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)

Clinical and fundamental research based on the pheochromocytoma cohort of the COMETE network has drastically improved our knowledge of pheochromocytoma (PH). Previously, it was widely thought that only 10 % of PH patients had familial forms and that the malignant phenotype of PH could not be diagnosed before the first metastasis had already occurred. Genetic studies of the COMETE DNA collection contributed to showing that 25% to 30% of patients in fact have hereditary PH, due to a germline mutation of the SDHB, SDHD, VHL, RET or NF1 genes. The high-quality post-surgical clinical data collected by the COMETE network also show that SDHB germline mutations are a major risk factor for malignancy and poor outcome. Fundamental research work on the COMETE tumour collection shows that SDH genes are new tumour suppressor genes and that succinate dehydrogenase inactivation induces abnormal stimulation of the hypoxia-angiogenesis pathway. Since 2001, work by the COMETE network has led to new recommendations for genetic counselling and genetic testing in pheochromocytoma, and also for patient management. Finally, it has identified new molecular mechanisms involved in PH-related tumorigenesis.
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PMID:[Achievements of the COMETE program in the genetics of pheochromocytoma]. 1866 85

Patients with acute myeloid leukemia (AML) harboring three or more acquired chromosome aberrations in the absence of the prognostically favorable t(8;21)(q22;q22), inv(16)(p13q22)/t(6;16)(p13;q22), and t(15;17)(q22;q21) aberrations form a separate category - AML with a complex karyotype. They constitute 10% to 12% of all AML patents, with the incidence of complex karyotypes increasing with the more advanced age. Recent studies using molecular-cytogenetic techniques (spectral karyotyping [SKY], multiplex fluorescence in situ hybridization [M-FISH]) and array comparative genomic hybridization (a-CGH) considerably improved characterization of previously unidentified, partially identified, or cryptic chromosome aberrations, and allowed precise delineation of genomic imbalances. The emerging nonrandom pattern of abnormalities includes relative paucity, but not absence, of balanced rearrangements (translocations, insertions, or inversions), predominance of aberrations leading to loss of chromosome material (monosomies, deletions, and unbalanced translocations) that involve, in decreasing order, chromosome arms 5q, 17p, 7q, 18q, 16q, 17q, 12p, 20q, 18p, and 3p, and the presence of recurrent, albeit less frequent and often hidden (in marker chromosomes and unbalanced translocations) aberrations leading to overrepresentation of segments from 8q, 11q, 21q, 22q, 1p, 9p, and 13q. Several candidate genes have been identified as targets of genomic losses, for example, TP53, CTNNA1, NF1, ETV6, and TCF4, and amplifications, for example, ERG, ETS2, APP, ETS1, FLI1, MLL, DDX6, GAB2, MYC, TRIB1, and CDX2. Treatment outcomes of complex karyotype patients receiving chemotherapy are very poor. They can be improved to some extent by allogeneic stem cell transplantation in younger patients. It is hoped that better understanding of genomic alterations will result in identification of novel therapeutic targets and improved prognosis in patients with complex karyotypes.
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PMID:Cytogenetic, molecular genetic, and clinical characteristics of acute myeloid leukemia with a complex karyotype. 1869 87

Recently, the KIF1B beta gene on 1p36, a region commonly deleted in neural crest cancers, was found to be a proapoptotic factor for sympathetic precursors. KIF1B beta mutations were detected in pheochromocytomas and neuroblastomas, two sympathetic lineage tumors, suggesting a role for this gene in cancer. Here, we studied five individuals from a three-generation cancer-prone family with a KIF1B beta germline variant and seven of their tumors, both of neural crest and nonneural origin. Genetic studies including sequencing, copy number analysis and fluorescence in situ-hybridization (FISH) showed retention of both KIF1B beta alleles in all neural crest-derived tumors in this family, consistent with haploinsufficiency or methylation of the wild-type allele. In contrast, the lung adenocarcinoma from one mutation carrier had somatic loss of the wild-type allele in agreement with a classical two-hit inactivation. Global transcription analysis of KIF1B beta mutant pheochromocytomas revealed that these tumors are transcriptionally related to pheochromocytomas with RET and NF1 mutations but independent from SDH- and VHL-associated tumors. Furthermore, KIF1B beta-mutant tumors are uniquely enriched for pathways related to glutamate metabolism and the oxidative stress response. Our data start to delineate the signals that are disrupted by KIF1B beta dysfunction in pheochromocytomas and suggest that loss of this gene may also be permissive to the development of nonneural crest malignancies. This may imply the existence of a tissue-specific gene dosage requirement for its tumorigenesis.
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PMID:A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. 1872 16

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
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PMID:Comprehensive genomic characterization defines human glioblastoma genes and core pathways. 1877 90

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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PMID:Somatic mutations affect key pathways in lung adenocarcinoma. 1894 47

We uncovered a role for ERK signaling in GABA release, long-term potentiation (LTP), and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for learning disabilities in neurofibromatosis type I (NF1). Our results demonstrate that neurofibromin modulates ERK/synapsin I-dependent GABA release, which in turn modulates hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased GABA release in the hippocampus, and this was reversed by pharmacological downregulation of ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a subthreshold dose of a GABA(A) antagonist. Accordingly, Cre deletions of Nf1 showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP, and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning.
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PMID:Neurofibromin regulation of ERK signaling modulates GABA release and learning. 1898 65

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Approximately 85% of GISTs harbor activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) gene and approximately 95% of GISTs are positive for KIT (CD117) by immunohistochemistry. Nevertheless, approximately 5% of GISTs lack KIT expression. Inhibition of KIT and PDGFRA by tyrosine kinase inhibitors has revolutionized the treatment of GISTs and demands accurate tumor classification. DOG1.1 is a recently described mouse monoclonal antibody reported to have superior sensitivity and specificity compared with KIT (CD117) and CD34. We evaluated this new antibody on a group of 81 GISTs obtained from 74 patients with special regard to KIT-negative GISTs (n=28), pediatric GISTs (n=11), and GISTs associated with neurofibromatosis type I (NF1) (n=16). Conventional GISTs (n=26) were also included. All conventional KIT-positive GISTs, all NF1-associated GISTs, and 9/11 pediatric GISTs expressed DOG1.1. DOG1.1 was expressed in 10/28 (36%) of KIT-negative tumors. The staining pattern was cytoplasmic and/or membranous. This study demonstrates that DOG1.1 is a sensitive immunohistochemical marker for GIST, comparable with KIT, with the additional benefit of detecting 36% of KIT-negative GISTs. DOG1.1 is also a sensitive marker for unusual GIST subgroups lacking KIT or PDGFRA mutations. In tumors that are negative for both KIT and DOG1.1, mutational screening may be required to confirm the diagnosis of GIST.
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PMID:Monoclonal antibody DOG1.1 shows higher sensitivity than KIT in the diagnosis of gastrointestinal stromal tumors, including unusual subtypes. 1901 64

Defining growth factor requirements for progenitors facilitates their characterization and amplification. We characterize a peripheral nervous system embryonic dorsal root ganglion progenitor population using in vitro clonal sphere-formation assays. Cells differentiate into glial cells, smooth muscle/fibroblast (SM/Fb)-like cells, and neurons. Genetic and pharmacologic tools revealed that sphere formation requires signaling from the EGFR tyrosine kinase. Nf1 loss of function amplifies this progenitor pool, which becomes hypersensitive to growth factors and confers tumorigenesis. DhhCre;Nf1(fl/fl) mouse neurofibromas contain a progenitor population with similar growth requirements, potential, and marker expression. In humans, NF1 mutation predisposes to benign neurofibromas, incurable peripheral nerve tumors. Prospective identification of human EGFR(+);P75(+) neurofibroma cells enriched EGF-dependent sphere-forming cells. Neurofibroma spheres contain glial-like progenitors that differentiate into neurons and SM/Fb-like cells in vitro and form benign neurofibroma-like lesions in nude mice. We suggest that expansion of an EGFR-expressing early glial progenitor contributes to neurofibroma formation.
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PMID:Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. 1904 82

TWIST is an important transcription factor during embryonic development and has recently been found to promote the epithelial-mesenchymal transition (EMT) phenomenon seen during the initial steps of tumor metastasis. To further investigate the potential targets and interacting genes of TWIST in human gastric cancer, we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion. Moreover, TWIST-depleted HGC-27 cells showed a reversal of the morphologic and molecular changes associated with EMT. These results provide evidence that TWIST regulates the expression of several genes involved in the differentiation, adhesion, and proliferation of gastric cancer cells. The role of TWIST in the development of certain types of gastric cancer is discussed.
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PMID:Gene expression profiling in TWIST-depleted gastric cancer cells. 1905 Dec 71

Colorectal polyps containing S-100-positive neural proliferations in the lamina propria that lack ganglion cells have been variously referred to as "neuromas" or "neurofibromas." However, these lesions have not been systematically examined, and whether they are associated with type 1 neurofibromatosis (NF1) or other inherited syndromes is unknown. The aim of this study was to evaluate the clinicopathologic and immunohistochemical features of these lesions, in comparison to colorectal neurofibromas from known NF1 patients. Morphologically similar lesions from 26 patients (mean age, 62 y; range, 46 to 88 y; male/female ratio, 10/16) were retrieved from surgical pathology and consult files. Clinical and endoscopic data were obtained, and immunohistochemistry for S-100 protein, glial fibrillary acidic protein, neurofilament protein (NFP), epithelial membrane antigen, claudin-1, CD34, smooth muscle actin, and KIT was performed. The findings were compared with those in mucosal biopsies of 5 submucosal neurofibromas from NF1 patients. All 26 polyps were sessile, ranging from 1 to 6 mm in size (mean, 2.5 mm). Most arose in the distal colon (15 rectosigmoid, 7 descending, 2 transverse, and 2 ascending), and were incidentally found at screening colonoscopy. After a mean follow-up of 6.5 years (range, 3 mo to 17.5 y), none of the patients developed other neural polyps, and none had evidence of NF1 or other inherited syndromes. Histologically, the lamina propria of the polyps contained a diffuse cellular proliferation of uniform bland spindle cells with elongated, tapering nuclei, abundant, dense eosinophilic cytoplasm, and indistinct cell borders, entrapping adjacent crypts. No nuclear atypia, pleomorphism, mitotic activity, or associated ganglion cells were observed. All showed strong staining for S-100 protein in essentially 100% of cells. NFP highlighted rare axons in 7 lesions. All other markers were negative. The 5 neurofibromas showed similar histologic features, but were generally less uniformly cellular, showed some intralesional heterogeneity, and showed less extensive staining for S-100 protein; all contained scattered NFP-positive axons. In summary, solitary colorectal polyps containing pure Schwann cell proliferations in the lamina propria are not associated with NF1. Distinguishing these lesions from NF1-associated neurofibromas is difficult based on histologic features; the presence of an underlying submucosal nodule or mass should be excluded endoscopically, and immunohistochemistry should be performed. Although their nature is uncertain, we propose the interim designation "mucosal Schwann cell 'hamartoma'" to avoid confusion with the neural lesions that have significant associations with inherited syndromes.
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PMID:Mucosal Schwann cell "hamartoma": clinicopathologic study of 26 neural colorectal polyps distinct from neurofibromas and mucosal neuromas. 1906 3


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