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)

Neoplastic transformation of pigment cells in the teleostean fish Xiphophorus is mediated by a cellular oncogene (Tu). Normally. Tu is suppressed by multiple regulating genes (R). Depending on impairment and loss of R genes, Tu is permitted to express itself phenotypically. In the pigment cell system, different degrees of Tu expression lead to small spots of transformed cells or to benign or malignant melanoma. All neoplastic and nonneoplastic cells of all Xiphophorus genotypes tested thus far appear to contain the cellular homolog (c-src) of the avian sarcoma virus oncogene (v-src). The evidence for this stems from the detectability of a Mr 60,000 phosphoprotein with associated kinase activity (pp60c-src) that reacts with antiserum against viral pp60src. We followed the inheritance of Tu (identified by spots and melanomas) compared to the expression of c-src identified by the pp60c-src-associated protein kinase). By quantitative determination of kinase activity in immunoprecipitated pp60c-src from fish showing different degrees of Tu expression, we have investigated whether there exists a correlation between the expression of c-src and Tu. In genotypes with the same genetic background, cells from Tu-containing fish express more pp60c-src than do cells from fish lacking Tu. In genotypes carrying a Tu gene and which show differences in the amount of gene expression due to a different extent of repression by regulating genes, analysis of kinase activity revealed that an increase of Tu expression is correlated with an elevated level of pp60c-src-associated kinase activity. Our findings may indicate that c-src activity in Xiphophorus is modulated by the Tu gene product or that Tu and c-src are regulated coordinately.
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PMID:Correlations of inheritance and expression between a tumor gene and the cellular homolog of the Rous sarcoma virus-transforming gene in Xiphophorus. 628 5

A mouse MAb3 50H.19 raised against the human melanoma cell line MEL-T binds to carcinoma cell lines, carcinoma biopsy material, and certain epithelia of normal tissues. It immunoprecipitates two components from carcinoma cell lines, a major component of 22 kd which is O-glycosylated and a minor one of 24 kd which is additionally N-glycosylated. The immunocomplexed 50H.19 antigen exhibits protein kinase activity with substrate-specificity for casein and phosvitin, but not for histones. It phosphorylates on serine and threonine, but not tyrosine residues. Enzyme activity is cyclic AMP-independent.
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PMID:Human tumor cell membrane glycoprotein associated with protein kinase activity. 651 Nov 25

We have previously reported [(1980) J. Biol. Chem. 255, 5999-6002] that retinoic acid inhibited growth and increased cyclic-AMP-dependent protein kinase activity in mouse melanoma cells. A variant melanoma line having depressed levels of cyclic-AMP-dependent protein kinase was not growth-inhibited by retinoic acid. In this report we describe the effect of retinoic acid on cyclic AMP binding proteins in B16 mouse melanoma cells. Using the technique of photoaffinity labeling, we found three major proteins of Mr 49 000, 52 000, and 55 000 which were specifically labeled with 8-N3-[32P]AMP in both control and treated cells. Based upon their molecular weight, relative affinity for 8-N3-[32P]AMP and comigration with standards, we have designated the 49 000-Mr and 55 000-Mr species as RI and RII respectively. The position of the intermediate band (Mr 52 000) was not affected by pre-incubation with ATP or alkaline phosphatase, and two-dimensional gel analysis indicated that it had the same pI as RI. Retinoic acid increased the 8-N3-[32P]AMP labeling of RI within 24 h, reaching a maximal six fold increase by 48 h. These increases were limited to the 40 000 X g supernatant fraction and occurred prior to any growth inhibition. By using increasing concentrations of 8-N3-cAMP we were able to construct a saturation curve for RI binding. Calculation of apparent Kd values from these curves showed nearly identical affinities for RI binding of 8-N3-cAMP from control and retinoic-acid-treated cells. Therefore we conclude that retinoic acid is increasing the amount of RI rather than altering its properties. Corroboration of these results was obtained by DEAE-cellulose chromatography. Peak I (corresponding to type I protein kinase) from retinoid-treated cells was increased about six fold in binding activity.
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PMID:The effect of retinoic acid on cyclic-AMP-binding proteins in mouse melanoma cells. 669 18

The pineal hormone melatonin modulates constitutive protein secretion from melanoma M2R cells. Nanomolar concentrations of melatonin inhibited protein secretion early after plating or at low cell density, but facilitated it late after plating or at high cell density. Inhibition by melatonin of adenylate cyclase is the best known downstream response to melatonin. We have therefore examined the involvement of cAMP in the melatonin-mediated modulation of protein secretion from the melanoma cells. Melatonin slightly but significantly reduced cell cAMP content when effecting inhibition and marginally increased cAMP levels when effecting facilitation of protein secretion. Dibutyryl cAMP abrogated the melatonin-mediated inhibition but not facilitation of protein secretion without affecting basal secretion. Accordingly, forskolin prevented the inhibitory action of melatonin on protein secretion without affecting basal secretion. The selective protein kinase A inhibitor H-89 did not alter the inhibitory effect of melatonin at low cell density and slightly facilitated secretion at high cell density with or without melatonin. Thus, melatonin's effects on protein secretion may not be mediated via cAMP. Nevertheless, changes in cAMP or protein kinase A activity can abrogate, or mask, the melatonin-mediated responses.
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PMID:Modulation by melatonin of protein secretion from melanoma cells: is cAMP involved? 748 20

The WAF1 gene, located on chromosome 6p, encodes a M(r) 21,000 protein (p21) that can arrest cell growth by associating with and inhibiting cyclin-dependent kinase complexes that are necessary for cells to exit Gr. Transcriptional activation of WAF1 can be accomplished by increasing levels of p53 protein induced by various cellular stresses, including DNA damage. Metastatic melanomas are paradoxical in that most overexpress wild-type p53 protein, yet cell growth is not inhibited. Thus, it is possible that lack of growth suppression in melanomas is due, in part, to mutations in the WAF1 gene. Therefore, we examined the entire coding region of the WAF1 gene in 24 metastatic melanoma cell lines and three normal melanocyte lines by single-strand conformation polymorphism (SSCP) analysis and direct DNA sequencing. We similarly examined the DNA from lymphoblastoid cell lines, derived from nine individuals belonging to seven melanoma-prone families, in which haplotypes of markers on 6p cosegregate with melanoma for germline mutations in the WAF1 gene. Results indicate that (i) mutation of the WAF1 gene is an infrequent event in individuals with sporadic melanoma or predisposed to familial melanoma and (ii) the uncontrolled growth of melanoma cells is not due to mutation of the WAF1 gene. However, expression studies found a wide variation in the level of p21 protein in melanoma cells, suggesting that aberrant regulation of p21 may play a role in melanoma development. Moreover, there was no predictable relationship between p21 expression and p53 expression, indicating that other, p53-independent, pathways may be important for the regulation of p21 in melanoma cells.
Melanoma Res 1995 Aug
PMID:Mutations and defective expression of the WAF1 p21 tumour-suppressor gene in malignant melanomas. 749 59

The process of tumor cell invasion of the basement membrane is proposed to consist of three steps: attachment, local proteolysis and migration. 12-(S)-HETE, a 12-lipoxygenase metabolite of arachidonic acid, upregulates surface expression of integrin cytoadhesins and an autocrine motility factor receptor, suggesting that this metabolite may play an important regulatory function in tumor cell invasion. In the present study, we determined whether 12-(S)-HETE affects surface expression and/or release of cathepsin B, a cysteine protease that has been implicated in focal degradation of basement membrane. Secretion and distribution of cathepsin B was evaluated in two model systems for various stages of neoplastic progression: (i) murine B16 melanoma lines of low (B16-F1) and high (B16a) lung colonization potential, and (ii) immortalized and ras-transfected MCF-10 human breast epithelial cells that differ in their invasive capacities in vitro. In the B16a cells, 12-(S)-HETE induced release of native and latent cathepsin B activity and concomitantly reduced cell-associated cathepsin B immunoreactivity. In contrast, 12-(S)-HETE did not induce the release of cathepsin B from B16-F1 cells, suggesting that there may be an enhanced response to 12-(S)-HETE in more malignant cells. This was confirmed in the MCF-10 system, in which 12-(S)-HETE was able to induce the release of cathepsin B from the ras-transfected cells, but not from the immortal cells. A simultaneous reduction in staining for cathepsin B was observed in the ras-transfected cells, but not in their immortal counterparts. The release of cathepsin B may be mediated by PKC as pretreatment of B16a cells with the selective PKC inhibitor calphostin C, but not with the PKA inhibitor H8, prevented the stimulated release of cathepsin B. In B16a cells, the release of cathepsin B was accompanied by a translocation toward the cell periphery of vesicles staining for cathepsin B, resulting in focal areas of accumulation of cathepsin B. After 12-(S)-HETE stimulation of the ras-transfected MCF-10 cells, cathepsin B was distributed homogeneously on the apical surface. Thus, 12-(S)-HETE can upregulate the surface expression on tumor cells of proteins able to mediate each of the three steps of tumor cell invasion: adhesion, degradation, and migration.
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PMID:A lipoxygenase metabolite, 12-(S)-HETE, stimulates protein kinase C-mediated release of cathepsin B from malignant cells. 752 40

p16INK4A and p15INK4B were initially identified as potent inhibitors of activated cyclin/cyclin-dependent kinase complexes. These genes were colocalized to chromosome 9p21, and p16 was subsequently found to be mutated in familial melanoma and deleted in a wide variety of sporadic cancers. We recently found that de novo methylation of a 5' CpG island led to transcriptional block of full-length p16 in many neoplasms. However, the presence of a truncated p16 transcript in methylated cell lines led us to investigate the presence of an alternative promoter or initiation site. We have now identified an abundant alternative p16 transcript in both methylated and unmethylated cell lines generated from a novel sequence (exon 1 beta) potentially involved in the complex regulation of these critical cell cycle genes.
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PMID:A novel p16INK4A transcript. 754 8

Local administration of high-dose r-TNF alpha with IFN gamma in the limbs of melanoma patients has proved to be a very promising treatment. To understand the role played by the effect of TNF on melanoma cells in tumor destruction, we have investigated the expression of TNF-receptors in melanoma cells using monoclonal antibodies specific for the type-A (75-kDa) and the type-B (55-kDa) TNF receptors. Flow cytometric analysis of cultured melanoma cells indicated the presence of both types of receptor. Quantificative differences in the relative levels of receptors were observed for different cells lines, although the type-B receptor was generally more strongly expressed. Similar results were obtained by immunohistochemistry on cryosections from tumor samples. Positive staining of variable intensity was observed for the type-B TNF-receptor in a high percentage of tumor cells. The type-A TNF-receptor was also detected, but with a weaker staining. The total TNF-binding activity of cultured melanoma cells, as measured by binding of 125I-labeled TNF alpha, was up-regulated between 2- and 4-fold by incubation of cells with activators of protein kinase A or IFN gamma. Treatment of cultured melanoma cells with dbc-AMP resulted in a selective induction of type-A TNF-receptors, without affecting the type-B receptor level. In contrast, IFN gamma was able to induce either type of receptor in a cell-line-dependent fashion. Addition of TNF alpha to melanoma cells induced the activation of the nuclear transcription factor kappa B, as measured in an electrophoretic mobility shift assay, thus indicating the biological significance of the TNF-receptors on these cells.
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PMID:Expression of type A and B tumor necrosis factor (TNF) receptors on melanoma cells can be regulated by dbc-AMP and IFN gamma. 760 71

The P15 gene (MTS2) encodes a cyclin-dependent kinase (CDK) inhibitor with considerable sequence identity and biochemical similarity to the CDK inhibitor p16. It is closely linked to the P16 gene (MTS1) and is homozygously deleted in many tumor cell lines. These features suggest that p15 may be a tumor suppressor. We have determined the genomic structure of P15 and examined its pattern of mRNA expression. In addition, we have shown that ectopic expression of p15 inhibits growth of tumor-derived cell lines. We have also searched for P15 mutations in tumor cell lines and in 9p21-linked melanoma kindreds. Other than the previously described homozygous deletions, no mutations of P15 were found. Collectively, these observations suggest a role for p15 in growth regulation, but a limited role for p15 in tumor progression.
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PMID:Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. 767 59

Melanin is specifically produced in melanocytes. The pathway for melanin biosynthesis is regulated by a number of melanocyte-specific proteins, including tyrosinase and tyrosinase-related protein-1 (TRP-1, b locus protein). To understand the regulation of melanogenesis, we examined tyrosinase activities, mRNA levels of tyrosinase and TRP-1, and eumelanin and pheomelanin contents in mouse B16-F1 melanoma cells after they had been treated with some melanotropic reagents. Cholera toxin, alpha-melanocyte-stimulating hormone, and dibutyryl cyclic AMP increased tyrosinase activity and stimulated eumelanin biosynthesis. These reagents elevated intracellular cAMP levels. In contrast, 12-O-tetradecanoylphorbol 13-acetate reduced tyrosinase activity and eumelanin synthesis. In all cases, the mRNA levels of tyrosinase and TRP-1 changed in parallel with tyrosinase activity and eumelanin content. TRP-1 was induced simultaneously with tyrosinase, although its inducibility was lower than that of tyrosinase. These results suggest that the expressions of tyrosinase and TRP-1 genes are coordinately regulated by melanotropic reagents through cAMP-dependent protein kinase and protein kinase C in mouse B16-F1 cells, and that their coordinate expression causes eumelanin biosynthesis.
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PMID:Eumelanin biosynthesis is regulated by coordinate expression of tyrosinase and tyrosinase-related protein-1 genes. 768 98


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