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)

In a separate study (F. Courjal et al., Cancer Res., 57: 4360-4367, 1997), we have analyzed by Southern blotting the relationship between DNA amplification and clinicopathological features of breast cancer. Six regions of recurrent amplifications were tested (8p12, 8q24, 11q13, 12q13, 17q12, and 20q13), and the results suggested that there was a relationship between DNA amplification profiles and breast tumor phenotype. We had delineated three subgroups of tumors showing distinct DNA amplification profiles and clinicopathological characteristics: group A, tumors showing amplification at 11q13 and/or 8p12 and/or 20q13; group B, tumors amplified at ERBB2 and/or MYC and/or MDM2/SAS; and group C, tumors with no detectable amplification. The aim of the present work was to characterize extensively the amplification profiles in the different subgroups of tumors. Sixty-one breast tumors distributed in all three subgroups were studied by comparative genomic hybridization (CGH). There was an overall good agreement between Southern blotting results and CGH data. As expected, CGH revealed gains undetected by Southern blotting. Most of these gains occurred in regions for which no adapted probes were available but also revealed nondetected amplifications at 8q24 or 20q13. Tumors showed multiple aberrations with a medium number of 5.6 copy number variations/tumor, whereas, according to Southern blotting results, 38% of the tumors analyzed were devoid of any amplification. This proportion fell to 6.5% after CGH analysis. Recurrent gains were observed in tumors from all three subgroups, albeit at varying incidences, and involved 1q, 8q, 17q23-q24, and 20q13. Gains covered large regions of DNA and could possibly include several cores of amplification. Some events, such as gains at 16p11-p12 and 14q or losses at 22q, showed more restricted distributions, suggesting the existence of additional sets of preferential coamplifications. The complexity of genetic profiles revealed by CGH indicates that breast cancer development depends on a large (yet undetermined) number of genetic events. The description of molecular phenotypes in breast cancer may therefore prove to be complex, and it should be interesting to see how many breast tumor subtypes will be defined in the end.
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PMID:Comparative genomic hybridization analysis of breast tumors with predetermined profiles of DNA amplification. 933 Nov

A stem-cell myeloproliferative disorder involving T- and B-cell, and myeloid lineages, is associated with three different translocations with a breakpoint in region p11-12 of chromosome 8: t(6;8)(q27;p11), t(8;9)(p11;q33), and t(8;13)(p12;q12), respectively. Using fluorescence in situ hybridization (FISH), we have analysed blood cells from a series of five patients carrying these different translocations. We have identified cosmids from chromosome region 8p11-12 that span the breakpoint in all the cases. They are specific for the FCFR1 gene that encodes a receptor for members of the FGF family. The breakpoint was further detected by Southern and pulsed-field gel electrophoresis analyses with probes from the FGFR1 locus.
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PMID:t(6;8), t(8;9) and t(8;13) translocations associated with stem cell myeloproliferative disorders have close or identical breakpoints in chromosome region 8p11-12. 948 86

A permanent cell line, U-BLC1, was established from a primary transitional-cell carcinoma, TCC, of the urinary bladder. Karyotype analysis showed the line to be highly aberrant, with a near-triploid chromosome number of 68 to 73. Comparative genomic hybridization revealed some distinct differences between the primary tumor and the established cell line. Karyotype analysis showed 3 marker chromosomes with homogeneously staining regions, HSRs, in the cell line. The HSRs were isolated by microdissection and the microdissection probes were hybridized to normal metaphase chromosomes. The HSRs contain sequences known to be frequently involved in amplification in transitional-cell carcinoma of the bladder, 6p22, 7p11-p12, 9p23-pter, and one region not yet reported to be amplified in primary TCC of the bladder, 1p31-p32. A candidate-gene approach showed that in the region 7p11-p12 the EGFR locus is amplified and highly expressed.
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PMID:Detailed marker chromosome analysis in cell line U-BLC1, established from transitional-cell carcinoma of the bladder. 1007 25

We describe a survey of genetic changes by comparative genomic hybridization (CGH) in 11 human breast cancer cell lines recently established in our laboratory. The most common gains took place at 8q (73%), 1 q (64%), 7q (64%), 3q (45%) and 7p (45%), whereas losses were most frequent at Xp (54%), 8p (45%), 18q (45%) and Xq (45%). Many of the cell lines displayed prominent, localized DNA amplifications by CGH. One-third of these loci affected breast cancer oncogenes, whose amplifications were validated with specific probes: 17q12 (two cell lines with ERBB2 amplifications), 11q13 (two with cyclin-D1), 8p11-p12 (two with FGFR1) and 10q25 (one with FGFR2). Gains and amplifications affecting 8q were the most common genetic alterations in these cell lines with the minimal, common region of involvement at 8q22-q23. No high-level MYC (at 8q24) amplifications were found in any of the cell lines. Two-thirds of the amplification sites took place at loci not associated with established oncogenes, such as 1q41-q43, 7q21-q22, 7q31, 8q23, 9p21-p23, 11p12-p14, 15q12-q14, 16q13-q21, 17q23, 20p11-p12 and 20q13. Several of these locations have not been previously reported and may harbour important genes whose amplification is selected for during cancer development. In summary, this set of breast cancer cell lines displaying prominent DNA amplifications should facilitate discovery and functional analysis of genes and signal transduction pathways contributing to breast cancer development.
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PMID:Molecular cytogenetic analysis of 11 new breast cancer cell lines. 1060 29

Gastrointestinal stromal/smooth muscle tumors are uncommon neoplasms for which current criteria for diagnosing malignancy (size and mitotic index) sometimes fail to predict outcome. Cytogenetic studies reveal frequent chromosome 1 abnormalities in these tumors, but significant underlying molecular changes have not been elucidated, and their significance is unknown. DNA was obtained from the formalin-fixed, paraffin-embedded tissue of 80 gastrointestinal stromal/smooth muscle tumors. Tumors were topographically microdissected from surrounding normal tissue; microsatellite markers from tumor and normal tissue were amplified by PCR in the regions of chromosome 1p36 (D1S199, D1S228, D1S450, D1S214, D1S243), 1p12 (D1S418),1p13 (D1S252, D1S514), and 1q32(D1S103). The presence or absence of heterozygosity for each case was mapped at each informative marker. Relationships among loss of heterozygosity (LOH), tumor size, mitotic index, and survival were investigated using correlation analysis, Kaplan-Meier plots, and the Cox model. LOH at 1p36 was found in 24 of 80 cases, suggesting the possibility of a tumor suppressor gene at 1 p36 near the site of a suspected neuroblastoma tumor suppressor gene. Patients whose tumors demonstrated LOH at 1 p36 had significantly shorter survival (p = 0.017) than those whose tumors did not. LOH at 1 p36 retained independent prognostic significance in a multivariate model that included KIT mutation status and tumor size; the mitotic index, however, did not retain independent significance in such a model. LOH was observed at 1 p12-1p13 (most frequently at 1p13.3) in 19 of 80 cases, but loss of heterozygosity at this site did not influence survival. No LOH was observed near 1q32. These findings provide strong evidence for a prognostically significant tumor suppressor gene in the region of chromosome 1p36.3.
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PMID:Loss of heterozygosity at 1p36 predicts poor prognosis in gastrointestinal stromal/smooth muscle tumors. 1061 97

The hallmark of the 8p12 stem cell myeloproliferative disorder (MPD) is the disruption of the FGFR1 gene, which encodes a tyrosine kinase receptor for members of the fibroblast growth factor family. FGFR1 can be fused to at least 3 partner genes at chromosomal regions 6q27, 9q33, or 13q12. We report here the cloning of the t(8;9)(p12;q33) and the detection of a novel fusion betweenFGFR1 and the CEP110 gene, which codes for a novel centrosome-associated protein with a unique cell-cycle distribution. CEP110 is widely expressed at various levels in different tissues and is predicted to encode a 994-amino acid coiled-coil protein with 4 consensus leucine zippers [L-X(6)-L-X(6)-L-X(6)-L]. Both reciprocal fusion transcripts are expressed in the patient's cells. The CEP110-FGFR1 fusion protein encodes an aberrant tyrosine kinase of circa 150-kd, which retains most of CEP110 with the leucine zipper motifs and the catalytic domain of FGFR1. Transient expression studies show that the CEP110-FGFR1 protein has a constitutive kinase activity and is located within the cell cytoplasm. (Blood. 2000;95:1788-1796)
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PMID:FGFR1 is fused to the centrosome-associated protein CEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33). 1068 39

Human T-lymphotropic virus type 1 (HTLV-1) is a complex retrovirus encoding regulatory and accessory genes in four open reading frames (ORF I to IV) of the pX region. Emerging evidence indicates an important role for the pX ORF I-encoded accessory protein p12(I) in viral replication, but its contribution to viral pathogenesis remains to be defined. p12(I) is a conserved, membrane-associated protein containing four SH3-binding motifs (PXXP). Its interaction with the interleukin-2 (IL-2) receptor beta- and gamma-chains implies an involvement of p12(I) in intracellular signaling pathways. In addition, we have demonstrated that expression of pX ORF I p12(I) is essential for persistent infection in rabbits. In contrast, standard in vitro systems have thus far failed to demonstrate a contribution of p12(I) to viral infectivity and ultimately cellular transformation. In this study we developed multiple in vitro coculture assays to evaluate the role of p12(I) in viral infectivity in quiescent peripheral blood mononuclear cells to more accurately reflect the virus-cell interactions as they occur in vivo. Using these assays, we demonstrate a dramatic reduction in viral infectivity in quiescent T lymphocytes for a p12 mutant viral clone (ACH.p12) in comparison to the wild-type clone ACH. Moreover, addition of IL-2 and phytohemagglutinin during the infection completely rescued the ability of ACH.p12 to infect primary lymphocytes. When newly infected primary lymphocytes are used to passage virus, ACH.p12 also exhibited a reduced ability to productively infect activated lymphocytes. Our data are the first to demonstrate a functional role for pX ORF I in the infection of primary lymphocytes and suggest a role for p12(I) in activation of host cells during early stages of infection.
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PMID:Human T-lymphotropic virus type 1 open reading frame I p12(I) is required for efficient viral infectivity in primary lymphocytes. 1102 9

Human T lymphotropic virus type 1 (HTLV-1) is a complex retrovirus containing regulatory and accessory genes encoded in four open reading frames (ORF I-IV) of the pX region. It is not clear what role pX ORFs I and II-encoded proteins have in the pathogenesis of the lymphoproliferative diseases associated with HTLV-1 infection. The conserved ORF I encodes for a hydrophobic 12-kDa protein, p12, (I) that contains four SH3 binding motifs (PXXP) that localizes to cellular endomembranes when overexpressed in cultured cells. Differential splicing of pX ORF II results in the production of two nuclear proteins, p13(II) and p30(II). p13(II) also localizes to mitochondria. p30(II) shares homology with the POU family of transcription factors. We have identified functional roles of pX ORF I and ORF II in establishment and maintenance of infection in a rabbit model. To functionally study p12(I) we have tested a proviral clone with selective ablation of ORF I (ACH.p12(I)) for its ability to infect quiescent peripheral blood mononuclear cells (PBMC). Our data indicate that T cells infected with the wild-type clone of HTLV-1 (ACH) are more efficient than ACH.p12(I) in infecting quiescent PBMC. These findings parallel our animal model data and suggest a role for p12(I) in the activation of quiescent lymphocytes, a prerequisite for effective viral replication in vivo. To test the ability of p30(II) to function as a transcription factor we have constructed p30(II) as a Gal4-fusion protein. When transfected with Gal4-driven luciferase reporter genes, the p30(II)-Gal4-fusion protein induces transcriptional activity up to 50-fold in both 293 and HeLa-Tat cells. These systems will be useful to identify molecular mechanisms that explain the functional role of pX ORF I and ORF II-encoded proteins in HTLV-1 replication.
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PMID:In vitro and in vivo functional analysis of human T cell lymphotropic virus type 1 pX open reading frames I and II. 1108 Aug 23

Glioblastoma multiforme (GBM) is the most common primary tumor occurring in the central nervous system of adults. Although progress has been made in clinical management of this tumor, little is known about the molecular defects underlying the initiation and progression of GBM. To address these issues, we have characterized five cases of GBM using cytogenetics, comparative genomic hybridization (CGH), fluorescence in situ hybridization (FISH), and direct sequencing. All of these tumors were observed to have clonal chromosome aberrations. Complicated chromosome translocations including der(18)t(2;4;12;18), der(X)t(X;10)(q27.1;p12.1) and der(10)t(10;15)(p11.23;q11.2), and der(1) (:1p31-->1q44::7q11. 3-->7qter) were seen in three tumors. Loss of the CDKN2 gene was noted in four tumors. A gain of copy number of the Cathepsin L gene was seen in two tumors. Amplification of the CDK4, MDM2, and GLI/CHOP genes was noted in two tumors, and amplification of the PDGFR gene was detected in one tumor. Mutation of exon 5 of the TP53 gene was found in three tumors. No mutation of the BCL10 gene was detected in five cases of GBM analyzed, although deletion of chromosome 1p was seen in two tumors. These results provide information for further investigation of GBM.
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PMID:Molecular and cytogenetic analysis of glioblastoma multiforme. 1110 17

Studies by comparative genomic hybridization revealed that the chromosomal regions 3p25 and 8p11-p12 are recurrently amplified in bladder cancer. To investigate the prevalence of DNA copy number alterations in these chromosomal regions and study their clinical significance, we used probes for the RAF1 (3p25) and FGFR1 (8p12) genes for fluorescence in situ hybridization. A tissue microarray containing 2317 tumors was analyzed. The analysis revealed RAF1 amplification in 4.0% and FGFR1 amplification in 3.4% of interpretable tumors. In addition, deletions were found at the 3p25 locus in 2.2% and at the 8p11-12 locus in 9.9% of interpretable tumors. Both amplifications and deletions of RAF1 and FGFR1 were significantly associated with high tumor grade (P < 0.0001), advanced stage (P < 0.0001), and poor survival (P < 0.05) if tumors of all of the stages where analyzed together. RAF1 amplifications were associated with subsequent tumor progression in pT1 carcinomas (P < 0.05). The marked differences in the frequency of all of the analyzed changes between pTa grade 1/grade 2 and pT1-4 carcinomas support the concept of these tumor groups representing different tumor entities.
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PMID:High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. 1138 83


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