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)

Epidemiological studies have shown that inhalation of radon, a radioactive gas, is associated with an increased risk for lung cancer. We have developed a model of radon-induced rat lung tumors to characterize cytogenetic and molecular events involved in radon-induced lung tumorigenesis. Using comparative genomic hybridization (CGH), gains and losses of genetic material were investigated in a series of 13 carcinomas and four adenomas of the lung. Frequent losses occurred at 4q12-21, 5q11-33, and 15q, which are homologous to human chromosome (HSA) bands 7q21-36, 1p31-36/9p21-31, and 13q14.1-14.3/3p14.2, respectively. These regions are frequently (30-80%) deleted in human lung cancer and contain tumor suppressor genes or proto-oncogenes such as MET, CDKN2A/p16/MTS1, CDKN2B/p15/MTS2, FHIT, and RB1 or yet to be identified genes. Frequent gains involved 6, 7q34-qter, and 19q; chromosomes 6 and 7 being homologous to human 2p21-25 and 8q21-24 where the MYCN and MYC oncogenes are located. The genetic similarities between rat and human lung cancer suggest common underlying mechanisms for tumor evolution in both species. Moreover, cytogenetic and molecular genetic analyses of radon-induced rat lung tumors could help to better understand the development and progression of radon-induced lung cancer in man.
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PMID:CGH analysis of radon-induced rat lung tumors indicates similarities with human lung cancers. 1091 87

Gastrointestinal stromal tumors (GISTs) are distinctive, KIT positive mesenchymal neoplasms. The genetic alterations leading to the malignant behavior of these tumors are not well known. In this study, we looked for recurrent numerical chromosomal changes, which may be associated with malignant GISTs, using interphase fluorescence in situ hybridization (FISH). Fourteen malignant primary tumors and two intra-abdominal recurrences were analyzed. Nine benign tumors were studied for comparison. In all cases, the presence of mutations in exons 9, 11 and 13 of the KIT gene were evaluated. Sixteen centromeric enumeration probes (CEP) for chromosomes 1, 2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 15, 16, 17, 18, and X and three locus specific probes (LSI) for 22q11.2 (BCR-locus), 13q14 (RB1-locus) and 14q32 (IgH-locus) were used. The most common changes seen in malignant GISTs were losses of 14q32 and 22q11. However, these changes were commonly detected in benign tumors and represent early changes related to the pathogenesis of GISTs. Losses of chromosomes 1 and 9 were the only recurrent numerical changes seen exclusively in malignant GISTs. Other recurrent numerical changes seen predominantly in malignant tumors were gain of chromosome 8 and losses of chromosomes 7 and 15. The concurrent loss of chromosome 7 and gain of chromosome 8 (in 4 cases) was never seen together with loss of chromosomes 9 or 15 and only once with loss of chromosome 1. Mutations in KIT were found in the majority of malignant GISTs (64%) confirming a previously shown correlation between presence of such mutations and malignancy. KIT mutations were seen in four of five malignant GISTs with loss of chromosome 9, but only in one of four malignant tumors with loss of chromosome 1. These observations may reflect the different pathways leading to malignant transformation of GISTs.
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PMID:Chromosomal aberrations in malignant gastrointestinal stromal tumors: correlation with c-KIT gene mutation. 1145 25

C-cell hyperplasias are normally multifocal in multiple endocrine neoplasia type 2A. We compared clonality, microsatellite pattern of tumor suppressor genes, and cellular kinetics of C-cell hyperplasia foci in each thyroid lobe. We selected 11 females from multiple endocrine neoplasia type 2A kindred treated with thyroidectomy due to hypercalcitoninemia. C-cell hyperplasia foci were microdissected for DNA extraction to analyze the methylation pattern of androgen receptor alleles and microsatellite regions (TP53, RB1, WT1, and NF1). Consecutive sections were selected for MIB-1, pRB1, p53, Mdm-2, and p21WAF1 immunostaining, DNA content analysis, and in situ end labeling. Appropriate tissue controls were run. Only two patients had medullary thyroid carcinoma foci. Nine informative C-cell hyperplasia patients showed germline point mutation in RET, eight of them with the same androgen receptor allele preferentially methylated in both lobes. C-cell hyperplasia foci showed heterogeneous DNA deletions revealed by loss of heterozygosity of TP53 (12 of 20), RB1 (6 of 14), and WT1 (4 of 20) and hypodiploid G0/G1 cells (14 of 20), low cellular turnover (MIB-1 index 4.5%, in situ end labeling index 0.03%), and significantly high nuclear area to DNA index ratio. MEN 2A (germline point mutation in RET codon 634) C-cell hyperplasias are monoclonal and genetically heterogeneous and show down-regulated apoptosis, findings consistent with an intraepithelial neoplasia. Concordant X-chromosome inactivation and interstitial gene deletions suggest clone expansions of precursors occurring at a point in embryonic development before divergence of each thyroid lobe and may represent a paradigm for other germline mutations.
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PMID:Germline RET 634 mutation positive MEN 2A-related C-cell hyperplasias have genetic features consistent with intraepithelial neoplasia. 1150 37

The recent cloning of a second estrogen receptor (ER), designated ERbeta, has prompted a reevaluation of the role of ERs in breast cancer. We have developed and validated a real-time RT-PCR assay to quantify ERalpha and ERbeta gene expression at the mRNA level in a series of 131 patients with unilateral invasive primary breast cancer. Although ERbeta expression showed wide variations in tumor tissues, its range (nearly three orders of magnitude) was smaller than that of ERalpha (nearly four orders of magnitude), suggesting that ERbeta is more tightly controlled than ERalpha. We observed a negative correlation between ERalpha and ERbeta expression. 'ERalpha-negative' tumors (containing very low ERalpha mRNA levels) were associated with SBR histopathological grade III, RB1 underexpression and ERBB2 overexpression, confirming that ERalpha negativity delineates poorly differentiated tumors. The amount of ERalpha mRNA (but not that of ERbeta mRNA) increased with age and was consequently higher in postmenopausal patients' tumors. Expression of ERalpha (but not that of ERbeta) also correlated strongly with progesterone receptor (PR) and PS2 expression, suggesting that ERalpha has stronger transcriptional activity than ERbeta towards genes containing an ERE (estrogen response element) in their promoters. Interestingly, we found a negative correlation between the expression of ERbeta (but not ERalpha) and CCND1, which contains an AP1 element but not an ERE in its promoter. Taken together, these data confirm that ERalpha and ERbeta play different roles in breast cancer, partly by mediating the transcription of various genes via different types of DNA enhancer. PR and PS2 seem to be mainly ERalpha-responsive genes, whereas CCND1 may be mainly ERbeta-responsive. Our findings also underline the need for a reliable method, providing full range of quantitative values, to determine ERalpha and ERbeta status in the clinical setting.
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PMID:Quantification of estrogen receptor alpha and beta expression in sporadic breast cancer. 1178 24

It is often assumed that MAPK pathways drive proliferation of normal uroepithelial (UEC) and urothelial carcinoma (TCC) cells. To check this assumption, activities and inducibilities of promoters containing serum-response elements (SRE) or AP-1 binding sites were investigated in cultured UEC and seven TCC lines. Reporter plasmids dependent on SRE or AP-1 sites were highly active in UEC, but significantly less so in TCC lines. Reporter activity in TCC lines could be induced by constitutively active MEKK4 or TPA. Accordingly, phosphorylation of the MAPK pathway components MEK, ERK, and ELK1 was most pronounced in UEC and lower in TCC lines. MAPK-dependent promoter activities and bromodeoxyuridine incorporation decreased in UEC upon withdrawal of growth factors, but less so in TCC lines, in which serum diminution increased apoptosis. Likewise, E2F-dependent promoters responded to growth factors in UEC, but were more serum-independent in the TCC lines, which lack either RB1 or p16(INK4A). MEK inhibitors inhibited BrdU incorporation in UEC more strongly than in TCC lines. Thus, proliferation of normal uroepithelial cells is indeed associated with activation of MAPK pathways. However, autonomous proliferation of TCC lines--unexpectedly--appears much less dependent on MAPK activation and may rather be promoted by defects in cell cycle regulation.
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PMID:Activities of MAP-kinase pathways in normal uroepithelial cells and urothelial carcinoma cell lines. 1249 Jan 93

Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo-13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo-13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo-13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.
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PMID:Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression. 1253 1

Natural killer and natural killer-like T cell lymphomas represent a rare type of non-Hodgkin's lymphoma originally described to involve the upper aerodigestive tract. This malignancy has been increasingly observed in other extranodal sites, particularly in the skin. Patients with cutaneous natural killer cell lymphoma generally have a poor prognosis; however, the etiology and the underlying molecular pathogenesis remain unclear. This study aimed to investigate comprehensively genomic changes in blastic natural killer and extranodal natural killer-like T cell lymphoma with cutaneous involvement. Comparative genomic hybridization showed chromosome imbalances in six of eight cases studied (75%). The mean number of chromosome imbalances per sample was 2.18+/-1.63 with similar number of gains (1.18+/-1.17) and losses (1.00+/-1.34). The most frequent DNA copy number changes observed were losses of 9/9p (83%), followed by loss of 13q and gain of 7 (67%). Similar patterns of chromosome imbalances were observed in both blastic natural killer and cutaneous natural killer-like T cell lymphomas. Loss of the RB1 gene at 13q14.2 was detected in one blastic natural killer cell lymphoma with 13q loss using a gene dosage assay, and in one cutaneous natural killer-like T cell lymphoma without 13q loss using fluorescent in situ hybridization. Genomic microarray analysis identified oncogene copy number gains of PAK1 and JUNB in three of four cases studied, and gains of RAF1, CTSB, FGFR1, and BCR in two cases. Real-time polymerase chain reaction detected amplification of CTSB and RAF1 in four of five cases analyzed, JUNB and MYCN in three cases, and REL and YES1 in two cases, respectively. In conjunction with this study, an extensive literature search for the published G-banded karyotypes of four subsets of natural killer cell lymphomas was conducted, which showed a nonrandom pattern of multiple chromosome aberrations. These results reveal consistent genetic alterations in cutaneous natural killer cell lymphomas, and provide a basis for further investigation of molecular pathogenesis in this malignancy.
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PMID:Genomic alterations in blastic natural killer/extranodal natural killer-like T cell lymphoma with cutaneous involvement. 1292 24

A literature review found 265 articles on testicular germ cell tumors (TGCTs) detailing the copy number of chromosomal regions and expression of 245 genes. An initial precursor stage, intratubular germ cell neoplasia (IGCN), is characterized by triploidization and an upregulation of KIT, ALPP, CCDN2, and ZNF354A, and a downregulation of CDKN2D. TGCT regularly have a series of chromosomal aberrations: a decrease in copy number at 4q21 approximately qter and 5q14 approximately qter; an increase at 7p21 approximately pter, 7q21 approximately q33, and 8q12 approximately q23 (especially high increase in seminoma); a decrease at 11p11 approximately p15 and 11q14 approximately q24; an increase at 12p11 approximately pter; a decrease at 13q14 approximately q31; an increase of 17q11 approximately q21 (only for nonseminoma); a decrease of 18q12 approximately qter; and an increase at 21q21 approximately qter, 22q11 approximately qter (only for seminoma), and Xq. Macroscopically overt TGCT is associated with a characteristic series of abnormalities in the retinoblastoma pathway including upregulation of cyclin D2 and p27 and downregulation of RB1 and the cyclin-dependent kinase inhibitors p16, p18, p19, and p21. TGCT thus has a synergistic pattern in gene expressions of the retinoblastoma pathway that is rare in other malignancies.
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PMID:Chromosomes, genes, and development of testicular germ cell tumors. 1517 50

Genomic microarray systems can simultaneously provide substantial genetic and chromosomal information in a relatively short time. We have analyzed genomic DNA from frozen sections of 30 cases of primary glioblastomas by GenoSensor Array 300 in order to characterize gene amplifications, gene deletions, and chromosomal information in the whole genome. Genes that were frequently amplified included RFC2/CYLN2 (63.3%), EGFR (53.3%), IL6 (53.3%), ABCB1 (MDR1) (36.7%), and PDGFRA (26.7%). Genes that were frequently deleted included (56.7%), FGFR2 (66.7%), MTAP (60.0%), DMBT1 CDKN2A (p16)/MTAP (50.0%), PIK3CA (43.3%), and EGR2 (43.3%), but deletion of RB1 or TP53 was rarely detected. Chromosomal gains were observed frequently for 7q (33.3%), 7p (20.0%), and 17q (13.3%). Loss of the 10q was frequently detected in 13 of 30 cases (46.7%). Loss of the entire chromosome 10 was seen in 9 of 30 cases (30.0%), and was often accompanied by EGFR amplification (7 cases, 77.8%). The GenoSensor Array 300 proved to be useful for identification of genome-wide molecular changes in glioblastomas. The obtained microarray profile can also yield valuable insight into the molecular events underlying carcinogenesis of brain tumors and may provide clues about clinical correlations, including response to treatment.
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PMID:Genetic analysis of human glioblastomas using a genomic microarray system. 1569 66

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14(ARF)and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy.
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PMID:Mutations in Rb1 pathway-related genes are associated with poor prognosis in anaplastic astrocytomas. 1597 Sep 25


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