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)

The BRAF gene has been shown to be a major target for mutations in papillary thyroid carcinoma (PTC) (36-69%), which forms almost all of the over 2000 cases of thyroid carcinoma that have occurred in Chernobyl. BRAF is activated by point mutation, and were it to occur at a high frequency in Chernobyl-related tumors, it would challenge the dominant role of double-strand breaks in radiation-induced PTC. In a previous study, we detected the BRAF V600E mutation in 46% (23 of 50) of sporadic adult PTC. Using the same methodology, we have analyzed 34 post-Chernobyl PTC and detected RET/PTC rearrangements in 14 (41%) and BRAF mutations (V600E) in four (12%). These two alterations did not coexist in any PTCs. The mean age at exposure of patients with PTC showing BRAF mutation was higher than that of patients with tumors without BRAF mutation irrespective of their RET status. We have also analyzed 17 sporadic cases of childhood PTC and found that only one (6%) harbored the BRAF V600E mutation. We conclude that the frequency of BRAF mutations is significantly lower (P = 0.0008) in post-Chernobyl PTC than in adult sporadic PTC, whereas no significant difference was found between post-Chernobyl and sporadic childhood PTCs.
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PMID:BRAF mutations are not a major event in post-Chernobyl childhood thyroid carcinomas. 1535 19

A high prevalence of the activating BRAF mutation, BRAF(T1796A), is observed in adult papillary thyroid carcinomas (PTCs). The prognosis of childhood PTCs is generally fairly good despite the fact that distant metastases are often documented in these cases. To investigate the differences between the characteristics of childhood and adult PTCs, we analyzed both BRAF(T1796A) and RAS mutations in 31 Japanese and 48 post-Chernobyl Ukrainian thyroid carcinomas. In the 31 Japanese childhood cases, BRAF(T1796A) was found in only one instance (3.2%), and no RAS mutations were detected. In the Ukrainian subjects, of the 15 childhood and the 33 adolescent and young adult PTCs examined, the BRAF(T1796A) mutation was found in zero and eight cases, respectively, and RAS mutations were found in two of the young adult cases. In addition, 17 of the 48 Ukrainian cases showed expression of the RET tyrosine kinase region, indicating the existence of RET/PTC rearrangements. Unlike adult PTCs, we could detect no positive association between BRAF(T1796A) mutations and clinical parameters in the childhood carcinomas, suggesting that a low prevalence of BRAF(T1796A) is a common feature of PTCs in children regardless of radiation exposure levels. The differences in the prevalence of BRAF(T1796A) mutations between childhood and adult cases of PTC may well reflect inherent differences in the clinical features of these cancers between the two age groups.
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PMID:Low frequency of BRAFT1796A mutations in childhood thyroid carcinomas. 1535 19

Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras-Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/- mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.
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PMID:Therapies to slow polycystic kidney disease. 1536 92

BAY 43-9006 is an oral inhibitor of CRAF, wild-type BRAF, mutant V599E BRAF, vascular endothelial growth factor receptor (VEGFR) 2, VEGFR3, mVEGFR2, FLT-3, platelet-derived growth factor receptor, p38, and c-kit among other kinases. A Phase I study of BAY 43-9006 identified 400 mg orally twice daily as the recommended Phase II dose. The Phase II results of a study of BAY 43-9006 at 400 mg orally twice daily were particularly interesting in patients with renal cell carcinoma. Data from the first 41 patients with renal cell carcinoma showed that 30% of patients had stable disease (defined as between 25% reduction and 25% growth), 40% had responded (defined as >25% reduction), and 30% had progressed. Disease could be stabilized for periods in excess of a year. Some lesions became cystic and could actually enlarge while developing a low attenuation core. This phenomenon is recognized in the treatment of gastrointestinal stromal tumors with imatinib mesylate. The toxic effects of BAY 43-9006 were manageable and included hypertension, edema, diarrhea, hand and foot syndrome, rash, and hair loss where the rash involved the scalp. There was an impression of tachyphylaxis such that patients who required a dose reduction could be restored to full dose after a few months. A Phase III randomized, placebo-controlled trial of BAY 43-9006 has started for patients whose renal cell carcinoma has progressed within 6 months of immunotherapy. Combination studies with interferon, interleukin 2, bevacizumab, and chemotherapy are under consideration. The therapeutic targets of BAY 43-9006 in renal cell carcinoma remain unclear. Unlike melanoma, BRAF mutations have not been found in renal cell carcinoma. Other candidate targets include VEGFR2 and VEGFR3.
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PMID:Kinase inhibition with BAY 43-9006 in renal cell carcinoma. 1544 36

Rearrangements of the RET proto-oncogene (RET/PTC) and BRAF gene mutations are the major genetic alterations in the etiopathogenesis of papillary thyroid carcinoma (PTC). We have analyzed a series of 118 benign and malignant follicular cell-derived thyroid tumors for RET/PTC rearrangements and BRAF gene mutations. Oncogenic rearrangements of RET proto-oncogene was revealed by semiquantitative RT-PCR of simultaneously generated fragments corresponding to tyrosine kinase (TK) and extracellular RET domains. The clear quantitative shift toward the TK fragment is indicative for the presence of RET rearrangements. The overall frequency of RET/PTC rearrangements in PTC was 14% (12 of 85), including 7 RET/PTC1, 2 RET/PTC3, 1 deltaRFP/RET and 2 apparently uncharacterized rearrangements. The most common T1796A transversion in BRAF gene was detected in 55 of 91 PTC (60%) using mutant-allele-specific PCR. We also identified two additional mutations: the substitution G1753A (E585K) and a case of 12-bp deletion in BRAF exon 15. Moreover, there was no overlap between PTC harboring BRAF and RET/PTC mutations, which altogether were present in 75.8% of cases (69 of 91). Taken together, our observations are consistent with the notion that BRAF mutations appear to be an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. Neither RET/PTC rearrangements nor BRAF muta-tions were detected in any of 3 follicular thyroid carcinomas, 11 follicular adenomas and 13 nodular goiters. The high prevalence of BRAF mutations and RET/PTC rearrangements in PTCs and the specificity of these alterations to PTC make them potentially important markers for the preoperative tumor diagnosis.
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PMID:[Molecular analysis of structural abnormalities in papillary thyroid carcinoma gene]. 1545 36

The RAS/RAF signaling pathway is an important mediator of tumor cell proliferation and angiogenesis. The novel bi-aryl urea BAY 43-9006 is a potent inhibitor of Raf-1, a member of the RAF/MEK/ERK signaling pathway. Additional characterization showed that BAY 43-9006 suppresses both wild-type and V599E mutant BRAF activity in vitro. In addition, BAY 43-9006 demonstrated significant activity against several receptor tyrosine kinases involved in neovascularization and tumor progression, including vascular endothelial growth factor receptor (VEGFR)-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT. In cellular mechanistic assays, BAY 43-9006 demonstrated inhibition of the mitogen-activated protein kinase pathway in colon, pancreatic, and breast tumor cell lines expressing mutant KRAS or wild-type or mutant BRAF, whereas non-small-cell lung cancer cell lines expressing mutant KRAS were insensitive to inhibition of the mitogen-activated protein kinase pathway by BAY 43-9006. Potent inhibition of VEGFR-2, platelet-derived growth factor receptor beta, and VEGFR-3 cellular receptor autophosphorylation was also observed for BAY 43-9006. Once daily oral dosing of BAY 43-9006 demonstrated broad-spectrum antitumor activity in colon, breast, and non-small-cell lung cancer xenograft models. Immunohistochemistry demonstrated a close association between inhibition of tumor growth and inhibition of the extracellular signal-regulated kinases (ERKs) 1/2 phosphorylation in two of three xenograft models examined, consistent with inhibition of the RAF/MEK/ERK pathway in some but not all models. Additional analyses of microvessel density and microvessel area in the same tumor sections using antimurine CD31 antibodies demonstrated significant inhibition of neovascularization in all three of the xenograft models. These data demonstrate that BAY 43-9006 is a novel dual action RAF kinase and VEGFR inhibitor that targets tumor cell proliferation and tumor angiogenesis.
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PMID:BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. 1546 6

Point mutations in BRAF are genetic hallmarks of papillary thyroid carcinoma (PTC). In this retrospective study, we examined thyroid aspirates and corresponding paraffin-embedded surgical samples for the presence of BRAF mutations. Altogether, we examined 96 cases, including 69 PTCs, 19 follicular adenomas, and eight nontoxic nodular goiters for BRAF; 60 of these samples were also examined for RET/PTC rearrangements. The results were correlated with the cytological diagnosis and the final histopathology. The BRAF mutation (V599E) was detected in 38% of the samples that were PTC on histopathology; RET/PTC was found in 18% of the PTC cases. In all the cases, the presence of the genetic alteration was confirmed in the surgically resected tumor. The identification of BRAF mutation and RET/PTC refined the diagnosis of PTC in five of 15 samples that were considered either indeterminate or insufficient at cytology. No mutation was found in aspirates of follicular adenomas and nontoxic nodular goiters. These results indicate that BRAF mutation and RET/PTC rearrangements are molecular markers of PTC that can be applied to FNA in adjunct to traditional cytology.
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PMID:Analysis of BRAF point mutation and RET/PTC rearrangement refines the fine-needle aspiration diagnosis of papillary thyroid carcinoma. 1547 23

Although several multiprotein complexes containing MAPKs (mitogen-activated protein kinases) have been identified using overexpression of kinases and scaffold proteins, the components of the complexes and their physical properties at endogenous expression levels have not been defined. We characterized a large protein complex containing a nerve-growth-factor-activated ERK (extracellular-signal-regulated kinase) and MEK (MAPK/ERK kinase) in rat pheochromocytoma (PC12) cells. This protein complex fractionated into a high-speed pellet and was resistant to non-ionic detergent treatments that solubilized membranes. Disruption of protein-protein interactions by treatment with high salt was required to facilitate immunoprecipitation of active ERK1 and co-precipitation of MEK1. Microtubule fragments were also present in the detergent-resistant high-speed pellet, and some kinases were bound to them, especially ERK1b (an alternatively spliced isoform of ERK1), which showed a strong preference for binding microtubules. The large protein complex containing ERK1 and MEK1 was resolved by velocity sedimentation from fragments of microtubules; however, it did not contain other scaffolding components known to bind ERK and MEK. B-Raf was also present in a distinct detergent-resistant, microtubule-independent protein complex slightly larger than that containing ERK and MEK. We conclude that there are two independent nerve growth factor-regulated 'signalling particles' with an estimated size of 60-75 S, one containing ERK1 and MEK1 and the other containing B-Raf. These signalling particles may have a role in the temporal and spatial regulation of kinase activity inside cells.
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PMID:Distinct signalling particles containing ERK/MEK and B-Raf in PC12 cells. 1550 Apr 39

Aberrant activation of Ras signaling is a common finding in human glioblastomas. To determine the contribution of Ras gene mutations to this aberration, we screened 94 glioblastomas for mutations in the three Ras family genes NRAS, KRAS and HRAS. All tumors were additionally analyzed for mutations in BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties. Mutation analysis of the entire coding regions of NRAS and KRAS, as well as the known mutation hot-spot sites in HRAS, identified somatic point mutations in two glioblastomas, both affecting codon 12 of NRAS (c.35G>A, p.G12D). Three additional tumors carried BRAF mutations altering the known hot-spot codon 599 (c.1796T>A, p.V599E). None of these five glioblastomas showed amplification of the EGFR or PDGFRA genes, while three of the tumors, including two with NRAS and one with BRAF mutation, demonstrated PTEN missense mutations or loss of PTEN mRNA expression. Taken together, our data suggest activating mutations in NRAS or BRAF as a molecular alteration that contributes to aberrant Ras signaling in a small fraction of glioblastomas.
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PMID:Mutation analysis of the Ras pathway genes NRAS, HRAS, KRAS and BRAF in glioblastomas. 1551 9

Most human malignancies are caused by somatic alterations within the cancer genome, leading to oncogene activation or tumor suppressor gene inactivation. The sequence of the human genome has enabled systematic approaches to identify cancer genome alterations, including point mutations, copy number increases and decreases, loss of allelic heterozygosity, and chromosome translocations. Systematic cancer genome analysis has recently led to the discovery of somatic mutations in the BRAF, PIK3CA, and EGFR genes, among others. With further development of targeted cancer therapies and improvement in genome analysis technology, genome-wide surveys of cancer will likely become tools for diagnosis as well as discovery.
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PMID:Somatic alterations in the human cancer genome. 1554 26


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