Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of reactive oxygen intermediates and protein kinase C in the induction of expression of the c-jun gene in human ML-2 leukemic cells and normal human DET-551 fibroblasts by comparing the effects of exposure to either ionizing radiation or H2O2 in the presence or absence of appropriate inhibitors. In these cell types, the radiation- and H2O2-mediated increase in c-jun mRNA levels could be prevented by pretreatment of the cells with N-acetylcysteine, an antioxidant, or H7, an inhibitor of protein kinase C and protein kinase A, but not by HA1004, a specific inhibitor of protein kinase A and G. These results suggest a role for protein kinase C and reactive oxygen intermediates in the induction of c-jun gene expression in both normal and tumor cells. We also investigated potential differences in c-jun gene expression induced by radiation or H2O2 in normal and tumor cells by examining steady-state c-jun mRNA levels in a number of human fibroblast, leukemia, melanoma, sarcoma and carcinoma cell types. We observed heterogeneity in the steady-state level of c-jun mRNA in both the untreated normal and tumor cells and in such cells exposed to ionizing radiation or to H2O2. Exposure to radiation produced a varied response which ranged from little or no induction to an increase in the steady-state level of the c-jun mRNA of more than two orders of magnitude. Exposure to H2O2 gave a pattern similar to that of ionizing radiation. The basis for the differential induction in response to these agents may be attributable to either cell lineage or genetic heterogeneity or a combination of these two parameters.
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PMID:Heterogeneity in c-jun gene expression in normal and malignant cells exposed to either ionizing radiation or hydrogen peroxide. 772 34

A wide range of growth factors has been identified in recent years, some of which have been found to play a crucial role in neoplastic processes. Some tumours produce considerable amounts of these peptides and their requirement for growth factors is often much reduced leading to a degree of autonomy which may itself contribute to tumourigenicity. In addition, growth factors such as TGF-alpha, PDGF, FGF and IGFs have been found to be overexpressed in tumours. The growth factor effector pathway is thus open to intervention, e.g. by blocking the receptor using specific antibodies or interfering with posttranscriptional activation. This is even more evident as oncogenes such as erbB and v-sis encode for growth factor receptors. Soluble receptors, due to high affinity binding, might also be used to sequester growth factors from its specific membrane-bound receptors. Tyrosine-specific protein kinase activity may be inhibited by tyrosine analogues such as erbstatin or by more specific tyrosine-kinase inhibitors. Some therapeutical concepts have already been developed in clinical trials. Tumour necrosis factor (TNF) has successfully been used in extremity melanoma and sarcoma and monoclonal antibodies directed against the EGF receptor has also been applied in patients with advanced squamous lung cancer. Synthetic growth factor analogues which bind to the receptor without eliciting a signal may soon become a supplementary part in cancer treatment. Growth factor action is also blocked by suramin and its analogues and clinical phase I and II trials are underway. These novel therapeutical aspects will profoundly change the nature of cancer treatment.
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PMID:Growth factors, cytokines and soluble forms of receptor molecules in cancer patients. 776 4

Melanogenesis in melanoma cells can be enhanced by psoralens in the absence of UV light. Melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase, DOPAchrome tautomerase (DCT), and tyrosinase-related protein-1 (TRP-1, gp75). To get more insight on the molecular mechanisms involved in psoralens-induced melanogenesis, we determined tyrosinase and DCT activities as well as mRNA and protein levels of tyrosinase, DCT, and TRP-1 in S91 mouse melanoma cells treated by 5-MOP. High concentration of 5-MOP (5 x 10(-5) M) induced a time-dependent increase of tyrosinase activity and melanin content, which was correlated to an increase of both mRNA and protein levels of tyrosinase. These results demonstrate that the 5-MOP stimulation of melanogenesis is related to increased tyrosinase synthesis. In addition, 5-MOP stimulated TRP-1 synthesis and induced a dose-dependent decrease of DCT activity without any modification in the expression of the protein. We explored then the signalling pathways involved in 5-MOP-induced melanogenesis and, particularly, the role of cyclic AMP and protein kinase C (PKC). A small stimulation of cyclic AMP production was observed in presence of 5-MOP. Furthermore, 1-oleoyl-2-acetylglycerol (OAG), a PKC activator, potentiated the 5-MOP stimulation of tyrosinase activity, while calphostin, a specific PKC inhibitor, inhibited the 5-MOP induction of tyrosinase activity. Phorbol-myristate acetate (PMA), described as a strong activator of PKC, inhibited also the effect of 5-MOP when used at long term. Taken together, these results demonstrate that in murine melanoma cells 5-MOP stimulates melanogenesis by increasing activity and synthesis of tyrosinase. Tyrosinase and TRP-1 expression are coordinately regulated by 5-MOP. Furthermore, a negative correlation between melanogenesis and DCT activity was observed under 5-MOP stimulation. At least, PKA and PKC systems appear to play an important role in the melanogenic effect of 5-MOP.
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PMID:Regulation of melanogenesis induced by 5-methoxypsoralen without ultraviolet light in murine melanoma cells. 785 73

Aberrant function of protein kinases has been implicated in the development of melanoma. In an effort to define the molecular events involved in initiation and progression of this malignancy, we used RT-PCR to identify protein kinases in both normal and transformed melanocytes. Collectively, we identified seven clones corresponding to previously characterized protein kinases (JAK-1, TYK02, AXL/UFO, IGF1-R, KDR and FER) as well as the recently identified MLK-3/PTK1 protein kinase. Northern analysis was used to determine the expression pattern of each protein kinase in both normal melanocytes and a variety of melanoma cell lines. Relatively abundant levels of UFO/AXL and KDR mRNAs were observed in a subset of the melanoma cell lines whereas most of the remaining protein kinases were expressed at similar levels in both normal and transformed melanocytes.
Melanoma Res 1994 Oct
PMID:Protein kinases in normal and transformed melanocytes. 785 16

The benign dermal nevus can be transformed into malignant melanoma. The possibility that the transformation process is accompanied with enhanced casein kinase II (CK II) activity was investigated. The tissue samples were obtained by incisional biopsy, homogenized and ultracentrifuged. The supernatant was injected onto a Mono Q column. CK II was monitored with [gamma-32P]GTP and its specific substrate RRREEETEEE. The CK II stimulators, spermine and polylysine, the inhibitors heparin, quercetin, poly (Glu-Tyr) 4:1 and 2,3-bisphosphoglycerate were used for identification. CK II activity in metastatic melanoma samples was about 2.5-fold higher than in dermal nevus. These results support our hypothesis that CK II takes a central role in the non-transformed and transformed skin proliferation.
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PMID:Enhanced casein kinase II activity in metastatic melanoma. 794 92

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

The involvement of protein kinase C (PKC) in the mechanism of chemotaxis and invasiveness of human melanoma has been studied in 6 clones of 665/2 cell line characterized by a different integrin profile, differentiation grade and in vitro invasive ability. The levels of total protein kinase C activity revealed a direct correlation with the chemotactic and invasive ability of these clones. Protein kinase C inhibitors, sphingosine and staurosporine, reduced chemotaxis and invasiveness of the highly invasive clone 2/60, while 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) was ineffective. Immunofluorescence analysis revealed high levels of protein kinase C alpha in clone 2/60, while the less invasive clone 2/21 expressed low levels of protein kinase C alpha and beta, but surprisingly appreciable levels of protein kinase C gamma. Downregulation with phorbol 12-myristate 13-acetate (TPA) did not affect invasiveness of clone 2/60 unless the compound was present during the assay. H7 strongly increased invasiveness of clone 2/21 and was able to reverse the inhibitory effect of TPA on clone 2/60. Preliminary experiments showed higher levels of diacylglycerol in clones with lower protein kinase C, suggesting a constitutive downregulation of the enzyme in low invasive clones. Our results support a role for protein kinase C in the invasion process, but point out the complexity of the mechanism which might involve the proteolytic fragment of the enzyme, protein kinase M.
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PMID:Effect of protein kinase C inhibitors on invasiveness of human melanoma clones expressing different levels of protein kinase C isoenzymes. 815 65

Specific high-affinity receptors for alpha-melanocyte-stimulating hormone (alpha-MSH) are found in variable abundance on many melanoma cell lines. We have examined melanocortin peptides and other factors for their ability to regulate the number of MSH receptors in eleven human and two mouse melanoma cell lines. MSH induced up-regulation of its own receptors in three human cell lines and down-regulation in six human and two mouse melanoma cell lines. No regulation was observed in two human lines. Scatchard analysis revealed modulation of the number of receptors per cell without any change in affinity. The concentrations inducing half-maximal response for up- and down-regulation were 1.6 nM and 0.23 nM, respectively. ACTH1-17 and [Nle4,D-Phe7]-alpha-MSH were more potent, whereas ACTH1-24, desacetyl-alpha-MSH, and [Nle4]-alpha-MSH were less potent in receptor up-regulation as compared to alpha-MSH. Down-regulation but not up-regulation could be fully mimicked by Gs-protein activation and partially by elevation of cellular cAMP. Combination of different agents which increase cAMP was found to be counterregulatory. TPA and retinoic acid generally down-regulated MSH receptors but had no effect on HBL cells. Several protein kinase inhibitors increased MSH binding in B16 cells. MSH-induced receptor down-regulation and melanin synthesis were most effectively antagonized by selective inhibitors of cAMP-dependent protein kinase in these cells. Taken together, MSH receptors on melanoma cells are both positively and negatively regulated. Whereas cAMP-dependent protein kinase activation seems to be involved in down-regulation, the mechanism responsible for up-regulation remains to be elucidated.
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PMID:Homologous and heterologous regulation of alpha-melanocyte-stimulating hormone receptors in human and mouse melanoma cell lines. 816 86

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

Since S-nitrosylation of protein thiols is one of the cellular regulatory mechanisms induced by nitric oxide (NO), and since protein kinase C (PKC) has critical thiol residues which influence its kinase activity, we have determined whether NO could regulate this enzyme. Initial studies were carried out with purified PKC and the NO-generating agent S-nitrosocysteine. This agent decreased phosphotransferase activity of PKC in a Ca(2+)- and oxygen-dependent manner with an IC50 of 75 microM. Phorbol ester binding was affected partially only at higher concentrations (> 100 microM) of S-nitrosocysteine. This inactivation of PKC was blocked by the NO scavenger oxyhemoglobin or reversed by dithiothreitol. It is likely that NO initially induced an S-nitrosylation of vicinal thiols, which were then oxidized to form an intramolecular disulfide. Other NO-generating agents such as S-nitroso-N-acetylpenicillamine and sodium nitroprusside, as well as authentic NO gas, induced similar types of PKC modifications. In intact B16 melanoma cells treated with S-nitrosocysteine a rapid decrease in PKC activity in both cytosol and membrane was observed. Unlike in experiments with purified PKC, in intact cells treated with S-nitrosocysteine the phorbol ester binding also decreased to a rate equal to that of PKC activity. These modifications were readily reversed by treating the homogenates with dithiothreitol in test tubes or by removing the NO-generating source from intact cells. To determine whether the limited amounts of NO generated within the intact cells could induce this type of PKC modification, the macrophage cell line IC-21 was treated with lipopolysacharide and Ca2+ ionophore A23187 to induce the NO production. With an increase in generation of NO (3-12-h period) in these cells, a parallel and irreversible decrease in PKC activity and phorbol ester binding was observed. A specific inhibitor for NO synthase, NG-monomethyl-L-arginine, inhibited both the production of NO and PKC inactivation. In experiments using purified enzyme or intact cells there was no decrease in cAMP-dependent protein kinase activity. Conceivably, NO production for limited time induces a reversible inactivation of PKC due to the formation of a disulfide bridge(s), whereas the chronic production of NO could induce irreversible inactivation of PKC. The reversible or irreversible inactivations of PKC may in part influence NO-mediated cytoprotective or cytotoxic actions, respectively.
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PMID:Nitric oxide and nitric oxide-generating agents induce a reversible inactivation of protein kinase C activity and phorbol ester binding. 826 58


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