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)

Biphasic pulmonary blastoma is a rare lung tumor with epithelial and mesenchymal components. Genetic alterations in this tumor are largely unknown, except for the presence of beta-catenin and p53 mutations and the absence of KRAS mutation. To understand the molecular process of histogenesis of this tumor, a whole genome allelic imbalance (AI) scanning using a high-resolution single nucleotide polymorphism array as well as mutational analysis of the p53, EGFR, KRAS and beta-catenin genes were performed against the epithelial and mesenchymal components in the primary tumor and a metastatic tumor in a case of pulmonary blastoma. AI at chromosome regions 14q24-q32 and 17p11-p13 and beta-catenin mutation were commonly detected in all tumors. On the other hand, AI at chromosome regions 3p11-p14 and 9p21-p24 and p53 mutation were detected only in the mesenchymal component in the primary tumor but not in the epithelial component in the primary tumor and the brain metastasis. Likewise, AI at chromosome regions 6p24-p25 and 6q14-q27 was detected in the epithelial component in the primary tumor and the brain metastasis but not in the mesenchymal component in the primary tumor. Furthermore, the genetic alterations detected in the metastatic tumor were completely the same as those in the epithelial component in the primary tumor, indicating that a tumor cell(s) in the epithelial component in the primary tumor selectively metastasized to the brain. These results indicate that this biphasic tumor is of monoclonal origin and the phenotypic heterogeneity of the tumor is due to the differences in the accumulated genetic alterations in each component of the tumor.
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PMID:Clonality and heterogeneity of pulmonary blastoma from the viewpoint of genetic alterations: a case report. 1735 Jan 38

Cardio-facio-cutaneous (CFC) syndrome is a multiple congenital anomaly/mental retardation syndrome characterized by heart defects, a distinctive facial appearance, ectodermal abnormalities and mental retardation. Clinically, it overlaps with both Noonan syndrome and Costello syndrome, which are caused by mutations in two genes, PTPN11 and HRAS, respectively. Recently, we identified mutations in KRAS and BRAF in 19 of 43 individuals with CFC syndrome, suggesting that dysregulation of the RAS/RAF/MEK/ERK pathway is a molecular basis for CFC syndrome. The purpose of this study was to perform comprehensive mutation analysis in 56 patients with CFC syndrome and to investigate genotype-phenotype correlation. We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients. We detected one MAP2K1 mutation in three patients and four new MAP2K2 mutations in four patients out of 24 patients without KRAS or BRAF mutations in the previous study [Niihori et al., 2006]. No mutations were identified in MAPK3/1 (ERK1/2) in 21 patients without any mutations. In total, 35 of 56 (62.5%) patients with CFC syndrome had mutations (3 in KRAS, 24 in BRAF, and 8 in MAP2K1/2). No significant differences in clinical manifestations were found among 3 KRAS-positive patients, 16 BRAF-positive patients, and 6 MAP2K1/2-positive patients. Wrinkled palms and soles, hyperpigmentation and joint hyperextension, which have been commonly reported in Costello syndrome but not in CFC syndrome, were observed in 30-40% of the mutation-positive CFC patients, suggesting a significant clinical overlap between these two syndromes.
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PMID:Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. 1736 77

In lung adenocarcinomas, genetic alterations of PTEN are relatively rare and little has been reported concerning the relationship between PTEN transcriptional level and clinicopathologic features or genetic changes. This study was conducted to gain insight into clinicopathologic correlations. The transcriptional levels of PTEN were examined using real time RT-PCR and analyzed for correlations with clinicopathologic features and the mutation status of EGFR and KRAS. After confirming significant correlation for PTEN levels between macrodissected and microdissected materials (p<0.01), macrodissected samples from 115 lung adenocarcinomas were examined. There were no significant difference between the PTEN levels, divided into three ranges, and the mutation status of EGFR or KRAS. Noteworthy clinicopathologic correlations between PTEN transcriptional up/down-regulation and young age (p=0.0081, 61.7+/-8.7years versus 66.1+/-8.1years), smoking (p=0.032) and less differentiated adenocarcinomas (p=0.013) were identified. Whereas male patients demonstrated no prognostic association with PTEN levels, female cases with up-regulated PTEN expression had significantly worse survival compared with those with normal PTEN levels (p=0.0027). This study revealed distinct clinicopathologic correlations with PTEN transcriptional up/down-regulation.
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PMID:Up-regulation of PTEN at the transcriptional level is an adverse prognostic factor in female lung adenocarcinomas. 1745 61

We examined the genome-wide expression profiles of 86 primary lung adenocarcinomas and compared them with the mutation status of the four key molecules (EGFR, ERBB2, KRAS and BRAF) in the EGFR/KRAS/BRAF pathway. Unsupervised classification revealed two subtypes (the bronchial type and the alveolar type) of lung adenocarcinoma. Mutually exclusive somatic mutations of the epidermal growth factor receptor (EGFR) gene (36/86, 41.8%), K-ras gene (11/86, 12.8%) and BRAF gene (1/86, 1.1%) were detected. KRAS mutations were observed significantly frequently in bronchial-type tumors, whereas the frequencies of EGFR mutations were similar in both the alveolar and bronchial types. Twenty-seven genes showed increased expression in EGFR-mutated tumors and these included molecules that function in the EGFR/KRAS/BRAF pathway (EGFR, AKT1 and BCR). In particular, expression of BCR, which is required for EGFR protein degradation, was induced by EGF stimulation, suggesting a negative feedback loop in lung cancer. A subgroup of the alveolar type tumors showed significantly better prognosis than other tumors. Integrated analysis of genetic and gene expression profiling aimed to delineate inherent oncogenic pathways in cancer will be valuable not only for the understanding of molecular pathogenesis, but also for discovering novel biomarkers and predicting clinical outcome.
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PMID:Gene expression profiling of epidermal growth factor receptor/KRAS pathway activation in lung adenocarcinoma. 1745 62

c-KIT is a tyrosine kinase receptor found to be overexpressed in several tumours, namely, GISTs, breast, lung, prostate, ovarian and colorectal carcinomas (CRC). We aimed at determining the frequency of c-KIT expression and mutations in a series of 109 CRC cases (73 primary tumours and 36 lymph node metastases) characterised for KRAS and BRAF mutations. We also aimed at analysing the cellular effects of STI571/Gleevec in CRC-derived cell lines displaying c-KIT expression and KRAS or BRAF mutations. By immunohistochemistry, we found c-KIT overexpression in 15% (11/73) of primary tumours and in 14% (5/36) of metastasis; however, cases showing overexpression did not show c-kit mutations in hotspot regions. The majority (64%) of primary tumours with c-KIT overexpression had mutations at KRAS-BRAF genes. The same was true for 60% of the metastases. We treated CRC cell lines with STI571/Gleevec and verified that it inhibits proliferation and induces apoptosis in all cell lines. In conclusion, overexpression of c-KIT is observed in a subset of primary and CRC metastases in the absence of c-kit mutations. STI571/Gleevec increases apoptosis in CRC cell lines independently of its genetic profile, suggesting that STI571/Gleevec is likely to be an alternative drug for the clinical trials of CRC.
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PMID:A subset of colorectal carcinomas express c-KIT protein independently of BRAF and/or KRAS activation. 1748 4

The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4(-), CD8(-) alphabeta T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Gly13Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p21 Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders.
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PMID:NRAS mutation causes a human autoimmune lymphoproliferative syndrome. 1751 60

In the resected lung, additional small lesions are occasionally found incidentally, and include the full spectrum of preinvasive to invasive lesions under the current putative schema of the sequential development of lung cancer. In this study, we examined EGFR and KRAS gene mutations in 119 synchronous pulmonary lesions, including 40 precursor lesions (atypical adenomatous hyperplasia, AAH), 26 carcinomas in situ (non-mucinous bronchioloalveolar carcinoma, BAC), 14 minimally invasive adenocarcinomas, 34 overt invasive adenocarcinomas, and five of other subtypes of cancer. Although the mutually exclusive nature of KRAS and EGFR gene mutations was maintained even in preinvasive lesions, the incidences of the lesions along the putative progression schema were quite different. The KRAS gene was mutated in 33% of AAH, 12% of carcinomas in situ, 8% of minimally invasive adenocarcinomas and 0% of well-differentiated adenocarcinomas, whereas the frequencies of EGFR mutation did not fluctuate greatly, at 25%, 51%, 36%, 86% and 67%, respectively. These results are consistent with the findings of a published gene-targeted mouse model; the mice expressing oncogenic KRAS developed AAH but not invasive adenocarcinoma, whereas a spectrum of preinvasive to invasive adenocarcinomas was observed in the mice expressing mutant EGFR. Taking these factors together, it is suggested that AAH could develop by either KRAS or EGFR gene mutation, but AAH harbouring a KRAS gene mutation might not progress further to an invasive cancer.
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PMID:Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas. 1753 46

RASSF2, a member of the RAS association domain family 1 (RASSF1), is a candidate tumor suppressor gene (TSG) that is silenced by promoter hypermethylation in several human cancers. In this study, we examined the expression of RASSF2 mRNA and the promoter methylation status in lung cancer cell lines and in tumor samples of 106 primary non-small cell lung cancers (NSCLCs) by methylation-specific PCR. RASSF2 expression was absent in 26% of small cell lung cancers (SCLCs; n=27 lines) and 50% of NSCLCs (n=42 lines). Promoter methylation of RASSF2 was found in 18% of the SCLC cell lines (n=22) and 62% of the NSCLC cell lines (n=26), and the methylation status was tightly associated with the loss of RASSF2 expression. RASSF2 expression was restored by treatment with 5-aza-2-deoxycytidine and/or trichostatin-A in the NSCLC cell lines which were absent of the expression. RASSF2 methylation was found in 31% of primary NSCLC tumors, and methylation was more frequent in the specimens from non-smokers (18 of 40, 45%) than in the specimens from smokers (15 of 66, 23%, P=0.014). We also examined the association of RASSF2 methylation with mutations of KRAS and EGFR and with promoter hypermethylation of RASSF1A; however, we could not find a significant association between RASSF2 methylation and these genetic and epigenetic changes. Our results indicate that aberrant methylation of the RASSF2 gene with the subsequent loss of RASSF2 expression plays an important role in the pathogenesis of lung cancers.
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PMID:Epigenetic inactivation of the RAS-effector gene RASSF2 in lung cancers. 1754 18

Testicular germ cell tumours (TGCTs) are the leading cause of cancer deaths in young male Caucasians. Identifying changes in DNA copy number can pinpoint genes involved in tumour development. We defined the smallest overlapping regions of imbalance in TGCTs using array comparative genomic hybridization analysis. Novel regions, or regions which refined those previously reported, were identified. The expression profile of genes from 12p, which is invariably gained in TGCTs, and amplicons defined at 12p11.2-12.1 and 4q12, suggest KRAS and KIT involvement in TGCT and seminoma development, respectively. Amplification of these genes was not found in intratubular germ cell neoplasia adjacent to invasive disease showing these changes, suggesting their involvement in tumour progression. Activating mutations of RAS genes (KRAS or NRAS) and overexpression of KRAS were mutually exclusive events. These, correlations between the expression levels of KIT, KRAS and GRB7 (which encodes an adapter molecule known to interact with the KIT tyrosine kinase receptor) and other reported evidence reviewed here, are consistent with a role for activation of KIT and RAS signalling in TGCT development. In order to assess a role for KIT in seminomas, we modulated the level of KIT expression in TCam-2, a seminoma cell line. The likely seminomatous origin of this cell line was supported by demonstrating KIT and OCT3/4 overexpression and gain of 12p material. Reducing the expression of KIT in TCam-2 through RNA inhibition resulted in decreased cell viability. Further understanding of KIT and RAS signalling in TGCTs may lead to novel therapeutic approaches for these tumours.
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PMID:KIT and RAS signalling pathways in testicular germ cell tumours: new data and a review of the literature. 1757 50

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor EGFR are common in non-small cell lung cancer (NSCLC) of never smokers, whereas HER2 mutations are rare. We have analyzed EGFR and HER2 mutations and the expression of the two products of the CDKN2A gene (p14(arf) and p16(INK4a)) in 116 NSCLC that have been previously analyzed for TP53 and KRAS mutations in relation to smoking history of patients. EGFR mutations were detected in 20 of 116 (17%) tumors, whereas five (4.3%) tumors contained HER2 mutations. No tumor contained both mutations. Of tumors with EGFR or HER2 mutation, 72% were adenocarcinomas, 68% were from never smokers, and 32% were from former smokers. EGFR but not HER2 mutations were mutually exclusive with KRAS mutation. Among never smokers, 11 of 16 tumors with EGFR mutation also had TP53 mutation, in contrast with two of 17 tumors without EGFR mutation (P = 0.0008). Expression of p14(arf), but not p16(ink4a), was more frequently down-regulated in never smokers (62.5%) than ever smokers (35%; P = 0.008). All tumors with EGFR or HER2 mutations and wild-type TP53 showed down-regulation of p14(arf) expression. These observations suggest that functional inactivation of the p14(arf)/p53 connection is required in tumors with EGFR or HER2 mutations, consistent with the notion that these proteins are part of a fail-safe mechanism protecting cells against untimely or excessive mitotic signals.
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PMID:Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in non-small cell lung cancers in relation to smoking history. 1757 33


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