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)

Neurofibromatosis type 1 or Recklinghausen disease is one of the most common hereditary autosomal dominant diseases. The disease-causing gene can be found on chromosome 17 as an NF1 tumor suppressor gene. The mutation of this gene leads to the loss of tumor suppressor function, which in turn causes the development of benign and malignant tumors. In 25% of the cases gastrointestinal manifestations are found, most often GIST. The close correlation of the two diseases are well known in the literature, there are more than 160 published cases. GIST develops in 7% of patients with neurofibromatosis, and among these patients the occurrence of NF1 is 150-180 times more frequent than in the general population. Neurofibromatosis associated with GIST is a different entity and, unlike sporadic GIST, it is usually multiplex and almost always develops in the small bowel. There is a slightly higher incidence among women than in men, and the disease develops at young age. Histological characteristics include spindle cell type, skeinoid fibers and frequent S100 positivity. Low mitotic activity usually suggests better prognosis. c-KIT and PDGFRA mutation is very rare, in agreement with the hypothesis that the pathogenesis of NF1-GIST is not c-KIT dependent. It is presumed that neurofibromatosis associated and sporadic GIST have different pathogenesis, and that the development of GIST tumor in neurofibromatosis is part of the hereditary disease. c-KIT and PDGFRA mutations--as shown in a few known cases--probably develop at a later step of tumor genesis. Imatinib, which has revolutionized the therapy of GIST, cannot be used in this patient group, however, as of today not enough information is available.
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PMID:[Gastrointestinal stromal tumors in neurofibromatosis type 1]. 1914 98

We investigated the activation of platelet-derived growth factor (PDGF) receptor A (PDGFRA), PDGF receptor B (PDGFRB), epidermal growth factor receptor (EGFR), and their downstream pathways in malignant peripheral nerve sheath tumors (MPNSTs). PDGFRA, PDGFRB, and EGFR were immunohistochemically, biochemically, cytogenetically, and mutationally analyzed along with the detection of their cognate ligands in 16 neurofibromatosis type 1 (NF1)-related and 11 sporadic MPNSTs. The activation of the downstream receptor pathways was also studied by means of v-akt murine thymoma viral oncogene homolog (AKT), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR) Western blotting experiments, as well as rat sarcoma viral oncogene homolog (RAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA), and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutational analysis and fluorescence in situ hybridization. PDGFRA, PDGFRB, and EGFR were expressed/activated, with higher levels of EGFR expression/phosphorylation paralleling increasing EGFR gene copy numbers in the NF1-related cases (71%). Autocrine loop activation of these receptors along with their coactivation were suggested by the expression of the cognate ligands in the absence of mutations and the presence of receptor tyrosine kinase (RTK) heterodimers, respectively. Both MPNST groups showed AKT, ERK, and mTOR expression/phosphorylation. No BRAF, PI3KCA, or PTEN mutations were found in either group of MPNSTs, but 18% of the sporadic MPNSTs showed RAS mutations. PTEN monosomy segregated with the NF1-related cases (50%, p = 0.018), but PTEN protein was expressed in all but two cases. In conclusion, PDGFRA, PDGFRB, and EGFR seem to be promising molecular targets for tailored treatments in MPNST. In particular, the ligand- and heterodimerization-dependent RTK activation/expression coupled with a downstream signaling phosphorylation, mediated by the upstream receptors or RAS activation, may provide a rationale to apply combined RTK and mTOR inhibitor treatments both to sporadic and NF1-related cases.
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PMID:PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor. 1924 20

Multicentricity of gastrointestinal stromal tumors (GISTs) has been described only in patients with neurofibromatosis type 1 (NF1) or within the small intestine, and different pathogenetic mechanisms are involved. We report a case of synchronous sporadic gastric and jejunal GISTs, which were resected laparoscopically in a 67-year-old man. Immunohistochemical analysis revealed that both lesions were KIT (CD117)-positive, but that the gastric lesion was CD34-positive, whereas the jejunal one was Vimentin-, S-100-, and SMA-positive. Molecular analysis of mutations in KIT exons 9, 11, 13, and 17, and in PDGFRA exons 12 and 18 revealed the presence of a gastric sporadic GIST with a KIT mutation of the exon 11 and a jejunal sporadic GIST without KIT or PDGFRA mutations. To our knowledge, this is the first report of laparoscopically resected synchronous sporadic gastric and jejunal GISTs.
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PMID:Laparoscopic resection of sporadic synchronous gastric and jejunal gastrointestinal stromal tumors: report of a case. 1931 43

A 41-year-old female patient with neurofibromatosis type 1 (NF-1) presented with a breast lump and anaemia related to gastrointestinal bleeding. She was found to have malignant myoepithelioma of the breast and simultaneously multiple gastrointestinal stromal tumours (GISTs) of the small bowel. Molecular studies showed a silent germline mutation in exon 9 of the KIT gene of both tumours. The common gene mutations characteristic of sporadic GISTs were not identified in these tumours, consistent with the literature, suggesting that gene mutations in GISTs are either absent or late events in patients with NF-1.
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PMID:Malignant myoepithelioma arising in adenomyoepithelioma of the breast and coincident multiple gastrointestinal stromal tumours in a patient with neurofibromatosis type 1. 1956 Dec 36

To date, about 100 cases of ampullary NET are reported in International literature. These tumors can cause symptoms mainly secondary to their periampullary location. Up to 25% of patients have von Recklinghausen's disease. Carcinoid syndrome is uncommon, unless hepatic metastasis is present. Determination of histopathology is of utmost importance and involves specific immunohistochemical staining. The published data indicate that these tumors, metastasize in approximately half of cases irrespective of primary tumor size. Therefore, radical excision in the form of pancreaticoduodenectomy is recommended regardless of tumor size. Local excision should be confined to patients unable to tolerate more extensive surgery. We here report two case of ampullary neuroendocrine tumors presenting as melena and painless jaundice respectively in a 51-year old man and in a 54-year old man and review the relevant literature, giving special attention to the morphologic features, clinical characteristics, and treatment modalities associated with this disease process.
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PMID:Endocrine carcinoma of the major papilla: report of two cases and review of the literature. 1958 67

Neurofibromatosis type 1 (NF1) is a developmental and cancer predisposing syndrome resulting from haploinsufficiency or alteration in neurofibromin, a multifunctional protein that acts in various signaling pathways affecting morphogenetic processes and cell proliferation. Neurofibromin deficiency deregulates Ras/Raf/MEK/ERK and Ras/PI3K/AKT/PKB/mTOR signaling networks and intersected pathways including the cAMP-dependent protein kinase A (PKA) and the Rho-cofillin which acts on actin cytoskeleton reorganization, cell motility and adhesion. As the neurofibromin-mediated pathways are associated with biological effects depending on the cell lineage, deregulation induced by NF1 mutation clearly has cell type-specific effects. This review summarizes our increasing knowledge of NF1 as a disease rooted in defective developmental mechanisms that can also influence the potential for malignant growth. The cardinal features of NF1 patients, at birth and during life involve the cardiovascular, connective/skeletal and central nervous systems, as they reflect the NF1 mutation sensitivity of cell lineages committed to specifying these systems during embryonic development. A switch to neoplastic transformation may also occur in both the prenatal and postnatal life in cancer initiating cells of defined lineages, with the cooperation of a genetically and epigenetically modified tumor microenvironment. We emphasize how much of our current knowledge of the pathomechanisms of NF1 clinical signs and cancer has come from engineered mouse models and in vitro primary cells and cell lines exposed to inhibitors of signaling molecules. Advances in our knowledge of the developmental defects primed by the loss neurofibromin should reveal further associations between given NF1 mutations and tissue-specific symptoms, thus improving the clinical management of the patients.
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PMID:Developmental abnormalities and cancer predisposition in neurofibromatosis type 1. 1960 12

Gastrointestinal (GI) neoplasms are among many manifestations of the genetic disease neurofibromatosis type 1 (NF1). However, the physiological and pathological functions of the Nf1 gene in the GI system have not been fully studied, possibly because of a lack of mouse models. In this study, we generated conditional knockout mice with Nf1 deficiency in the GI tract. These mice develop gastric epithelial hyperplasia and inflammation together with increased cell proliferation and apoptosis. The gastric phenotypes observed in these mutant mice seem to be the consequence of loss of Nf1 in gastric fibroblasts, resulting in paracrine hyperactivation of the ERK pathway in the gastric epithelium. These mice provide a useful model to study the pathogenesis of GI lesions in a subset of patients with NF1 and to investigate the role of the Nf1 gene in the development of GI neoplasms.
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PMID:Mice lacking neurofibromin develop gastric hyperplasia. 1966 Nov 50

A 50-year-old man with von Recklinghausen's disease was admitted to our hospital for anemia. Abdominal computed tomography and small intestinal fiberscopy revealed a submucosal tumor in the third portion of the duodenum. CT during angiography showed three small tumor stains on the jejunum, which were not able to be diagnosed on contrast-enhanced CT. The operative findings showed a tumor in the third portion of the duodenum and three small tumors in the jejunum. These tumors, which were immunohistochemically positive for KIT, were diagnosed as multiple gastrointestinal stromal tumors of the duodenum and jejunum. For this case, CT during angiography was useful for localization and diagnosis of multiple lesions on the small intestines.
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PMID:[A case of multiple gastrointestinal stromal tumors of the duodenum and jejunum with von Recklinghausen's disease in which CT during angiography was useful for localization and diagnosis]. 1973 7

This report presents a case of multiple gastrointestinal stromal tumors (GIST) with neurofibromatosis type 1 (NF1). A 68-year-old woman was admitted to the hospital because of a tumor close to the head of the pancreas. Imaging studies revealed submucosal tumors of the duodenum. The retroperitoneal tumor was diagnosed before surgery. Besides the main tumor in the duodenum, multiple small submucosal tumors were found in the duodenum and upper part of the jejunum during the operation. All of these tumors were resected. The histological diagnosis of all these tumors was GISTs. These tumors were immunohistochemically positive for KIT, but they demonstrated no mutation in c-kit exons 9, 11, 13, and 17, and platelet-derived growth factor receptor alpha exons 12 and 18. No recurrence occurred for a year after surgery.
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PMID:Multiple gastrointestinal stromal tumors in neurofibromatosis type 1: report of a case. 1988 21

Piebaldism is a rare disorder present at birth and inherited as an autosomal dominant trait. It results from a mutation in the c-kit proto-oncogene and is associated with a defect in the migration and differentiation of melanoblasts from the neural crest. Clinical manifestations and phenotypic severity strongly correlates with the site of mutation within the KIT gene. Here we report a 3-year-old boy and his 33-year-old father with leukoderma and poliosis associated with clinical criteria for Neurofibromatosis type 1. Genetic study of both revealed a p.Gly610Asp mutation in the KIT gene. This familiar mutation has not yet been reported in the literature. There are rare reports of piebaldism in association with neurofibromatosis type I.
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PMID:Piebaldism and neurofibromatosis type 1: family report. 2213 69


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