, stem cell factor, and VEGF (kinase insert domain-containing receptor) that correlated with the inhibition of the mitogen-activated protein kinase activation, but did not affect the ligand-induced autophosphorylation of the receptors for insulin, insulin-like growth factor-I, or epidermal growth factor. CGP 41251 showed broad antiproliferative activity against various tumor and normal cell lines in vitro, and is able to reverse the p-glycoprotein-mediated multidrug resistance of tumor cells in vitro. CGP 41251 showed in vivo antitumor activity as single agent and inhibited angiogenesis in vivo. Thus, CGP 41251 may suppress tumor growth by inhibiting tumor angiogenesis (via its effects on the VEGF receptor tyrosine kinases) in addition to directly inhibiting tumor cell proliferation (via its effects on PKCs).
 ...
PMID:Inhibitors of protein kinases: CGP 41251, a protein kinase inhibitor with potential as an anticancer agent. 1045 7

With increasing size, multicellular prostate tumor spheroids develop regions of quiescent, multidrug-resistant cells expressing the cyclin-dependent kinase inhibitor p27(kip1). Treatment of small (diameter 60 +/- 20 micrometer) spheroids with 200 microM hydrogen peroxide (H(2)O(2)) resulted in cell cycle arrest owing to up-regulation of p27(kip1) and down-regulation of the transcription factor c-Fos. Incubation with 100 nM-1 microM H(2)O(2) led to up-regulation of c-Fos and enhanced tumor growth. Growth stimulation was inhibited by bisindolylmaleimide I, indicating a role for protein kinase C in the signaling cascade that involved the mitogen-activated protein kinase members MEK1,2, ERK1, -2, and c-Jun N-terminal kinase. Changes in Ca(2+) influx underlined the differential effects of H(2)O(2). Incubation with 200 microM H(2)O(2) released [Ca(2+)](i) from intracellular stores followed by prolonged Ca(2+) influx. Inhibition of influx by Ca(2+)-free media or Ni(2+), La(3+), Mn(2+) and SKF-96365 prevented the induction of quiescence and stimulated spheroid growth. Consequently, treatment with 200 microM H(2)O(2) in Ca(2+)-free media down-regulated p27(kip1) and increased Fos protein. ATP exerted effects comparably to those observed with H(2)O(2). Encoding growth stimulation by [Ca(2+)](i) release and induction of cell quiescence by prolonged Ca(2+) influx may provide a general mechanism for the control of tumor growth.
 ...
PMID:Growth stimulation versus induction of cell quiescence by hydrogen peroxide in prostate tumor spheroids is encoded by the duration of the Ca(2+) response. 1048 20


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