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)

The relationship between lung colonization and signal transduction was investigated for six B16 melanoma variants. A range of experimental metastatic potential (as determined by lung colonization), forskolin-stimulated cyclic AMP accumulation and FCS-stimulated protein kinase C activity was found. The major findings were that: (1) cells with the highest agonist-stimulated cyclic AMP production were those with the highest level of membrane-associated protein kinase C activity; (2) clones which differed in protein kinase C levels and distribution did so in the presence but not in the absence of foetal calf serum; and (3) no simple relationship was seen between either signal transduction system and lung colonization for all six variants. Altered ras expression was also excluded as an explanation for the differences in signal transduction and lung colonization potential which were observed. We conclude that differences in signal transduction in vitro between these cells do not relate simply to lung colonization potential in vivo.
Melanoma Res 1992 Sep
PMID:Signal transduction in murine B16 melanoma cells. 133 18

The involvement of signal transduction systems in the initial attachment of two murine B16 melanoma clones of differing metastatic potential to extracellular matrix components was examined to learn more of the early events in cell-matrix interaction. Clones of high and low metastatic capacity attached similarly in the absence of any stimulators, exhibiting a two phase time course of attachment with 100% attachment by 60 min. A slight difference in attachment characteristics between the clones was seen in response to phorbol ester stimulation, which significantly inhibited attachment of the low metastatic clone but which had no effect on the highly metastatic clone. Total protein kinase C activity and distribution was similar for both clones. Attachment of both clones was severely reduced, however, if intracellular calcium was elevated or intracellular calmodulin inhibited. This study suggests that signal transduction mechanisms are involved in melanoma cell attachment to matrix proteins and offers an approach to pharmacological manipulation of these cell-matrix interactions which may be relevant to reducing metastatic spread.
Melanoma Res 1992 Dec
PMID:Intracellular regulation of cell adhesion to extracellular matrix components in murine B16 melanoma cells. 133 99

The induction of differentiation, as evidenced by benign growth characteristics, dendritic morphology, pigmentation capability, and a mature antigenic phenotype, is an attractive theoretical basis for therapy in human melanoma. Melanoma differentiation can be experimentally induced by modulating intracellular pathways involving protein kinase C, tyrosine kinases, and protein kinase A, or by modulating nuclear transcription with retinoids, DNA-damaging agents, and chemotherapeutic drugs. Other experimental differentiating agents include the amino acid tyrosine, histamine receptor antagonists, polyamine antagonists, dimethylsulphoxide, caffeic acid ester, and butyrate. The mechanisms involved in the actions of many of these agents are beginning to be understood and the pathways are often intersecting; cross-talk in the form of negative and positive feedback loops is extensive. Uncoupling of pathways is also seen, with some agents leading to simultaneous increases in both differentiated and transformed characteristics. While clinical benefits of this approach have so far been sparse, greater understanding of the cellular pathways of differentiation may open new therapeutic options in melanoma.
Melanoma Res 1994 Aug
PMID:Cellular pathways leading to melanoma differentiation: therapeutic implications. 795 Mar 57

We have recently identified a gene encoding a calnexin-like protein (p90) by the immunoscreening of a human melanoma cDNA library, using a rabbit anti-human melanosomal antibody. This p90 protein was highly expressed by human melanocytes and associated with melanosomal membrane and endoplasmic reticulum. In this study we report the computer analysis of the predicted amino acid sequence of this calnexin-like melanosomal protein. We found that p90 is a membrane-bound protein whose large N-terminal domain is located within the melanosomal compartment; its shorter C-terminal is exposed to the cytosol and separated by a short transmembrane region. This p90 protein was found to have consensus sequences of a Ca(2+)-binding loop and a protein kinase C phosphorylation site at the N-terminal domain. The C-terminal domain, on the other hand, contained sequences of a casein kinase II phosphorylation site and two protein kinase A phosphorylation sites. Such functional motifs could provide signal transduction across the melanosomal membrane, the reception of melanogenic protein via carriers at the melanosomal membrane and the translocation of melanosomes in the melanocyte.
Melanoma Res 1993 Aug
PMID:cDNA-based functional domains of a calnexin-like melanosomal protein, p90. 821 59

Melanoma cells express receptors for melanocyte-stimulating hormone (MSH) in variable abundance. CGP 41251, a derivative of staurosporine with an increased selectivity for protein kinase C (PKC) inhibition, was found to modulate MSH receptors in human D10 and HBL cells and in the mouse B16 cell line. Up-regulation was observed in D10 and B16 cells at a concentration of 290 nM and 190 nM, respectively. In HBL cells, however, the PKC inhibitor induced a pronounced MSH receptor down-regulation with an EC50 of only 32 nM. In D10 and HBL cells, alpha-MSH and CGP 41251 synergistically regulated MSH receptors whereas these agents had an antagonistic effect in B16 cells. PKC stimulation by short-term treatment with phorbol ester had an opposite effect on MSH receptors as compared to CGP 41251. In B16 cells, CGP 41251 at a concentration of 100 nM increased the sensitivity to MSH-induced melanogenesis. The staurosporine derivative inhibited proliferation of HBL, B16, and D10 cells at EC50s of 180 nM, 190 nM, and 520 nM, respectively. Furthermore, CGP 41251 increased the dendricity of the cells. In a concentration range between 300 nM and 1 mu M, CGP 41251 induced a sharp increase of the mean cell diameter from 16 mu m to 19 mu m. Thus, the effects of the selective PKC inhibitor on MSH receptors are induced at lower concentrations than needed for the inhibition of proliferation or for the change in cell morphology. These results suggest that the number of MSH receptors expressed on the surface of cultured melanoma cells correlates with the level of constitutive PKC activity in individual cell lines.
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PMID:A selective protein kinase C inhibitor (CGP 41251) positively and negatively modulates melanoma cell MSH receptors. 890 45

Tumour cell arrest and the formation of stable adhesive interactions between tumour cells and endothelial cells or underlying matrix in the microvasculature are crucial steps in the metastatic process. We have developed a sensitive hydrodynamic adhesion assay to investigate the regulation of melanoma cell adhesion stabilization to the extracellular matrix protein fibronectin. Modulators of human MeWo melanoma Ca2+ concentration and stores, including ionomycin, thapsigargin, dantrolene and caffeine, inhibited cell adhesion stabilization to fibronectin; however, removal of Ca2+ from the extracellular medium did not affect stabilization. The calmodulin inhibitor W-7 and the protein kinase C inhibitor chelerythrine also blocked MeWo adhesion stabilization to fibronectin, as did the tyrosine kinase inhibitor genistein and the cytoskeletal inhibitor cytochalasin D. Manipulation of MeWo cell intracellular CAMP levels had no effect of adhesion stabilization to fibronectin, nor did treatment of cells with phorbol ester, pertussis toxin or cholera toxin. Drug treatments that inhibited adhesion stabilization also had significant effects on the actin cytoskeleton organization of the melanoma cells. This study suggests a role for calcium, calmodulin, protein kinase C and tyrosine kinases in the intracellular regulation of MeWo adhesive stabilization.
Melanoma Res 1996 Oct
PMID:Regulation of melanoma cell adhesion stabilization to fibronectin. 890 95

The purpose of this study was to examine which intracellular signalling systems influence the attachment of normal uveal melanocytes and uveal melanoma cells to extracellular matrix (ECM) proteins in vitro. Uveal melanocytes were found to attach strongly to fibronectin in preference to plastic, collagens type I, III or IV, or laminin. In contrast, uveal melanoma cells attached equally well to fibronectin and collagens I, III and IV in preference to plastic or laminin. Manipulation of intracellular cyclic AMP or protein kinase C had little, if any, effect on the attachment of either cell to fibronectin. In contrast, inhibition of calmodulin significantly inhibited the attachment of both normal and transformed cells, as did manipulating intracellular free calcium. We noted that the intracellular free calcium in melanoma cells was less than half that seen in melanocytes. Fibronectin, laminin and Arg-Gly-Asp (RGD) were all capable of acutely increasing the intracellular free calcium in both cells. ECM-induced increases in calcium were more apparent in low density than high density cells and appeared more sustained in melanocytes than in melanoma cells. We conclude that both normal and neoplastic uveal melanocytes require an intracellular signal or signals which involves calcium and calmodulin in the few minutes following cell binding to ECM proteins in order for successful cell attachment to occur. While the transformed cell does not differ significantly from the normal cell in this respect, this dependency on calcium and calmodulin may nevertheless offer an approach for pharmacological intervention in the prevention or arrest of metastatic spread and merits further investigation.
Melanoma Res 1997 Dec
PMID:Attachment of human uveal melanocytes and melanoma cells to extracellular matrix proteins involves intracellular calcium and calmodulin. 946 15

Bryostatin-1 is a protein kinase C regulator which has shown antitumour activity against B16 melanoma in animal models. Safety trials revealed this agent to be minimally toxic, thus a phase II trial of bryostatin-1 was conducted to determine its efficacy In patients with melanoma. Eighteen patients with metastatic melanoma, seven of whom had been previously treated, were enrolled in the study. Patients received bryostatin-1 25 microg/m2 intravenously weekly over 1 h for 3 out of 4 weeks. No objective responses were observed. One patient who had not previously received chemotherapy had stable disease for 4 months, and two patients (one previously treated) had a marked decrease in the skin component of their disease. The major toxicity was myalgia (one patient with grade III, two patients with grade II and five patients with grade I), with no grade IV toxicities reported. To Indirectly evaluate the stimulation of protein kinase C, a sensitive assay that measures the upregulation of the activated form of CD62 (glycoprotein IIb/IIIa) on platelets was performed. There was a statistically significant upregulation of this antigen 1 h after bryostatin-1 therapy. A bioassay based on the ability of bryostatin-1 to bind protein kinase C was used to measure bryostatin-1 levels in serum. This assay showed that bryostatin-1 has a volume of distribution of 2.1 l/m2, an elimination clearance of 32.9 ml/min per m2 and a half-life of 43.9 min. In conclusion, this phase II trial demonstrates that, although it is relatively non-toxic, bryostatin-1 therapy had minimal activity in metastatic melanoma.
Melanoma Res 1999 Dec
PMID:Treatment of patients with metastatic melanoma with bryostatin-1--a phase II study. 1066 72

Melanoma metastasis is almost uniformly fatal. The identification of signal transduction as crucial effectors for tumorigenesis suggests modalities of gene therapy as well as design of specific drugs. the possible use of nPKCdelta as a therapeutic target is reviewed and discussed. Motivated by recent results, we propose a model in which nPKCdelta modulates melanin synthesis as well as metastasis.
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PMID:nPKCdelta a new therapeutic marker for melanoma metastasis? (Review). 1076 48

In this study we analysed the effect of overexpressing novel protein kinase C delta isoform (n-PKC delta) on melanin synthesis and metastatic potential in the highly metastatic BL6 murine melanoma cells. The proliferative capacity in vitro and into matrigel in vivo were also examined. Although murine melanocytes express the n-PKC delta isoform, BL6 cells do not express this isoform at levels detectable by Western blot analysis. In untransfected and transfected cells we also studied the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), a modulator of specific isoforms of PKC, and of bryostatin 1, a potent immunomodulator and antineoplastic drug and a partial agonist of PKC. Our results demonstrate a pivotal role for this isoform in melanin synthesis and the close relationship between n-PKC delta expression and its association with the particulate fraction, melanogenesis and metastatic potential. In fact, heterogeneous BL6 cells overexpressing n-PKC delta and all the clones isolated showed increased intracellular melanin and metastatic capacity. TPA and bryostatin 1 decreased n-PKC delta expression, the intracellular melanin level and metastatic capacity in both cell lines. Therefore both treatments were able to abolish the effects of overexpressing n-PKC delta.
Melanoma Res 2000 Apr
PMID:Overexpression of novel protein kinase C delta in BL6 murine melanoma cells inhibits the proliferative capacity in vitro but enhances the metastatic potential in vivo. 1080 9


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