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)

Activating mutations of the genes for NRAS and BRAF, components of the p44/42 mitogen-activated protein kinase (MAPK) pathway, are common findings in melanoma. Recent evidence in several nonmelanoma cell systems supports the regulation of the inducible nitric oxide synthase (iNOS) gene by this pathway. On the basis of our data showing that melanoma iNOS expression predicts shortened patient survival, we formulated the hypothesis that activating mutations of NRAS or BRAF, which lead to constitutive activation of the p44/42 MAPK pathway, drive iNOS expression in human melanoma. In the present study, we have shown that inhibition of melanoma iNOS activity by S-methylisothiourea leads to decreased cell proliferation, confirming the importance of iNOS activity for melanoma cell growth. Regulation of melanoma iNOS expression by the p44/42 MAPK pathway was demonstrated by inhibition of the pathway by U0126, and by BRAF RNA interference. To explore this regulatory pathway in human tissue, 20 melanoma tumors were examined for NRAS and BRAF mutations, immunohistochemical evidence of ERK phosphorylation, and iNOS expression. A significant association was found among these three features. We conclude that in human melanoma, activating mutations of NRAS and BRAF drive constitutive iNOS expression and, implicitly, nitric oxide production, contributing to the poor survival of these patients.
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PMID:Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma. 1647 47

BRAF somatic mutations are frequently found in primary and metastatic melanomas and melanocytic naevi. Commonly found BRAF mutants stimulate constitutive RAF/MEK (mitogen-activated ERK-activating kinase)/ERK (extracellular signal-regulated kinase) pathway activation and act as transforming oncogenes in NIH-3T3 cells and immortalized murine melanocytes. The most common BRAF mutation is the V600E alteration, but over 30 distinct BRAF mutations, varying in biological activity, have been found and may be predictive of clinically relevant tumour differences. The origin of these acquired mutations remains unknown, but melanomas have a different BRAF mutational spectrum from other tumours, possibly resulting from unique environmental exposures. In melanoma cases, BRAF mutations are frequently found in superficial spreading or nodular histological subtypes, in tumours on intermittently sun-exposed sites and in younger patients. Although evidence indicates that the activation of the RAF/MEK/ERK pathway influences the proliferation, invasion and survival of melanoma cells in vitro, the exact role of BRAF mutation in melanoma tumour progression, maintenance and outcome remains controversial. In addition, although BRAF and NRAS mutations are mutually exclusive in melanomas, other genetic events may complement BRAF mutation to produce biological activity similar to NRAS mutation. Nonetheless, preclinical and early clinical studies predict that RAF/MEK/ERK pathway inhibitors will have therapeutic activity towards melanoma, but that tumour subclassification by BRAF/NRAS mutational status may be necessary to evaluate their efficacy.
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PMID:BRAF somatic mutations in malignant melanoma and melanocytic naevi. 1656 64

Malignant pleural mesothelioma (MPM) is an asbestos-related malignancy that is highly resistant to current therapeutic modalities. We established four MPM cell lines (ACC-MESO-1, ACC-MESO-4, Y-MESO-8A and Y-MESO-8D) from Japanese patients, with the latter two from the same patient with biphasic-like characteristics of MPM, showing epithelial and sarcomatous phenotypes, respectively, in cell culture. These cells grew well in RPMI-1640 medium supplemented with 10% fetal bovine serum under 5% CO2. Mutation and expression analyses demonstrated that the tumor suppressor gene NF2, which is known to be one of the most frequently mutated in MPM, is mutated in ACC-MESO-1. We detected homozygous deletion of p16INK4A/p14ARF in all four MPM cell lines. However, mutations of other tumor suppressor genes, including TP53, and protooncogenes, including KRAS, NRAS, BRAF, EGFR and HER2, were not found in these cell lines. Polymerase chain reaction amplification of the simian virus 40 sequence did not detect any products. We also analyzed genetic alterations of six other MPM cell lines and confirmed frequent mutations of NF2 and p16INK4A/p14ARF. To characterize the biological differences between Y-MESO-8A and Y-MESO-8D, we carried out cDNA microarray analysis and detected genes that were differentially expressed in these two cell lines. Thus, our new MPM cell lines seem to be useful as new models for studying various aspects of the biology of human MPM as well as materials for the development of future therapies.
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PMID:Establishment and characterization of four malignant pleural mesothelioma cell lines from Japanese patients. 1663 Jan 36

The aim of this study was to identify amplified oncogenes in endometrial cancer using array-based comparative genomic hybridization (array CGH). Despite its prevalence, the molecular mechanisms of endometrial carcinogenesis are still poorly understood. The selected array CGH allows the simultaneous examination of 58 oncogenes commonly amplified in human cancers and is capable of achieving increased mapping resolution compared with conventional CGH. A subset of 8 specimens from a bank of 60 malignant and normal specimens was selected for array analysis to identify potential genes of interest. TaqMan polymerase chain reaction was carried out on the 60 specimens to examine if aberrations at the genomic level correlated with gene expression and to compare expression in normal and malignant samples. Oncogenes amplified in the endometrial cancers included AR, PIK3CA, MET, HRAS, NRAS, D17S1670, FGFR1, CTSB, RPS6KB1, LAMC2, MYC, PDGFRA, FGF4/FGF3, PAKI, and FGR. Three genes were examined at the messenger RNA level. AR and PIK3CA were higher in normal specimens, and MET was higher in malignant samples, suggesting a role for MET in endometrial cancer. Newer arrays examining more genes and larger sample numbers are necessary to elucidate the carcinogenic pathway in endometrial cancer.
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PMID:Genome-wide analysis of deoxyribonucleic acid in endometrial cancer using comparative genomic hybridization microarrays. 1668 70

AML1-ETO collaborates with further genetic abnormalities to induce acute myeloid leukaemia (AML). We analysed 99 patients with an AML1-ETO rearrangement for additional aberrations. Frequent genetic abnormalities were, loss of a sex chromosome (56/99, 56.5%) and del(9)(q22) (24/99, 24.2%). The most frequent molecular aberrations were mutations of KITD816 (3/23, 13%) and NRAS (8/89, 8.9%). Further molecular abnormalities were FLT3 mutations (3/87, 3.4%), AML1 (1/26, 3.8%) and PU1 (1/14, 7.1%). MLL-PTD, KRAS and CEBPA mutations were not found. These clinical findings support the model that AML1-ETO collaborates with other genetic alterations, such as mutations of receptor tyrosine kinases, to induce AML.
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PMID:Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukaemia with t(8;21)/AML1-ETO. 1693 18

Activating mutations in either BRAF or NRAS are seen in a significant number of malignant melanomas, but their incidence appears to be dependent to ultraviolet light exposure. Thus, BRAF mutations have the highest incidence in non-chronic sun damaged (CSD), and are uncommon in acral, mucosal and CSD melanomas. More recently, activating KIT mutations have been described in rare cases of metastatic melanoma, without further reference to their clinical phenotypes. This finding is intriguing since KIT expression is downregulated in most melanomas progressing to more aggressive lesions. In this study, we investigated a group of anal melanomas for the presence of BRAF, NRAS, KIT and PDGFRA mutations. A heterozygous KIT exon 11 L576P substitution was identified in 3 of 20 cases tested. The 3 KIT mutation-carrying tumors were strongly immunopositive for KIT protein. No KIT mutations were identified in tumors with less than 4+ KIT immunostaining. NRAS mutation was identified in one tumor. No BRAF or PDGFRA mutations were identified in either KIT positive or negative anal melanomas. In vitro drug testing of stable transformant Ba/F3 KIT(L576P) mutant cells showed sensitivity for dasatinib (previously known as BMS-354825), a dual SRC/ABL kinase inhibitor, and imatinib. However, compared to an imatinib-sensitive KIT mutant, dasatinib was potent at lower doses than imatinib in the KIT(L576P) mutant. These results suggest that a subset of anal melanomas show activating KIT mutations, which are susceptible for therapy with specific kinase inhibitors.
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PMID:L576P KIT mutation in anal melanomas correlates with KIT protein expression and is sensitive to specific kinase inhibition. 1737 1

The FIP1L1-PDGFRA fusion gene has been described in patients with eosinophilia-associated myeloproliferative disorders (Eos-MPD). Here, we report on seven FIP1L1-PDGFRA-positive patients who presented with acute myeloid leukemia (AML, n=5) or lymphoblastic T-cell non-Hodgkin-lymphoma (n=2) in conjunction with AML or Eos-MPD. All patients were male, the median age was 58 years (range, 40-66). AML patients were negative for common mutations of FLT3, NRAS, NPM1, KIT, MLL and JAK2; one patient revealed a splice mutation of RUNX1 exon 7. Patients were treated with imatinib (100 mg, n=5; 400 mg, n=2) either as monotherapy (n=2), as maintenance treatment after intensive chemotherapy (n=3) or in overt relapse 43 and 72 months, respectively, after primary diagnosis and treatment of FIP1L1-PDGFRA-positive disease (n=2). All patients are alive, disease-free and in complete hematologic and complete molecular remission after a median time of 20 months (range, 9-36) on imatinib. The median time to achievement of complete molecular remission was 6 months (range, 1-14). We conclude that all eosinophilia-associated hematological malignancies should be screened for the presence of the FIP1L1-PDGFRA fusion gene as they are excellent candidates for treatment with tyrosine kinase inhibitors even if they present with an aggressive phenotype such as AML.
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PMID:Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma. 1737 85

AML1/RUNX1 is implicated in leukemogenesis on the basis of the AML1-ETO fusion transcript as well as somatic mutations in its DNA-binding domain. Somatic mutations in RUNX1 are preferentially detected in acute myeloid leukemia (AML) M0, myeloid malignancies with acquired trisomy 21, and certain myelodysplastic syndrome (MDS) cases. By correlating the presence of RUNX1 mutations with cytogenetic and molecular aberration in a large cohort of AML M0 (N = 90) at diagnosis, we detected RUNX1 mutations in 46% of cases, with all trisomy 13 cases (n = 18) being affected. No mutations of NRAS or KIT were detected in the RUNX1-mutated group and FLT3 mutations were equally distributed between RUNX1-mutated and unmutated samples. Likewise, a high incidence of RUNX1 mutations (80%) was detected in cases with trisomy 13 from other French-American-British (FAB) subgroups (n = 20). As FLT3 is localized on chromosome 13, we hypothesized that RUNX1 mutations might cooperate with trisomy 13 in leukemogenesis by increasing FLT3 transcript levels. Quantitation of FLT3 transcript levels revealed a highly significant (P < .001) about 5-fold increase in AML with RUNX1 mutations and trisomy 13 compared with samples without trisomy 13. The results of the present study indicate that in the absence of FLT3 mutations, FLT3 overexpression might be a mechanism for FLT3 activation, which cooperates with RUNX1 mutations in leukemogenesis.
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PMID:Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. 1748 49

Core binding factor (CBF) leukemias, characterized by either inv(16)/t(16;16) or t(8;21), constitute acute myeloid leukemia (AML) subgroups with favorable prognosis. However, there exists substantial biologic and clinical heterogeneity within these cytogenetic groups that is not fully reflected by the current classification system. To improve the molecular characterization we profiled gene expression in a large series (n = 93) of AML patients with CBF leukemia [(inv (16), n = 55; t(8;21), n = 38)]. By unsupervised hierarchical clustering we were able to define a subgroup of CBF cases (n = 35) characterized by shorter overall survival times (P = .03). While there was no obvious correlation with fusion gene transcript levels, FLT3 tyrosine kinase domain, KIT, and NRAS mutations, the newly defined inv(16)/t(8;21) subgroup was associated with elevated white blood cell counts and FLT3 internal tandem duplications (P = .011 and P = .026, respectively). Supervised analyses of gene expression suggested alternative cooperating pathways leading to transformation. In the "favorable" CBF leukemias, antiapoptotic mechanisms and deregulated mTOR signaling and, in the newly defined "unfavorable" subgroup, aberrant MAPK signaling and chemotherapy-resistance mechanisms might play a role. While the leukemogenic relevance of these signatures remains to be validated, their existence nevertheless supports a prognostically relevant biologic basis for the heterogeneity observed in CBF leukemia.
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PMID:Gene-expression profiling identifies distinct subclasses of core binding factor acute myeloid leukemia. 1748 51

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


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