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)

Constitutive activation of MEK-ERK signaling is often found in melanomas. Here, we identify a mechanism that links ERK with JNK signaling in human melanoma. Constitutively active ERK increases c-Jun transcription and stability, which are mediated by CREB and GSK3, respectively. Subsequently, c-Jun increases transcription of target genes, including RACK1, an adaptor protein that enables PKC to phosphorylate and enhance JNK activity, enforcing a feed-forward mechanism of the JNK-Jun pathway. Activated c-Jun is also responsible for elevated cyclin D1 expression, which is frequently overexpressed in human melanoma. Our data reveal that, in human melanoma, the rewired ERK signaling pathway upregulates JNK and activates the c-Jun oncogene and its downstream targets, including RACK1 and cyclin D1.
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PMID:Rewired ERK-JNK signaling pathways in melanoma. 1748 34

Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a 'halo' SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway. Germline DNA from members of 111 multiple-case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.
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PMID:Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions. 1751 71

Cancer results from the interaction of multiple aberrations including activation of dominant oncogenes and upregulation of signal transduction pathways. Identification of the genes involved in malignant transformation is a pre-requisite for understanding cancer and improving its diagnosis and treatment. Quite a few of the genes that have been implicated in cancer are mutant or aberrantly expressed versions of genes that are important mediators of the normal growth that occurs during development. An important example of this is Vav1, a cytoplasmic signal transducer protein initially identified as an oncogene. Physiological expression of Vav1 is restricted to the hematopoietic system, where its best-known function is as a GDP/GTP nucleotide exchange factor for Rho/Rac GTPases, an activity strictly controlled by tyrosine phosphorylation. Vav1 was shown to regulate cytoskeletal rearrangement during activation of hematopoietic cells. Vav1 can also mediate other cellular functions including activation of the JNK, ERK, Ras, NF-kB, and NFAT pathways, in addition to association with numerous adapter proteins such as Shc, NCK, SLP-76, GRB2, and Crk. Although the oncogenic form of Vav1 has not been detected in clinical human tumors, its wild-type form has recently been implicated in mammalian malignancies such as neuroblastoma, melanoma, pancreatic tumors and B-cell chronic lymphocytic leukemia. This review addresses the physiological function of wild-type Vav1, its mode of activation as an oncogene, and its emerging role as a transforming protein in human cancer.
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PMID:Flesh and blood: the story of Vav1, a gene that signals in hematopoietic cells but can be transforming in human malignancies. 1759 Feb 70

The influence of environmental factors (cytokines, matrix components, serum factors and O(2) level) on expression of receptors for angiogenic versus angiostatic CXC chemokines in human microvascular endothelial cells has not been extensively investigated. Our semi-quantitative RT-PCR analysis demonstrated that TNF-alpha and IFN-gamma repressed CXCR4 mRNA levels in immortalized human microvascular endothelial HMEC-1 cells after 4 h, whereas only TNF-alpha displayed inhibitory activity in primary human microvascular endothelial cells (HMVEC). CXCR4 mRNA expression was not affected by VEGF, GM-CSF, IL-1beta or various basal membrane matrix components, but was significantly up-regulated after serum starvation and/or hypoxic treatment of the microvascular endothelial cells. The alternative CXCL12 receptor, CXCR7/RDC1, was also up-regulated by hypoxia in HMEC-1 cells, although less consistently than CXCR4. Furthermore, hypoxia and serum starvation were required for cell surface display of CXCR4 and CXCL12 induction of ERK activation in HMEC-1 cells. In contrast, CXCR2 and CXCR3 mRNA levels remained, respectively, low and undetectable under all the conditions tested, and surface expression of CXCR2, CXCR3 and CXCR7 on the HMEC- 1 cells could not be demonstrated by FACS. In the human SK-MEL-5 melanoma cell line, CXCR4 mRNA expression was also increased under hypoxic conditions, whereas CXCR2 mRNA levels remained low and levels of CXCR3 and CXCR7 were undetectable. However, immunohistochemical staining of human metastatic melanoma sections demonstrated that CXCR2, CXCR3, CXCR4 and CXCR7 are expressed on tumor cells and, to a lesser extent, on endothelial cells. These results demonstrate that the tumor microenvironment regulates chemokine receptor expression through both cytokine and oxygen levels.
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PMID:Hypoxia enhances CXCR4 expression in human microvascular endothelial cells and human melanoma cells. 1759 38

The Raf-MEK-ERK signaling pathway is critical for cell survival, growth, proliferation and tumorigenesis. Among the three isoforms of Raf protein kinases, in vitro and in vivo studies have shown that B-Raf functions as the primary MEK activator. B-Raf is one of the most frequently mutated genes in human cancers with a high prevalence in melanoma, and many of the B-Raf mutations activate the kinase activity of B-Raf. B-Raf kinase represents an excellent target for anticancer therapy based on preclinical target validation, epidemiology and drugability. Several small-molecule inhibitors of B-Raf kinase are currently undergoing clinical evaluation, with others due to enter clinical development in the near future.
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PMID:B-Raf kinase inhibitors for cancer treatment. 1762 74

Protein kinase C (PKC) has been shown to be a signal transducer during tumorigenesis, tumor cell invasion, and metastasis. Recent studies have reported that the PKC inhibitor, 7-hydroxystaurosporine, inhibits tumor cell invasion. However, the molecular mechanisms of this inhibition of invasion and metastasis are not well understood. In the present study, we attempt to clarify the mechanism by which H7, a PKC inhibitor, inhibits tumor cell invasion and metastasis in the melanoma cell line B16BL6. It was found that H7 inhibits B16BL6 cell invasion and metastasis. We also observed that H7 inhibits the mRNA expression and protein activities of matrix metalloproteinase (MMP)-1, -2, -9 and MT1-MMP. Furthermore, H7 suppresses phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2). However, other signal transduction factors, such as p38 mitogen-activated protein kinase (p38MAPK) and c-Jun N-terminal kinase 1/2 (JNK1/2), were unaffected. Moreover, U0126, a MEK1/2 inhibitor, also inhibited B16BL6 cell invasion and metastasis, as well as the mRNA expression and protein activities of MMP-1, -2, -9 and MT1-MMP. This indicates that H7 inhibits signal transduction through the PKC/MEK/ERK pathway, thereby inhibiting B16BL6 cell invasion and metastasis. These results suggest that PKC inhibitors have potential clinical applications in the treatment of tumor cell metastasis.
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PMID:The protein kinase C inhibitor, H7, inhibits tumor cell invasion and metastasis in mouse melanoma via suppression of ERK1/2. 1763 10

It is well known that c-kit is related to pigmentation as well as to the oncology target protein. The objective of this study was to discover a skin-whitening agent that regulates c-kit activity. We have developed a high-throughput screening system using recombinant human c-kit protein. Approximately 10,000 synthetic compounds were screened for their effect on c-kit activity. Phenyl-imidazole sulfonamide derivatives showed inhibitory activity on c-kit phosphorylation in vitro. The effects of one derivative, [4-t-butylphenyl]-N-(4-imidazol-1-yl phenyl)sulfonamide (ISCK03), on stem-cell factor (SCF)/c-kit cellular signaling in 501mel human melanoma cells were examined further. Pretreatment of 501mel cells with ISCK03 inhibited SCF-induced c-kit phosphorylation dose dependently. ISCK03 also inhibited p44/42 ERK mitogen-activated protein kinase (MAPK) phosphorylation, which is known to be involved in SCF/c-kit downstream signaling. However ISCK03 did not inhibit hepatocyte growth factor (HGF)-induced phosphorylation of p44/42 ERK proteins. To determine the in vivo potency of ISCK03, it was orally administered to depilated C57BL/6 mice. Interestingly, oral administration of ISCK03 induced the dose-dependent depigmentation of newly regrown hair, and this was reversed with cessation of ISCK03 treatment. Finally, to investigate whether the inhibitory effect of ISCK03 on SCF/c-kit signaling abolished UV-induced pigmentation, ISCK03 was applied to UV-induced pigmented spots on brownish guinea pig skin. The topical application of ISCK03 promoted the depigmentation of UV-induced hyperpigmented spots. Fontana-Masson staining analysis showed epidermal melanin was diminished in spots treated with ISCK03. These results indicate that phenyl-imidazole sulfonamide derivatives are potent c-kit inhibitors and might be used as skin-whitening agents.
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PMID:[4-t-butylphenyl]-N-(4-imidazol-1-yl phenyl)sulfonamide (ISCK03) inhibits SCF/c-kit signaling in 501mel human melanoma cells and abolishes melanin production in mice and brownish guinea pigs. 1765 83

Mutations in the BRAF gene are found in the majority of cutaneous malignant melanomas and subsets of other tumors. These mutations lead to constitutive activation of BRAF with increased downstream ERK (extracellular signal-regulated kinase) signaling; therefore, the development of RAF kinase inhibitors for targeted therapy is being actively pursued. A methodology that allows sensitive, cost-effective, high-throughput analysis of BRAF mutations will be needed to triage patients for specific molecular-based therapies. Pyrosequencing is a high-throughput, sequencing-by-synthesis method that is particularly useful for analysis of single nucleotide polymorphisms or hotspot mutations. Mutational analysis of BRAF is highly amenable to pyrosequencing because the majority of mutations in this gene localize to codons 600 and 601 and consist of single or dinucleotide substitutions. In this study, DNAs from a panel of melanocyte cell lines, melanoma cell lines, and melanoma tumors were used to validate a pyrosequencing assay to detect BRAF mutations. The assay demonstrates high accuracy and precision for detecting common and variant exon 15 BRAF mutations. Further, comparison of pyrosequencing data with 100K single nucleotide polymorphism microarray data allows characterization of BRAF amplification events that may accompany BRAF mutation. Pyro-sequencing serves as an excellent platform for BRAF genotyping of tumors from patients entering clinical trial.
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PMID:Application of a BRAF pyrosequencing assay for mutation detection and copy number analysis in malignant melanoma. 1769 Feb 12

The RAS/RAF/MEK/ERK signaling pathway has been a major clinical focus in oncology research in recent years. A clearer association of B-RAF mutations to cancers such as melanoma, papillary thyroid cancer and others has brought an increasing interest in chemotherapeutics that target this cellular signaling pathway. In this review, the authors summarize the current understanding of science and therapeutic use of the MEK inhibitors targeting the RAS/RAF/ MEK/ERK pathway. Clinical progresses of PD0325901 and AZD6244 are highlighted in addition to developments of new MEK inhibitors. Recently disclosed MEK inhibitors in two sub-divided classes, ATP noncompetitive and ATP competitive inhibitors are discussed.
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PMID:Recent advances of MEK inhibitors and their clinical progress. 1769 26

We examined the role of osteopontin (OPN) in NIK- and MEKK1-dependent MMP-9 activation, melanoma growth and lung metastasis and its clinical significance in malignant melanoma. Here we report that OPN induces alphavbeta3 integrin-mediated MEKK1-dependent JNK1 phosphorylation. OPN stimulates NIK- or JNK1-dependent c-Jun expression. In contrast, OPN induces MEKK1-dependent JNK1 activation that leads to downregulation of ERK1/2 activation. OPN triggers NIK- and MEKK1-dependent AP-1 activation whereas NIK-dependent AP-1 activation is independent of JNK1 that leads to pro-MMP-9 activation. In vivo studies indicate that the levels of pNIK and MMP-9 are significantly higher in the OPN-induced primary tumor and metastasized lung compared to control. Clinical data revealed that the enhanced level of OPN and pNIK expression in the skin biopsies correlates with Clark's level and Breslow thickness. Altogether, OPN regulates negative cross-talk between NIK/ERK and MEKK1/JNK1 pathways that controls melanoma progression.
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PMID:Osteopontin stimulates melanoma growth and lung metastasis through NIK/MEKK1-dependent MMP-9 activation pathways. 1778 54


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