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)

Melanocytic cells can produce two types of pigment, pheomelanin or eumelanin. We used two types of human melanoma cell lines to explore the regulation of pigmentation by biochemical and enzymatic studies. These two cell lines were previously designated as either pheomelanotic or of mixed type when cultured in a medium rich in cysteine. We analyzed the effects of L-cysteine depletion on melanin synthesis and the involvement of the tyrosinase-related proteins in the production of both eumelanin and pheomelanin. Cultures were exposed to L-cysteine concentrations ranging from 206 to 2.06 microM, and the following parameters were measured: tyrosine hydroxylase activity, intracellular L-cysteine and glutathione concentrations, eumelanin and pheomelanin formation, and tyrosinase-related protein-1 and -2 mRNA levels. Extracellular L-cysteine depletion significantly increased tyrosine hydroxylase activity and promoted both eumelanogenesis and visible pigmentation in both lines. In contrast, pheomelanogenesis was increased only in the pheomelanotic cell line. Whereas eumelanogenesis was apparent upon L-cysteine depletion, tyrosinase-related protein-1 expression was not induced in the pheomelanotic cells, and tyrosinase-related protein-2 expression remained unchanged. Thus, tyrosinase-related protein-1 mRNA expression seems to be concomitant with eumelanogenesis when the L-cysteine concentration is high, but does not appear essential for eumelanogenesis at low L-cysteine concentrations. The mechanisms governing pheomelanin to eumelanin balance are dependent on L-cysteine, glutathione, and tyrosinase-related protein-1 expression, but none of these factors alone appears to be dominant in directing the synthesis of a particular type of melanin.
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PMID:Cysteine deprivation promotes eumelanogenesis in human melanoma cells. 887 52

The melanosomal protein gp100 was recently described as an antigen associated with tumor rejection in adoptive immunotherapy using tumor-infiltrating lymphocytes. In this study, we investigated whether the expression of gp100 in melanoma cells correlates with responsiveness to treatment with interferon-alpha and interleukin-2. Using the monoclonal antibody HMB-45 recognizing gp100, we examined metastatic tissue resected before therapy in 44 patients with melanoma including 9 patients with subsequent complete or partial remission. A very heterogeneous pattern of gp100-expression was found between patients, but the percentage of gp-100 positive cells in different metastases resected from the same patient was rather constant. This suggests that the gp100 expression determined in a single metastasis may be judged as being representative for other metastatic lesions of a patient. We found no correlation between expression of gp100 and responsiveness to subsequent immunotherapy. Our results show that the lack of gp100 before therapy is not associated with decreased responsiveness to subsequent cytokine treatment.
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PMID:Expression of gp100 in melanoma metastases resected before or after treatment with IFN alpha and IL-2. 894 77

The infusion of TIL586 along with interleukin-2 into the autologous patient with metastatic melanoma resulted in the objective regression of tumor. A gene encoding a tumor antigen recognized by TIL586 was previously isolated and shown to encode gp75 or TRP-1. Here we report that TRP-2 was identified as a second tumor antigen recognized by a HLA-A31-restricted CTL clone derived from the TIL586 cell line. The peptide LLPGGRPYR epitope was subsequently identified from the coding region of TRP-2 based on studies of the recognition of truncated TRP-2 cDNAs and the HLA-A31 binding motif. This epitope peptide was capable of sensitizing target cells for lysis by a CTL clone at 1 nM peptide concentration. Although some modified peptides could be recognized by the CTL clone, none were found to be better recognized by T cells than the parental peptide. Like other melamona differentiation antigens, TRP-2 was only expressed in melanoma, melanocytes, and retina, but not in other human tissues tested.
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PMID:Identification of TRP-2 as a human tumor antigen recognized by cytotoxic T lymphocytes. 897 76

Current evidence suggests that melanogenesis is controlled by epidermal paracrine modulators. We have analyzed the effects of transforming growth factor-beta1 (TGF-beta1) on the basal melanogenic activities of B16/F10 mouse melanoma cells. TGF-beta1 treatment (48 h) elicited a concentration-dependent decrease in basal tyrosine hydroxylase and 3,4-dihydroxyphenylalanine (Dopa) oxidase activities, to less than 30% of the control values but had no effect on dopachrome tautomerase activity (TRP-2). The inhibition affected to similar extents the Dopa oxidase activity associated to tyrosinase-related protein-1 (TRP-1) and tyrosinase. This inhibition was noticeable between 1 and 3 h after the addition of the cytokine, and maximal after 6 h of treatment. The decrease in the enzymatic activity was paralleled by a decrease in the abundance of the TRP-1 and tyrosinase proteins. TGF-beta1 mediated this effect by increasing the rate of degradation of tyrosinase and TRP-1. Conversely, after 48 h of treatment, the expression of the tyrosinase gene decreased only slightly, while TRP-1 and TRP-2 gene expression was not affected. An increased rate of proteolytic degradation of TRP-1 and tyrosinase seems the main mechanism accounting for the inhibitory effect of TGF-beta1 on the melanogenic activity of B16/F10 cells.
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PMID:Transforming growth factor-beta1 inhibits basal melanogenesis in B16/F10 mouse melanoma cells by increasing the rate of degradation of tyrosinase and tyrosinase-related protein-1. 902 Jan 1

In this study we explored the possible application of MAT-1, which has been established as a monoclonal antibody against human tyrosinase, for detection of mouse tyrosinase. The MAT-1 reacted with B16 mouse melanoma cells, but not with tyrosinase-negative NIH-3T3 mouse fibroblasts. In western blot analysis of the large granule fraction (LGF) of B16 cells, MAT-1 detected a single protein of 80 kDa, whose size was close to that of human tyrosinase detected with MAT-1 in extracts of human melanocytes. Furthermore, the 80 kDa band that was detected with MAT-1 in the LGF of B16 cells was also detected by DOPA reaction. In order to confirm that the protein detected with MAT-1 is tyrosinase, a transient expression assay was carried out. When mouse tyrosinase or mouse tyrosinase-related protein-1, which shares high homology with human tyrosinase, was transiently expressed in tyrosinase-negative K1735 mouse melanoma cells by cDNA transfection, MAT-1 reacted only with the cells expressing mouse tyrosinase. These results indicate that MAT-1 specifically reacts with mouse tyrosinase.
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PMID:Detection of mouse tyrosinase with a monoclonal antibody MAT-1 against human tyrosinase. 912 53

Pigmentation of our skin, hair and eyes is essential for photoprotection, embryological development, detoxification and protective/cosmetic coloration. A number of proteins important to the production of melanin within melanosomes have now been identified including enzymatic and structural proteins encoded at the murine albino, brown, pinkeyed-dilution, MART1, slaty and silver loci. Interestingly, many of those melanosomal proteins (including epitopes derived from tyrosinase, TRP1/gp75, silver/gp100 and MART1/melan-A) function in vivo as targets of humoral and cellular autoimmune responses directed specifically against normal or transformed melanocytes. These findings have provided new impetus to research on immune responses to melanoma and, perhaps more importantly, examining why they are insufficient to provide protection against tumour growth and what type of immune therapy can be designed to correct that. The melanosome must now be considered beyond its function in pigmentation, and assumes the role of a valuable source for specific immune targets for malignant melanoma.
Melanoma Res 1997 Apr
PMID:Melanosomal proteins as melanoma-specific immune targets. 916 73

Both melanocytes and glial cells are derived embryologically from the neural ectoderm. Their malignant transformed counterparts, melanoma and glioma cells, respectively, may share common antigens. Numerous tumor-associated antigens have been identified in melanomas but only a few a gliomas. Using an established reverse transcriptase polymerase chain reaction plus Southern blot assay, we compared the mRNA expression of melanoma-associated antigens (MAAs) of melanomas to brain tumors primarily derived from glial cells. The MAAs studied included tyrosinase (Tyr), tyrosinase-related protein-1 and -2 (TRP-1 and TRP-2), gp100, human melanoma antigen-encoding genes 1 and 3 (MAGE-1 and MAGE-3), and melanotransferrin (p97). Glioblastoma multiforme (n = 21), anaplastic astrocytoma (n = 3), ependymoma (n = 2), meningioma (n = 3), oligodendroglioma (n = 1), and melanoma (n = 12) tumor specimens were assayed for MAA mRNA expression. Glioblastoma multiforme, astrocytoma, and melanoma cell lines were also assayed. We observed that individual MAA mRNAs were expressed in these brain tumors and cell lines at varying frequencies. The melanogenesis-pathway-related MAAs Tyr, TRP-1, TRP-2, and gp100 mRNAs were also expressed at different levels in normal brain tissues but at a much lower frequency than in glioblastoma multiforme and melanoma. MAGE-1 and MAGE-3 mRNA were expressed in different types of tumor specimens and cell lines but never in normal brain tissue. Tumor antigen p97 was expressed in all types of tumors and also in normal brain tissues. These studies demonstrate that melanomas and primary brain tumors express common MAAs and could be exploited in patients with malignant glioma by active specific immunotherapy against these common MAAs.
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PMID:Molecular detection of tumor-associated antigens shared by human cutaneous melanomas and gliomas. 917 5

Most of our knowledge of the mammalian tyrosinase related protein (TRP) activities is derived from studies using murine melanoma models, such as B16 or Cloudman S-91 melanocytes. Owing to the high degree of homology between the murine and human enzymes, it has been assumed that their kinetic behaviour could be similar. However, the protein sequences at the metal binding sites of the murine and human enzymes show some differences of possible functional relevance. These differences are more significant in the metal-A site than in the metal-B site. By using three human melanoma cell lines (HBL, SCL, and BEU), we have studied the catalytic abilities of the human melanogenic enzymes in comparison to those obtained for the counterpart murine enzymes isolated from B16 melanoma. We have found that TRP2 extracted from all cell lines show dopachrome tautomerase activity, although the activity levels in human malignant melanocytes are much lower than in mouse cells. Reconstitution experiments of the human enzyme indicate that TRP2 has Zn at its metal binding-sites. Although mouse tyrosinase does not show DHICA oxidase activity, and this step of the melanogenesis pathway is specifically catalyzed by mouse TRP1, the human enzyme seems to recognize carboxylated indoles. Thus, human tyrosinase could display some residual DHICA oxidase activity, and the function of human TRP1 could differ from that of the murine protein. Attempts to clarify the nature of the metal cofactor in TRP1 were unsuccessful. The enzyme contains mostly Fe and Cu, but the reconstitution of the enzymatic activity from the apoprotein with these ions was not possible.
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PMID:Comparison of TRPs from murine and human malignant melanocytes. 926 30

In the last five years, knowledge of human tumor antigens recognized by autologous cytolytic T lymphocytes (CTL) has increased considerably. So far, genetic and biochemical approaches have led to the molecular identification of three classes of antigens. Most of these antigens consist of peptides that are presented to T cells by HLA molecules. The first class comprises antigens encoded by genes such as MAGE, BAGE, and GAGE, which are expressed in various tumors of different histological origins, but not in normal tissues other than testis. The second class represents differentiation antigens encoded by genes that are only expressed in melanoma and normal melanocytes like tyrosinase, Melan-A/MART-1, gp100 and gp75. The third class includes antigens produced by unique point mutations in genes that are ubiquitously expressed. In most cases, the antigenic peptide is encoded by the mutated region of the gene. A number of these antigens provide promising targets for new protocols of specific cancer immunotherapy.
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PMID:Tumor antigens recognized by T lymphocytes. 926 77

Human melanoma-specific HLA-A2 restricted CTLs have recently been shown to recognize antigens expressed by melanoma lines and normal melanocytes, including Melan-A/Mart-1, gp100, gp75, and tyrosinase. Herein, we define HLA-A2-restricted CTL epitopes from a recently cloned melanocortin 1 receptor (MC1R), which belongs to a new subfamily of the G-protein-coupled receptors expressed on melanomas and melanocytes. Thirty-one MC1R-derived peptides were selected on the basis of HLA-A2-specific motifs and tested for their HLA-A2 binding capacity. Of a group of 12 high or intermediate HLA-A2 binding peptides, three nonamers, MC1R244 (TILLGIFFL), MC1R283 (FLALIICNA), and MC1R291 (AIIDPLIYA), were found to induce peptide-specific CTLs from peripheral blood mononuclear cells of healthy HLA-A2+ donors after repeated in vitro stimulation with peptide-pulsed antigen-presenting cells. The CTLs raised against these three HLA-A2+-restricted peptides could recognize naturally processed peptides from HLA-A2+ melanomas and from Cos7 cells cotransfected with MC1R and HLA-A2. CTLs induced by the MC1R291 peptide (but not induced or induced only to a very low extent by the other two MCR1 peptide epitopes) showed cross-reactions with two other members of the melanocortin receptor family, which are more broadly expressed on other tissues. Taken together, our findings have implications in relation both to autoimmunity and immunotherapy of malignant melanomas.
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PMID:Synthetic peptides derived from the melanocyte-stimulating hormone receptor MC1R can stimulate HLA-A2-restricted cytotoxic T lymphocytes that recognize naturally processed peptides on human melanoma cells. 933 Oct 97


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