Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0025202 (melanoma)
69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of human melanoma cells with the differentiation-inducing agent hexamethylene bisacetamide (HMBA) results in reciprocal changes in expression of melanocyte-specific genes tyrosinase-related proteins-1 and -2 (TYRP1 and TYRP2). In this study, we investigated the effects of HMBA on cultured neonatal human cutaneous melanocytes. Flow cytometric analysis showed that HMBA inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-dependent growth of melanocytes by reducing the population of cells entering the DNA synthesis phase of cell cycle. Melanocyte growth inhibition was accompanied by an increase in the number of cells exhibiting polydendritic morphology. This morphologic change was less pronounced when HMBA was added to melanocytes in the absence of TPA. Northern blot analyses of total cellular RNA showed that expression of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), TYRP1, Silver (SILV/Pmel17) gene was down-regulated by HMBA, while TYRP2 mRNA was up-regulated (> 10-fold). When the inducer was added to cells in the absence of TPA, there was > 50-fold increase in TYRP2 mRNA with a moderate increase in MITF, tyrosinase and SILV gene mRNAs and complete repression of TYRP1 gene. Studies using inhibitors for protein kinases involved in cell signaling pathways suggested that stress-activated kinase p38 and mitogen-activated protein kinase kinase MEK are involved in TPA-independent regulation of TYRP2 expression in melanocytes. These data show that treatment of proliferating melanocytes with the differentiation inducer HMBA results in a distinct change in morphology and up-regulation of TYRP2, while quiescent melanocytes respond by a dramatic increase in expression of TYRP2 without change in morphology. These results suggest an inverse relationship of TYRP2 gene regulatory mechanisms to melanocyte growth regulatory pathways.
...
PMID:Regulation of tyrosinase-related protein-2 (TYRP2) in human melanocytes: relationship to growth and morphology. 1131 Jul 93

The proliferation of human melanoma cell line A375-6 cells is inhibited by several cytokines, including interleukin-1 (IL-1). A375-R8 cells, a subclone of A375-6, are resistant to IL-1-induced growth inhibition. The proliferation of both cell lines is inhibitable by tumor necrosis factor (TNF). In this study, we characterized the mechanisms of TNF-induced growth inhibition. TNF-induced growth inhibition in both cell lines was partially suppressed by a selective p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), whereas a combination of SB203580 and Z-VAD-fmk, an inhibitor for a wide range of caspases, completely blocked TNF-induced growth inhibition, indicating that TNF-induced growth inhibition is mediated by both p38 MAPK and caspases. However, Z-VAD-fmk alone suppressed TNF-induced growth inhibition in A375-R8, but not A375-6, cells, suggesting that there may exist a TNF-induced anti-apoptotic mechanism in A375-6 cells which is lost or mutated in A375-R8 cells. Evidence in support of this notion includes (1) TNF-induced apoptosis only in A375-R8, but not A375-6 cells; (2) cycloheximide enabled TNF to induce apoptosis even in A375-6 cells; and (3) somatic hybrid cells between A375-6 and A375-R8 cells are resistant to TNF-induced apoptosis. Since TNF-induced NF-kappa B activation, cell cycle arrest, RB dephosphorylation, and E2F downregulation are indistinguishable in both cell lines, none of these factors is likely to be involved in the TNF-induced anti-apoptotic mechanism in A375-6 cells. Our results indicate that TNF activates two distinct anti-proliferative pathways including p38 MAPK-dependent cell cycle arrest and caspase-mediated apoptosis, as well as an anti-apoptotic mechanism in melanoma cells.
...
PMID:Activation of two distinct anti-proliferative pathways, apoptosis and p38 MAP kinase-dependent cell cycle arrest, by tumor necrosis factor in human melanoma cell line A375. 1139 12

Mechanisms underlying radiation and chemotherapy resistance, the hallmark of human melanoma, are not well understood. Here we demonstrate that expression levels of signal adaptor protein TRAF2 coincide with melanoma resistance to UV-irradiation. Altered TRAF2 signaling by a form of TRAF2, which lacks the ring finger domain (TRAF2DeltaN), increases activities of p38 MAPK, ATF2, and the level of TNFalpha expression. Forced expression of TRAF2DeltaN in HHMSX highly metastatic melanoma cells that lack Fas expression and thus utilize the TNFalpha-TNFR1 as the major apoptotic pathway sensitized cells to UV-induced apoptosis. An over twofold increase in degree of apoptosis was observed in TRAF2DeltaN expressing cells that were treated with actinomycin D, anisomycin or with the radiomimetic drug neocarzinostatin. Sensitization by TRAF2DeltaN is selective since it was not observed in response to either Taxol or cis-platinum treatment. TRAF2DeltaN effects are primarily mediated via p38 since inhibition of p38 reduces, whereas activation of p38 promotes the level of UV-induced apoptosis. Conversely, activation of IKK attenuates the sensitization of melanoma by TRAF2DeltaN, indicating that p38-mediated suppression of NF-kappaB activity is among TRAF2DeltaN effects. Our finding identifies p38, TNFalpha and NF-kappaB among key players that efficiently sensitizes melanoma cells to UV-, ribotoxic (anisomycin) and radiomimetic chemicals-induced programmed cell death in response to aberrant TRAF2 signaling.
...
PMID:Expression of ring finger-deleted TRAF2 sensitizes metastatic melanoma cells to apoptosis via up-regulation of p38, TNFalpha and suppression of NF-kappaB activities. 1140 19

Interleukin-1 (IL-1) inhibits the proliferation of A375 human melanoma cells. We have demonstrated previously that p38 mitrogen-activated protein kinase (MAPK) mediated the antiproliferative effect of IL-1 partially through the downregulation of activity and protein level of ornithine decarboxylase (ODC). In this study, we investigated the role of CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), one of the p38 MAPK target transcriptional factors. The mRNA level of CHOP was not affected by IL-1 treatment in A375-6 cells. Unexpectedly, CHOP was constitutively phosphorylated, and IL-1 or p38 MAPK inhibitor, SB203580, did not affect the phosphorylation level. However, A375-6 cells exhibited enhanced sensitivity to IL-1 by transfecting CHOP expression plasmid and reduced sensitivity to IL-1 by antisense CHOP mRNA expression plasmid. Furthermore, CHOP appeared to regulate positively IL-6 production at the transcriptional level. The experiments using CHOP muteins revealed that dimerization ability - but not p38 MAPK-dependent phosphorylation or DNA binding activity - is important for the IL-6 inducing activity of CHOP. These results indicate that CHOP contributes to the IL-1 growth-inhibitory signal through augmenting IL-6 production.
...
PMID:CHOP, a basic leucine zipper transcriptional factor, contributes to the antiproliferative effect of IL-1 on A375 human melanoma cells through augmenting transcription of IL-6. 1142 63

Chemokines are secreted into the tumor microenvironment by tumor-infiltrating inflammatory cells as well as by tumor cells. Chemokine receptors mediate agonist-dependent cell responses, including migration and activation of several signaling pathways. In the present study we show that several human melanoma cell lines and melanoma cells on macroscopically infiltrated lymph nodes express the chemokine receptors CXCR3 and CXCR4. Using the highly invasive melanoma cell line BLM, we demonstrate that the chemokine Mig, a ligand for CXCR3, activates the small GTPases RhoA and Rac1, induces a reorganization of the actin cytoskeleton, and triggers cell chemotaxis and modulation of integrin VLA-5- and VLA-4-dependent cell adhesion to fibronectin. Furthermore, the chemokine SDF-1alpha, the ligand of CXCR4, triggered modulation of beta(1) integrin-dependent melanoma cell adhesion to fibronectin. Additionally, Mig and SDF-1alpha activated MAPKs p44/42 and p38 on melanoma cells. Expression of functional CXCR3 and CXCR4 receptors on melanoma cells indicates that they might contribute to cell motility during invasion as well as to regulation of cell proliferation and survival.
...
PMID:Expression of functional chemokine receptors CXCR3 and CXCR4 on human melanoma cells. 1157 Dec 98

We reported previously that endogenous p38 MAPK activity is elevated in invasive breast cancer cells and that constitutive p38 MAPK activity is important for overproduction of uPA in these cells (Huang, S., New, L., Pan, Z., Han, J., and Nemerow, G. R. (2000) J. Biol. Chem. 275, 12266-12272). However, it is unclear how elevated endogenous p38 MAPK activity is maintained in invasive breast cancer cells. In the present study, we found that blocking alpha(v) integrin functionality with a function-blocking monoclonal antibody or down-regulating alpha(v) integrin expression with alpha(v)-specific antisense oligonucleotides significantly decreased the levels of active p38 MAPK and inhibited cell-associated uPA expression in invasive breast cancer MDA-MB-231 cells. These results suggest a function link between alpha(v) integrin, p38 MAPK activity, and uPA expression in invasive tumor cells. We also found that vitronectin/alpha(v) integrin ligation specifically induced p38 MAPK activation and uPA up-regulation in invasive MDA-MB-231 cells but not in non-invasive MCF7 cells. Finally, using a panel of melanoma cells, we demonstrated that the cytoplasmic tail of alpha(v) integrin subunit is required for alpha(v) integrin ligation-induced p38 MAPK activation.
...
PMID:Alpha(v) integrin, p38 mitogen-activated protein kinase, and urokinase plasminogen activator are functionally linked in invasive breast cancer cells. 1160 83

Activating transcription factor 2 (ATF2/CRE-BP1) is implicated in transcriptional control of stress-responsive genes. A yeast two-hybrid screen identified TBP-interacting protein 49b (TIP49b), a component of the INO80 chromatin-remodeling complex, as a novel ATF2-interacting protein. TIP49b's association with ATF2 is phosphorylation dependent and requires amino acids 150 to 248 of ATF2 (ATF2(150-248)), which are implicated in intramolecular inhibition of ATF2 transcriptional activities. Forced expression of TIP49b efficiently attenuated ATF2 transcriptional activities under normal growth conditions as well as after UV treatment, ionizing irradiation, or activation of p38 kinase, all of which induced ATF2 phosphorylation and increased TIP49b-ATF2 association. Constitutive expression of ATF2(150-248) peptide outcompeted TIP49b interaction with ATF2 and alleviated the suppression of ATF2 transcriptional activities. Expression of ATF2(150-248) in fibroblasts or melanoma but not in ATF2-null cells caused a profound G(2)M arrest and increased degree of apoptosis following irradiation. The interaction between ATF2 and TIP49b constitutes a novel mechanism that serves to limit ATF2 transcriptional activities and highlights the central role of ATF2 in the control of the cell cycle and apoptosis in response to stress and DNA damage.
...
PMID:TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. 1171 76

Members of the mitogen-activated protein kinase (MAPK) superfamily, including p38 kinase and SAPK/JNK, play a central role in mediating cellular response to environmental stress, growth factors and cytokines. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine capable of eliciting mitogenic, motogenic and morphogenetic activities in responsive cells, and has been implicated in tumor development and metastasis. Binding of HGF/SF to its tyrosine kinase receptor c-Met stimulates multiple signal transduction pathways, leading to the activation of numerous transcription factors. We here report that HGF/SF can induce cyclin D1 expression in mouse melanoma cells, and that this up-regulation is mediated in part by the activating transcription factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced in the presence of either the p38 kinase-specific inhibitor SB203580, a dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially blocked by the PI3K-specific inhibitor as well. The upstream kinases for p38, MKK3/6, did not become activated following HGF/SF exposure, and ATF-2 activation was undiminished by transient transfection of a dominant negative MKK6 mutant. However, transcriptional up-regulation of cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific inhibitor, and cyclin D1 protein induction was partially blocked by a dominant negative ATF-2 mutant. Notably, the p38 kinase-specific inhibitor was able to block melanoma cell proliferation but not motility. We conclude that the ATF-2 transcription factor becomes activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the p38-ATF-2 pathway can help mediate proliferation signals in tumor cells through transcriptional activation of key cell cycle regulators.
...
PMID:Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1. 1185 Aug 17

Matrix metalloproteinase-1 (MMP-1) breaks down interstitial collagens, a major component of stromal tissue and a barrier for invading tumor cells. The degradation of collagen by MMP-1 may, therefore, provide one mechanism for facilitating tumor invasion and metastasis. Because of the potential for excessive matrix degradation, the expression of MMP-1 is tightly regulated, often by the mitogen-activated protein kinase (MAPK) pathway. The MAPK signal cascade consists of three separate pathways, the extracellular response kinase (ERK), p38 and Jun N-terminal kinase, which target proteins of the AP-1 and ETS families transcription of the gene. The MMP-1 promoter contains a single nucleotide polymorphism (SNP) at -1607 bp, which creates an ETS binding site by the addition of a guanine (5'-GGAT-3' or '2G SNP') compared to the 1G SNP (5'-GAT-3'), and enhances MMP-1 transcription. A2058 melanoma cells represent one tumor cell line that is homozygous for the 2G allele and that produces constitutively high levels of MMP-1. Thus, we used these cells to define the mechanism(s) responsible for this high level of expression. We show that inhibition of ERK 1/2 leads to the repression of MMP-1 transcription, and that both the 2G polymorphism and the adjacent AP-1 site at -1602 bp are necessary for high levels of MMP-1 transcription and for the inhibition of MMP-1 expression by PD098059, a specific ERK inhibitor. Furthermore, restoration of MMP-1 levels after ERK 1/2 inhibition requires de novo protein synthesis of a factor necessary for MMP-1 expression. Thus, this study suggests that the ERK 1/2 pathway targets the 2G polymorphism, and that the continuous synthesis of a protein(s) is necessary for the constitutive expression of MMP-1.
...
PMID:Erk 1/2 differentially regulates the expression from the 1G/2G single nucleotide polymorphism in the MMP-1 promoter in melanoma cells. 1199 78

Monocyte chemoattractant protein-1 (MCP-1) expression is found in malignant melanoma and melanoma metastases. Since areas of hypoxia/reoxygenation (H/R) are a common feature of malignant tumours and metastases, we addressed the question whether melanoma cells produce MCP-1 upon exposure to H/R. In the present study, we show that melanoma cells up-regulate MCP-1 mRNA and protein under H/R. By means of reporter gene analysis, we further demonstrate that H/R induces transcriptional activation of the MCP-1 promoter carrying a stimulatory protein-1 (SP1) and two nuclear factor-kappaB (NF-kappaB) binding motifs. Accordingly, H/R-stimulated melanoma cells showed enhanced binding activity of both transcription factors NF-kappaB and SP1 in electrophoretic mobility-shift assay. A common upstream activator of NF-kappaB, inhibitory kappaBalpha kinase, was not significantly activated under H/R conditions. Further analysis of upstream signalling events revealed that members of the mitogen-activated protein kinases family, namely extracellular signal-regulated protein kinase, c-Jun N-terminal kinase/ stress-activated protein kinase and p38 stress kinase, may be involved in MCP-1 transcriptional regulation under H/R. In summary, we conclude that H/R induces MCP-1 production in melanoma cells via the co-operative action of both transcription factors NF-kappaB and SP1, and involves mitogen-activated protein kinase signalling pathways. Functionally, H/R-induced MCP-1 production may contribute to tumour progression by committing selective pressure on tumour cells via chemoattraction and activation of tumour-infiltrating monocytes/macrophages.
...
PMID:Hypoxia/reoxygenation induction of monocyte chemoattractant protein-1 in melanoma cells: involvement of nuclear factor-kappaB, stimulatory protein-1 transcription factors and mitogen-activated protein kinase pathways. 1202 Mar 48


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---