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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway. Recent studies have reported that mutations of the BRAF gene were detected with varying frequencies in several cancers, notably more than 60% in melanoma. We analysed mutations of BRAF and RAS genes in 100 cases of thyroid carcinoma to investigate genetic aberrations in the RAS/RAF/MEK/MAP kinase pathway. BRAF mutations were detected exclusively in papillary carcinomas (40 in 76 cases: 53%), and were exclusively V599E, a mutation frequently observed in other carcinomas. NRAS mutation was observed in six cases (6%), all in histological types other than papillary carcinoma, and was exclusively Q61R. No mutations were found in KRAS or HRAS. Our results suggest that BRAF mutations may play a critical role in the carcinogenesis of papillary carcinoma of the thyroid.
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PMID:BRAF mutations in papillary carcinomas of the thyroid. 1450 25

We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.
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PMID:Microarray expression profiling in melanoma reveals a BRAF mutation signature. 1504 78

Cutaneous melanoma (CM) is the most lethal form of skin cancer. Along with some benign melanocytic tumors, the majority shows BRAF or NRAS mutation, but it is not known whether these are essential to all forms of melanocytic neoplasia. We screened 79 melanocytic tumors of different types for BRAF and NRAS mutations and looked at MAPK pathway activity using immunohistochemistry in a subset. Significant differences in BRAF exon 15 mutation frequency were found: 14/16 (87.5%) in common acquired naevi (CANs), 9/12 (75%) in CMs, 0/26 in Spitz naevi and 3/25 (12%) in blue naevi (p < 0.01). We looked at whether Spitz and blue naevi showed a compensatory increase in BRAF exon 11 and/or NRAS exons 1 and 2 mutations to account for the low BRAF exon 15 mutation frequency. NRAS mutations were found in only 1/16 (6.3%) Spitz naevi and 0/15 blue naevi. In addition, NRAS mutations were found in 2/11 (18.2%) CANs and 3/12 (25%) CMs. None of the tumors showed BRAF exon 11 mutations. Despite their low combined BRAF and NRAS mutation frequency, Spitz naevi showed strong MAPK pathway activation as measured by cytoplasmic expression of dually phosphorylated ERK1/2, while blue naevi had weak pathway activation. We conclude that BRAF and NRAS mutations are not necessary for melanocytic tumor development and that some types of tumor must arise by alternative mechanisms.
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PMID:High BRAF mutation frequency does not characterize all melanocytic tumor types. 1525 39

Comparative genomic hybridization (CGH) using 40 cell lines derived from malignant melanomas (MMs) revealed frequent amplification at 7q33-q34 containing BRAF gene, which often is mutated in MM. We found this gene to be amplified to a remarkable degree in the MM cell lines that exhibited high-level gains at 7q33-q34 in CGH. Among 40 cell lines, the eight lines that revealed neither BRAF nor NRAS mutations showed even higher levels of BRAF mRNA expression than the 32 mutated lines, although DNA amplification at 7q33-q34 was not detected in every lines overexpressing BRAF. MM cells that carried wild-type BRAF and NRAS showed constitutive overexpression of B-Raf protein and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), even after serum starvation. Not only downregulation of the endogenously overexpressed wild-type B-Raf by antisense oligonucleotide but also a treatment with an inhibitor of mitogen-activated protein kinase kinase (MAPKK, MEK) reduced phosphorylated ERK1/2 and cell growth, whereas the exogenously expressed wild-type B-Raf promoted cell growth in MM cells. Our results provide the evidence that overexpression of wild-type B-Raf, in part but not always as a result of gene amplification, is one of the mechanisms underlying constitutive activation of the MAPK pathway that stimulates growth of MM cells.
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PMID:Involvement of overexpressed wild-type BRAF in the growth of malignant melanoma cell lines. 1546 32

The majority of human melanomas harbor activating mutations in either the BRAF or NRAS gene. To date, the role of oncogenic NRAS in melanoma remains poorly defined and no current therapies are directed at specifically suppressing oncogenic NRAS in human melanoma tumors. The aim of our study, therefore, was to investigate the effects of suppressing oncogenic NRAS in human melanoma cell lines in vitro. Using both small interfering RNA- and plasmid based-RNA interference techniques, oncogenic NRAS was specifically suppressed in 2 human melanoma cell lines, 224 and BL, which harbor a codon 61 CAA (glutamine) to CGA (arginine) NRAS mutation. Suppression of oncogenic NRAS in these cell lines resulted in increased apoptosis. Furthermore, in 224 cells we demonstrated decreased phosphorylation of extracellular signal-regulated kinase (ERK) and Akt, and reduced expression of NF-kappaB and cyclin D1 in the N-Ras signaling pathway. In contrast, RNA interference directed at wild-type (WT) NRAS had no significant effect on apoptosis of 224 cells or 2 human melanoma cell lines (A375 and 397) containing WT NRAS but a codon 600 GTG (valine) to GAG (glutamate) mutation in BRAF. These data suggest that oncogenic NRAS is important for avoidance of apoptosis in melanomas that harbor the codon 61 NRAS mutation and emphasizes oncogenic NRAS as a therapeutic target in patients with tumors that harbor this mutation.
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PMID:Suppression of oncogenic NRAS by RNA interference induces apoptosis of human melanoma cells. 1568 5

Fibroblast growth factor receptor 3 (FGFR3) mutations are frequent in superficial urothelial cell carcinoma (UCC). Ras gene mutations are also found in UCC. As oncogenic activation of both FGFR3 and Ras is predicted to result in stimulation of the mitogen-activated protein kinase (MAPK) pathway, we hypothesized that these might be mutually exclusive events. HRAS mutation has been widely studied in UCC, but all three Ras gene family members have not been screened for mutation in the same sample series. We screened 98 bladder tumours and 31 bladder cell lines for mutations in FGFR3, HRAS, NRAS and KRAS2. FGFR3 mutations were present in 54 tumours (55%) and three cell lines (10%), and Ras gene mutations in 13 tumours (13%) and four cell lines (13%). These included mutations in all three Ras genes; ten in HRAS, four in KRAS2 and four in NRAS and these were not associated with either tumour grade or stage. In no cases were Ras and FGFR3 mutation found together. This mutual exclusion suggests that FGFR3 and Ras gene mutation may represent alternative means to confer the same phenotype on UCC cells. If these events have biological equivalence, Ras mutant invasive UCC may represent a novel subgroup.
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PMID:FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. 1589 85

One of the most attractive clinical targets for melanoma is the mitogen-activated protein kinase (MAPK) signaling pathway. In this study, we examined MAPK signaling activation in a total of 28 acral melanoma samples, consisting of 13 primary tumors and 15 metastases. In line with the previous reports, NRAS/BRAF mutations were rare; only one metastatic tumor had an NRAS E61R mutation, and one primary tumor and two metastases harbored BRAF V599E mutations. Western blot analyses, however, revealed phosphorylated extracellular signal-regulated kinase (ERK)1/2 proteins in 11 of 14 (78.5%) of the acral melanoma tumors. Furthermore, fluorescence in situ hybridization analyses revealed the prominent amplification of the cyclin D1 (CCND1) gene, which is an important down-stream effecter of the MAPK pathway, in 5 of 21 (23.8%) tumors examined. Interestingly, two of three tumors that were negative for phosphorylated ERK proteins according to western blot harbored CCND1 amplifications, suggesting that the increased gene dosage of CCND1 may exert effects similar to phosphorylated ERK proteins in cell growth. We conclude that, despite the low frequency of BRAF/NRAS mutations, the MAPK signaling pathway is constitutively activated in the majority of acral melanomas. This provides a rational basis to include acral melanomas into the clinical trials with MAPK inhibitors.
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PMID:Constitutive activation of the mitogen-activated protein kinase signaling pathway in acral melanomas. 1609 43

Mutations of RAS, RAF, and PTEN, all important members of the RAS/MAPK and PI3K/AKT cascades, are reported in a variety of human tumors, including melanomas and endometrial cancer. In endometrial cancer, mutually exclusive mutations of PTEN and KRAS have been reported. On the other hand, mutation of BRAF is highly frequent, and mutually exclusive mutations of BRAF and NRAS have also been reported in melanomas. In this study, we elucidated the involvement of the up-regulation of RAS/MAPK and PI3K/AKT cascades in the pathogenesis of endometrial cancer and melanoma by analyzing the genes and molecules in these cascades. Twelve cell lines, six melanoma and six endometrial cancer, were analyzed; 4 (67%) of the 6 melanomas had gene mutations in the RAS/MAPK cascade, and a decrease or loss of PTEN expression was also observed. These results suggested that simultaneous up-regulations in these two cascades play important roles in carcinogenesis of melanocytes. However, no activation of AKT by phosphorylation was observed. On the other hand, 4 (67%) of the 6 endometrial cancer cell lines had mutually exclusive up-regulations in these cascades. However, two cell lines with up-regulation of the PI3K/AKT cascade also had up-regulation in the RAS/MAPK cascade induced by inactivation of DUSP6. These results suggest that simultaneous up-regulation of RAS/MAPK and PI3K/AKT cascades are crucial events in the pathogenesis of melanocytes, whereas up-regulation of either the RAS/MAPK or PI3K/AKT cascade is crucial for the majority of endometrial cancers.
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PMID:Exploration of genetic alterations in human endometrial cancer and melanoma: distinct tumorigenic pathways that share a frequent abnormal PI3K/AKT cascade. 1627 42

The Sleeping Beauty (SB) transposon system can integrate foreign sequences of DNA in the genome of mouse somatic cells eliciting long-term expression in vivo. This technology holds great promise for human gene therapy as a nonviral technology to deliver therapeutic genes. SB also provides a means to study the effects of defined genetic elements, such as oncogenes, on somatic cells in mice. Here, we test the ability of the SB transposon system to facilitate somatic integration of a transposon containing an activated NRAS oncogene in mouse hepatocytes to elicit tumor formation. NRAS oncogene-driven tumors developed when such vectors were delivered to the livers of p19Arf-null or heterozygous mice. Delivery of the NRAS transposon cooperates with Arf loss to cause carcinomas of hepatocellular or biliary origin. These tumors allowed characterization of transposon integration and expression at the single-cell level, revealing robust NRAS expression and both transposase-mediated and random insertion of delivered vectors. Random integration and expression of the SB transposase plasmid was also observed in one instance. In addition, studies using effector loop mutants of activated NRAS provide evidence that mitogen-activated protein kinase activation alone cannot efficiently induce liver carcinomas. This system can be used to rapidly model tumors caused by defined genetic changes.
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PMID:Somatic integration of an oncogene-harboring Sleeping Beauty transposon models liver tumor development in the mouse. 1628 60

Aberrant signalling via platelet derived growth factor receptors (PDGFRs) and the RAS/MAPK pathway has been implicated in the development of medulloblastoma, the most common malignant brain tumour in childhood. To determine whether genetic mechanisms play a role in the activation of PDGFR-RAS/MAPK signalling in medulloblastoma, we performed a direct sequence analysis of the established mutational "hotspots" of known targets of activating mutations within the pathway (PDGFRA, NRAS, KRAS, HRAS and BRAF) and PDFRFB, in a cohort of 28 primary tumours. A synonymous sequence variation in PDGFRA (CCG to CCA; PRO 567 PRO) was detected in two cases (approximately 7%), but not in 150 normal chromosomes assessed, suggesting that the PDGFRA locus may be associated with medulloblastoma development in certain cases. No evidence for oncogenic mutations affecting NRAS, KRAS, HRAS, BRAF or PDFRFB was found in any case. These data demonstrate that activating mutations in established mutational hotspots within the PDGFR-RAS/MAPK pathway are rare events in medulloblastoma development, and suggest that alternative mechanisms are responsible for RAS/MAPK pathway activation in this disease.
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PMID:Mutational analysis of PDGFR-RAS/MAPK pathway activation in childhood medulloblastoma. 1643 86


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