Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidylate synthase (TS) provides the only de novo source of thymidylate for DNA synthesis and is a key target for cancer chemotherapeutic agents. We investigated the TS gene expression by semiquantitative reverse-transcriptase polymerase chain reaction in metastatic melanoma and compared the results with those from control tissues. The relative TS/beta-actin level ratios were 0.5, 0.9, 0.3, 0.4, and 0.5 (mean 0.5) in skin, lymph node, thyroid, muscle, and spleen, respectively. In metastatic melanoma samples, the ratios varied from 0.9 to 2.7 (mean 2.0). The differences of expression levels between these two groups of samples were statistically highly significant (p = 0.0000713). A similar statistical significance (p = 0.0002) was observed between patients achieving a complete response and patients who had progressive disease despite immunochemotherapy. There was no clear relationship between a high TS/ beta-actin ratio and the S phase fraction, as all melanomas had a high S phase fraction.
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PMID:Increased thymidylate synthase gene expression in metastatic melanoma. 907 87

Basic Fibroblast Growth Factor (bFGF/FGF2) is thought to play a decisive role in malignant progression. Aberrant expression of bFGF causes constitutive autocrine activation of its cognate receptor and autonomous growth of human melanoma cells or bFGF transformed fibroblasts in culture. It remains to be determined, however, whether the endogenous bFGF confers growth advantage to tumors and what are the downstream targets of the activated FGF receptor critical for its transforming capacity. We therefore transfected metastatic melanoma cells and bFGF transformed mouse fibroblasts with a dominant-negative mutant of the murine FGF receptor 1 (fgfr1/flg), comprising the extracellular and transmembrane domains but lacking the intracellular kinase domain (dnflg). Reverse transcriptase-PCR, 125I-bFGF binding and affinity labeling analyses show that the truncated receptor is targeted to the membrane and is expressed at much higher levels than the endogenous receptor in all of the selected clones. Expression of the dnflg dramatically reduces the basal as well as bFGF induced growth of these cells in vitro and also suppresses their tumorigenic potential in nude mice. The expression of the dnflg does not significantly alter the general level of tyrosyl-phosphorylated proteins in the trunsduced melanoma cells. Rather, a major downstream affected target is a Src-family kinase, whose activity, determined by an in vitro immune kinase assay, is stimulated in normal melanocytes by exogenous bFGF, and is markedly reduced in the dnflg-expressing melanoma cells. The present study demonstrates that direct interference with the activity of FGF receptors has a deleterious effect on cell proliferation and survival in vitro and in vivo leading to the suppression of melanoma tumor progression possibly through the inactivation of a Src-family kinase.
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PMID:Suppression of autocrine cell proliferation and tumorigenesis of human melanoma cells and fibroblast growth factor transformed fibroblasts by a kinase-deficient FGF receptor 1: evidence for the involvement of Src-family kinases. 922 63

The vascular endothelial growth factor is produced by a large variety of human tumors, including melanoma, in which it appears to play an important role in the process of tumor-induced angiogenesis. Little information is available on the role of placenta growth factor, a member of the vascular endothelial growth factor family of cytokines, in tumor angiogenesis, even though placenta growth factor/vascular endothelial growth factor heterodimers have been recently isolated from tumor cells. To investigate the role of placenta growth factor and vascular endothelial growth factor homodimers and heterodimers in melanoma angiogenesis and growth, 19 human melanoma cell lines derived from primary or metastatic tumors were characterized for the expression of these cytokines and their receptors. Release of placenta growth factor and vascular endothelial growth factor polypeptides into the supernatant of human melanoma cells was demonstrated. Reverse transcriptase polymerase chain reaction analysis showed the presence of mRNAs encoding at least three different vascular endothelial growth factor isoforms (VEGF(121), VEGF(165), and VEGF(189)) and transcripts for two placenta growth factor isoforms (PlGF-1 and PlGF-2) in human melanoma cells. In addition, placenta growth factor expression in human melanoma in vivo was detected by immunohistochemical staining of tumor specimens. Both primary and metastatic melanoma cells were found to express the mRNAs encoding for vascular endothelial growth factor and placenta growth factor receptors (KDR, Flt-1, neuropilin-1, and neuropilin-2), and exposure of melanoma cells to these cytokines resulted in a specific proliferative response, supporting the hypothesis of a role of these angiogenic factors in melanoma growth. J Invest Dermatol 115:1000-1007 2000
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PMID:Human melanoma cells secrete and respond to placenta growth factor and vascular endothelial growth factor. 1112 Nov 33

We investigated the role of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in the growth regulation. Primary (PM-WK and KHm-4), recurrent primary (RPM-EP and RPM-MC), lymph node metastatic (MM-AN, MM-BP and MM-RU), and a visceral metastatic (MM-LH) melanoma cell lines were used. Reverse transcriptase-coupled polymerase chain reaction and Western blotting revealed that all expressed and produced TIMP-1 and TIMP-2 except for PM-WK, which neither expressed nor produced TIMP-1. TIMP-1 and TIMP-2 secretion levels were measured by enzyme-linked immunosorbent assay in supernatants of cells. We found that the TIMP-1 production level was correlated with the cell migration rate. Moreover, TIMP-1 enhanced the cell migration of PM-WK. The growth of the primary melanoma cell lines was stimulated by TIMP-1 and inhibited by TIMP-2. In contrast, the growth of the visceral metastatic melanoma cell line was stimulated by TIMP-2.
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PMID:Differential growth regulation in human melanoma cell lines by TIMP-1 and TIMP-2. 1160 52

Cutaneous melanomas have been found to express several immunogenic differentiation melanoma-associated antigens (MAAs) that have been suggested to play an important role in disease outcome. Adaptive host immunity to MAAs has shown some level of control on melanoma progression. To date, there has been no definitive report correlating the level of differentiated MAAs gene expression in melanomas with overall disease outcome. Metastasis of melanoma to distant visceral organ sites usually indicates a survival of less than 1 year; however, a subset of patients who undergo cytoreductive surgery of distant metastases survive for a longer period. We hypothesized that the gene expression level of differentiation MAAs in metastatic melanoma (AJCC stage IV) lesions would be predictive of survival. We focused on three known differentiation MAAs: tyrosinase (TYR), TYR-related protein 2 (TRP-2), and melanoma antigen recognized by T cells 1 (MART-1); all three of them are known to induce immune responses in melanoma patients and are frequently expressed in melanomas. A quantitative reverse-transcriptase RealTime PCR (qRT) assay was developed for these MAAs to assess mRNA expression in metastatic melanoma tumors obtained from cytoreductive surgery of AJCC stage IV melanoma patients (n = 35). Patients were followed up for over 60 months. There was a variation in mRNA copy levels for individual MAAs in melanoma tumors. Elevated MAA mRNA copy levels of TYR and TRP-2 significantly (P < 0.03 and < 0.009, respectively) correlated with improved overall survival. Patients having at least one MAA expressed in their tumors had a significantly (P = 0.01) better overall survival (median 16 months). These studies demonstrate that levels of differentiated MAA mRNA expression of advanced-stage metastatic melanomas can be used as molecular predictive factors of disease outcome. The studies also imply that an assessment of melanoma tumor MAAs may provide a stratification factor targeted for active-specific immunotherapy.
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PMID:Expression of differentiation melanoma-associated antigen genes is associated with favorable disease outcome in advanced-stage melanomas. 1254

Malignant melanoma is one of the most rapidly increasing cancer types, and patients with metastatic disease have a very poor prognosis. Detection of metastatic melanoma cells in circulation may aid the clinician in assessing tumor progression, metastatic potential, and response to therapy. Tyrosinase is a key enzyme in melanin biosynthesis. The gene is actively expressed in melanocytes and melanoma cells. Melan A is a differentiation antigen that is expressed in melanocytes. The presence of these molecules in blood is considered a marker for circulating melanoma cells. In this study, we analyzed the usefulness of this marker combination in evaluating the response to therapy in the blood of 30 patients with malignant melanoma. Circulating cells were detected by a reverse-transcriptase-polymerase-chain reaction. The tyrosinase expression was observed in 9 (30%) patients and Melan A in 19 (63.3%) patients before therapy. Following treatment, the tyrosinase mRNA was detected in only one patient, while Melan A transcripts were still present in 14 patients. We suggest that this molecular assay can identify circulating melanoma cells that express melanoma-associated antigens and may provide an early indication of therapy effectiveness.
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PMID:Detection of circulating melanoma cells by a two-marker polymerase chain reaction assay in relation to therapy. 1268 15

Downregulation of the immune system facilitates tumor progression at different stages of cutaneous melanoma. Sentinel nodes, the first lymph nodes on lymphatics draining directly from a primary melanoma, are immune downregulated by tumor-generated immunosuppressive cytokines, including interleukin-10 (IL-10). To better understand the kinetics of sentinel node suppression, we investigated IL-10 expression by melanoma cells and tumor-associated macrophages and lymphocytes at different stages of primary melanoma evolution. We used reverse-transcriptase in situ PCR to identify the cellular sources of IL-10 mRNA in 39 melanomas. IL-10 mRNA was identified in tumor cells of 2 of 6 melanomas in situ (33%), of 17 of 21 invasive melanomas (81%) and of 11 of 12 metastatic melanomas (92%). Higher IL-10 expression correlates with tumor progression, with differences between melanoma in situ, invasive melanoma and metastatic melanoma. In primary melanomas, the IL-10 mRNA content of tumor cells correlates with Clark's level. There was significantly more IL-10 mRNA in vertical growth-phase melanoma cells than in radial growth-phase cells. In a logistic regression model, moderate-to-high IL-10 mRNA expression by tumor cells was significantly associated with vertical growth-phase melanoma. IL-10 mRNA was detected in melanoma-associated macrophages and lymphocytes. In invasive melanomas, IL-10 mRNA reactivity of macrophages decreased as Clark's level increased. Alterations of immunity by IL-10 derived from melanoma cells and melanoma-associated macrophages and lymphocytes potentially facilitate evolution of the primary melanoma and render regional lymph nodes susceptible to metastases.
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PMID:IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence. 2131 76