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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In contrast to cutaneous melanoma, there is no evidence that BRAF mutations are involved in the activation of the mitogen-activated protein kinase (MAPK) pathway in uveal melanoma, although there is increasing evidence that this pathway is activated frequently in the latter tumours. In this study, we performed mutation analysis of the RAS and BRAF genes in a panel of 11 uveal melanoma cell lines and 19 primary uveal melanoma tumours. In addition, Western blot and immunohistochemical analyses were performed on downstream members of the MAPK pathway in order to assess the contribution of each of these components. No mutations were found in any of the three RAS gene family members and only one cell line carried a BRAF mutation (V599E). Despite this, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK), ERK and ELK were constitutively activated in all samples. These data suggest that activation of the MAPK pathway is commonly involved in the development of uveal melanoma, but occurs through a mechanism different to that of cutaneous melanoma.
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PMID:Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. 1592 60

Numerous BRAF mutations have been detected in melanoma biopsy specimens and cell lines. In contrast, several studies report lack of BRAF mutations in uveal melanoma including primary and metastatic choroidal and ciliary body melanomas. To our knowledge, for the first time, here we report a case of choroidal melanoma harboring the BRAF mutation (V600E). The activation of RAF/MEK/ERK pathway, although independent of BRAF mutation, was reported in uveal melanoma. The presence of V600E mutation indicates that the RAF/MEK/ERK pathway, in addition to cutaneous melanoma progression, may play a role in the choroidal melanoma development.
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PMID:Detection of BRAF gene mutation in primary choroidal melanoma tissue. 1641 Jul 17

Mutated B-Raf-mediated constitutive activation of ERK1/2 is involved in about 66% of cutaneous melanoma. By contrast, activating mutations in B-RAF are rare in ocular melanoma. This study aimed to determine the role of wild-type B-Raf ((WT)B-Raf) in uveal melanoma cell growth. We used cell lines derived from primary tumors of uveal melanoma to assess the role of (WT)B-Raf in cell proliferation and to characterize its upstream regulators and downstream effectors. Melanoma cell lines expressing (WT)B-Raf and (WT)Ras grew with similar proliferation rates, showed constitutive activation of ERK1/2, and had similar levels of B-Raf expression and B-Raf kinase activity as melanoma cell lines expressing the activating V600E mutation ((V600E)B-Raf). They were equally as sensitive to pharmacological inhibition of MEK1/2 for cell proliferation and transformation as (V600E)B-Raf cells. siRNA-mediated depletion of Raf-1 did not affect either ERK1/2 activation, whereas siRNA-mediated depletion of B-Raf reduced cell proliferation by up to 65% through the inhibition of ERK1/2 activation, irrespective of the mutational status of B-Raf. Pharmacological inhibition of cAMP-dependent protein kinase (PKA) and siRNA-mediated depletion of PKA greatly reduced B-Raf activity, ERK1/2 activation, and cell proliferation in (WT)B-Raf cells, whereas it did not affect (V600E)B-Raf cells, demonstrating a key role of PKA in mediating (WT)B-Raf/ERK signaling for uveal melanoma cell growth. Moreover, inactivation or depletion of PKA did not affect Rap-1 activity, and Rap-1 depletion did not affect either B-Raf activity or ERK1/2 activation. This ruled out a role for Rap1 in the PKA-mediated B-Raf/ERK activation in (WT)B-Raf cells. Finally, we demonstrated the importance of cyclin D1 in mediating PKA/(WT)B-Raf signaling for cell proliferation. Altogether, our results suggest that the PKA/B-Raf pathway is a potential target for therapeutic strategies against (WT)B-Raf-expressing uveal melanoma.
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PMID:Extracellular signal-regulated kinase-dependent proliferation is mediated through the protein kinase A/B-Raf pathway in human uveal melanoma cells. 1645 69

Angiogenesis is essential for tumor progression and metastasis; however, the angiogenesis regulators that are biologically relevant for melanoma are still unknown. In this study, we analyzed the circulating serum levels of potent angiogenic factors, including vascular endothelial growth factor (VEGF), angiogenin, transforming growth factor-beta1 and VEGF receptors, VEGFR1 and VEGFR2, in human melanoma patients. One hundred and fourteen patients with histopathologically verified cutaneous melanoma at different stages and 30 healthy controls were investigated. Serum levels of angiogenic factors and VEGF receptors were quantitatively analyzed by solid-phase enzyme-linked immunosorbent assay. The age of the patients (61 men and 53 women) ranged from 18 to 80 years; median age was 51 years. Serum transforming growth factor-beta1 (P < 0.001), VEGF (P = 0.006) and VEGFR1 (P = 0.007) levels were significantly higher in patients with melanoma than in the control group. No significant differences, however, exist in the serum angiogenin and VEGFR2 levels between melanoma patients and the controls. The positive correlations of elevated serum levels of transforming growth factor-beta1, VEGF and VEGFR1 with advanced stages of disease were found. Significant relationship was found only between serum levels of VEGF and VEGFR2. Elevated serum transforming growth factor-beta1 (P < 0.001) and VEGF levels (P = 0.0012) were found to be poor prognostic factors. Serum level of angiogenin and VEGF receptors, however, had no effect on survival. Our data suggest that the angiogenic serum factors, including VEGF, transforming growth factor-beta1 and VEGFR1, but not angiogenin and VEGFR2 were increased in melanoma patients, especially associated with advanced disease stages. The mechanism of VEGF regulation of angiogenesis may in part be due to enhanced proliferation of VEGFRs, especially VEGFR1.
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PMID:Circulating serum levels of angiogenic factors and vascular endothelial growth factor receptors 1 and 2 in melanoma patients. 1701 89

The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense "antagomir" oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma.
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PMID:The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. 1841 45

With the aim to correlate BRAF mutation status with gene expression in human primary cutaneous melanomas, and thus to get more insight on the consequences of BRAF mutation on cell biology, we analyzed all expression data obtained in melanomas from which DNA was extracted from the same tissue slides that were used for the expression study. A cohort of 69 frozen primary melanoma whose oligonucleotide micro-array expression data were available, were genotyped for BRAF and NRAS genes. The expression data from these melanomas were re-analyzed according to BRAF mutational status. A set of 250 probes representing 209 genes that were significantly (raw P< or =0.001) associated with BRAF mutation status was identified and 17 of these were previously shown to be implicated in cutaneous melanoma progression or pigmentation pathway-associated genes driven by the microphthalmia transcription factor (MITF). The list of 34 top probes contained no more than 1% of false discoveries with a probability of 0.95. Among the genes that differentiated most strongly between BRAF mutated and non-mutated melanomas, there were those involved in melanoma immune response such as MAGE-D2, CD63, and HSP70. These findings support the immunogenicity of BRAF(V600E), eliciting patients T-cell responses in various in vitro assays. The genes whose expression is associated with BRAF mutations are not simply restricted to the MAPK/ERK signaling but also converge to enhanced immune responsiveness, cell motility and melanosomes processing involved in the adaptative UV response.
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PMID:Gene expression signature associated with BRAF mutations in human primary cutaneous melanomas. 1938 16

RET proto-oncogene encodes a receptor tyrosine kinase whose ligand is glial cell line-derived neurotrophic factor (GDNF), and its polymorphism at G691S juxtamembrane region (RETp) is a germline polymorphism. Cutaneous melanomas, particularly the desmoplastic subtype, are highly neurotropic; thus we sought to determine the frequency of RETp in cutaneous melanoma and its functional responsiveness to GDNF. RETp was assessed in 71 non-desmoplastic cutaneous melanomas (non-DMs) and 70 desmoplastic melanomas (DMs). Melanoma cell lines with RETp, RET wild type (RETwt), BRAF V600E mutation (BRAFmt) or BRAF wild type (BRAFwt) were assessed for functional activity. RETp frequency was significantly higher in DMs (61%) than in non-DMs (31%, P<0.001). BRAFmt was detected in only 11% of DMs. GDNF stimulation significantly amplified cell proliferation, migration and invasion in RETp, but not in RETwt melanoma cells. GDNF stimulation of RETp cell lines enhanced phosphorylation of extracellular signal-regulated kinase (ERK) and Akt of the RET-RAS-RAF-ERK and RET-phosphatidylinositol 3-kinase (PI3K)-Akt pathways, respectively. GDNF response of RETp cells in signal transduction and other functional studies were not affected by BRAFmt. The study demonstrates that RETp is frequently found in cutaneous melanoma, particularly desmoplastic subtypes, and responds to GDNF inducing events favorable for tumor progression.
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PMID:Functional RET G691S polymorphism in cutaneous malignant melanoma. 1956 46

In melanoma, mutations in KIT are most frequent in acral and mucosal subtypes and rarely reported in cutaneous melanomas particularly those associated with intermittent UV exposure. Conversely melanomas arising within chronic sun damaged skin are considered to harbour KIT mutations at higher rates. To characterize the frequency of KIT mutations in a representative melanoma population, 261 patients from two Australian melanoma centres were prospectively screened for mutations in exons 11, 13 and 17 of the KIT gene. A total of 257 patients had cutaneous melanoma arising from non-acral sites and four were acral melanomas. No mucosal or ocular melanomas were analysed. KIT mutations were identified in five tumours (2% of the entire cohort) including two acral melanomas. Two of the three non-acral melanomas with KIT mutations were associated with markers of chronic sun damage as assessed by the degree of skin elastosis. In the remaining cohort, 43% had chronically sun damaged skin. This report confirms that within an Australian population, KIT mutations are infrequent in cutaneous melanomas associated with both intermittent and chronic sun exposed skin.
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PMID:Mutations in KIT occur at low frequency in melanomas arising from anatomical sites associated with chronic and intermittent sun exposure. 2008 73

Nevus of Ota is a variant of congenital nevus, which is morphologically paucicellular and resembles a common blue nevus. Although nevus of Ota is a risk factor for uveal melanoma in white people, the development of cutaneous melanoma within nevus of Ota is a very rare occurrence with only a few reported cases. We present a case of a long-standing nevus of Ota, with radiologic imaging demonstrating a large retro-orbital mass and a biopsy showing melanoma. The histopathology of the eye exenteration specimen illustrated various stages of melanocytic progression including areas resembling a nevus of Ota, blue nevus, cellular blue nevus, and melanoma. There was heterogeneity in the overtly malignant sections with some areas displaying expansile nodules of blander appearing spindled cells, whereas other areas were composed of epithelioid cells with higher mitotic counts and zones of necrosis. The extensive lesion also infiltrated the soft tissue and bone. We performed gene mutation analysis for GNAQ, BRAF, NRAS, and KIT and fluorescence in situ hybridization (FISH) targeting commonly altered chromosomal loci in melanoma and comparative genomic hybridization (CGH). Copy number changes typical of melanoma were identified by both FISH and CGH in the morphologically malignant areas illustrating the relationship of tumor progression and the progressive acquisition of genetic aberrations.
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PMID:Molecular analysis of a case of nevus of ota showing progressive evolution to melanoma with intermediate stages resembling cellular blue nevus. 2011 Jul 97

BRAF is a member of the RAF kinase family, which acts in the ERK/MAP kinase pathway, a signalling cascade that regulates cellular proliferation, differentiation and survival. Single point mutations can turn BRAF into an oncogene, but there appears to be a cell type/tumour specific relevance for BRAF kinase-activating mutations, since they are found predominantly in cutaneous melanoma. With the success of targeting other oncogenic kinases such as BCR-ABL, KIT or members of the epidermal-growth factor receptor (EGFR) family in other cancers, the expectations were high when the first RAF kinase-targeting drug (sorafenib) reached clinical trials. However, disappointingly the first studies using sorafenib in melanoma patients did not show the anticipated single agent efficacy. More recently, the resolution of the BRAF crystal structure has led to the development of better, more specific BRAF inhibitors such as the Plexxikon compound, PLX4032, which induced a dramatic response rate in phase I trials, validating BRAF as a clinically relevant target. In addition, our understanding of melanoma biology and the role BRAF is playing therein has improved significantly. The complexity in the ERK/MAP kinase pathway including important feedback mechanisms has been dissected, and the relevance of cross-talks with other signalling pathways has been revealed, suggesting strategies for the design of improved, more efficient combinatorial therapies. This review highlights the relevance of BRAF and the ERK/MAP kinase pathway for melanoma cell biology and discusses some of the recent advances in both, the understanding of BRAF function in melanoma and the development of improved BRAF targeting inhibitors.
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PMID:BRAF as therapeutic target in melanoma. 2035 May 35


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