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  • 101
    Keywords: CELLS ; human ; DISTINCT ; GENE ; GENES ; PROTEIN ; PROTEINS ; COMPLEX ; DOMAIN ; SEQUENCE ; SEQUENCES ; VARIANTS ; MOUSE ; IDENTIFICATION ; PATTERNS ; PROMOTERS ; HUMAN GENOME ; LOCALIZATION ; KAPPA-B ; DOMAINS ; SUBCELLULAR-LOCALIZATION ; RE ; VARIANT ; LOCUS ; EVENTS ; OPEN READING FRAMES ; function ; SPLICING VARIANTS ; transcriptome ; MAMMALIAN GENOMES ; PRE-MESSENGER-RNA
    Abstract: We report the first genome-wide identification and characterization of alternative splicing in human gene transcripts based on analysis of the full-length cDNAs. Applying both manual and computational analyses for 56 419 completely sequenced and precisely annotated full-length cDNAs selected for the H-Invitational human transcriptome annotation meetings, we identified 6877 alternative splicing genes with 18 297 different alternative splicing variants. A total of 37 670 exons were involved in these alternative splicing events. The encoded protein sequences were affected in 6005 of the 6877 genes. Notably, alternative splicing affected protein motifs in 3015 genes, subcellular localizations in 2982 genes and transmembrane domains in 1348 genes. We also identified interesting patterns of alternative splicing, in which two distinct genes seemed to be bridged, nested or having overlapping protein coding sequences (CDSs) of different reading frames (multiple CDS). In these cases, completely unrelated proteins are encoded by a single locus. Genome-wide annotations of alternative splicing, relying on full-length cDNAs, should lay firm groundwork for exploring in detail the diversification of protein function, which is mediated by the fast expanding universe of alternative splicing variants
    Type of Publication: Journal article published
    PubMed ID: 16914452
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  • 102
    Keywords: APOPTOSIS ; EXPRESSION ; Germany ; DEATH ; GENE ; GENES ; ACTIVATION ; IDENTIFICATION ; PLASMA ; MUTATION ; PLASMA-MEMBRANE ; MORPHOLOGY ; SELECTION ; RE ; ACCELERATOR
    Abstract: A sophisticated hunt for genes differentially expressed during early T-cell development has led to the identification of Gimap4, a gene with a promising expression profile during T-cell development, However, gene-knockout reveals that Gimap4 does not play a role in T-cell development, selection, and activation, but that instead it acts as an accelerator of T-cell death during the final transition from a cell with apoptotic morphology to one with a disintegrated plasma membrane
    Type of Publication: Journal article published
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  • 103
    Keywords: EXPRESSION ; carcinoma ; CELL ; Germany ; neoplasms ; EXPOSURE ; RISK ; GENE ; GENES ; DNA ; GENETIC POLYMORPHISMS ; SKIN ; ASSOCIATION ; FREQUENCY ; polymorphism ; POLYMORPHISMS ; single nucleotide polymorphism ; FREQUENCIES ; BREAST-CANCER ; PROMOTER ; PROMOTERS ; AGE ; SNP ; REGION ; GENOTYPES ; REGIONS ; POLYMERASE-CHAIN-REACTION ; case-control studies ; IMMUNE-RESPONSE ; basal cell carcinoma ; CELL CARCINOMA ; case-control study ; RE ; SINGLE NUCLEOTIDE POLYMORPHISMS ; SNPs ; RHEUMATOID-ARTHRITIS ; INFLAMMATORY CYTOKINES ; case control studies ; INTERVAL ; single-nucleotide ; PROMOTER REGION ; GENOMIC DNA ; female ; ALLELE FREQUENCIES ; odds ratio ; genomic ; interleukin ; SQUAMOUS-CELL ; ALLELE-FREQUENCY ; PRIMERS ; ENVIRONMENTAL-FACTORS ; SUN EXPOSURE ; allele-specific primers ; CUTANEOUS BASAL ; DNA pooling ; heterosis ; LARGE-SCALE ASSOCIATION ; quantitative sequencing
    Abstract: Background Basal cell carcinoma (BCC) is one of the most common neoplasms in the world. Development of BCC is associated with environmental factors (especially sun exposure) as well as heritable factors. Objectives To analyse three single nucleotide polymorphisms (SNPs) in the promoter regions of interleukin (IL) genes in genomic DNA from 527 cases of BCC and 530 matched controls and to examine if DNA pooling is a useful method on which to base decisions regarding further SNP analysis. Methods The SNPs analysed were IL6-597, IL10-1082 and IL1B-511. The SNPs were first analysed from pooled DNA and afterwards from individual samples. The DNA pools resulted from a division of the samples into cases and controls, female and male, and three age groups. In these pools the allele frequencies were estimated by two methods, real-time polymerase chain reaction with allele-specific primers, and quantitative sequencing. Results No significant association was found when the allele frequencies in cases and controls were compared. However, by analysis of the individual genotypes we found SNP IL6-597 G/A to be significantly associated with BCC risk (P = 0.007). Hereby the heterozygous genotype 'GA' had a protective effect (odds ratio 0.64, 95% confidence interval 0.49-0.84). No significant association was found for IL10-1082 and IL1B-511. Conclusions The association of SNP IL6-597 with BCC could be found only by individual genotyping, but would have been missed if only data from the pooling analysis had been known
    Type of Publication: Journal article published
    PubMed ID: 17107380
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  • 104
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; carcinoma ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; GENE ; GENES ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; treatment ; 5-FLUOROURACIL ; prevention ; resistance ; AGE ; NUDE-MICE ; CELL-LINE ; chemotherapy ; LINE ; CARCINOMAS ; specificity ; CISPLATIN ; pancreatic cancer ; CANCER-THERAPY ; CYTOTOXICITY ; signaling ; GEMCITABINE ; RE ; PANCREATIC-CANCER ; cancer therapy ; pancreatic ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; in vivo ; surgical resection
    Abstract: Background: Chemotherapy for pancreatic carcinoma often has severe side effects that limit its efficacy. The glucocorticoid (GC) dexamethasone (DEX) is frequently used as co-treatment to prevent side effects of chemotherapy such as nausea, for palliative purposes and to treat allergic reactions. While the potent pro-apoptotic properties and the supportive effects of GCs to tumour therapy in lymphoid cells are well studied, the impact of GCs to cytotoxic treatment of pancreatic carcinoma is unknown. Methods: A prospective study of DEX-mediated resistance was performed using a pancreatic carcinoma xenografted to nude mice, 20 surgical resections and 10 established pancreatic carcinoma cell lines. Antiapoptotic signaling in response to DEX was examined by Western blot analysis. Results: In vitro, DEX inhibited drug-induced apoptosis and promoted the growth in all of 10 examined malignant cells. Ex vivo, DEX used in physiological concentrations significantly prevented the cytotoxic effect of gemcitabine and cisplatin in 18 of 20 freshly isolated cell lines from resected pancreatic tumours. No correlation with age, gender, histology, TNM and induction of therapy resistance by DEX co-treatment could be detected. In vivo, DEX totally prevented cytotoxicity of chemotherapy to pancreatic carcinoma cells xenografted to nude mice. Mechanistically, DEX upregulated pro-survival factors and anti-apoptotic genes in established pancreatic carcinoma cells. Conclusion: These data show that DEX induces therapy resistance in pancreatic carcinoma cells and raise the question whether GC-mediated protection of tumour cells from cancer therapy may be dangerous for patients
    Type of Publication: Journal article published
    PubMed ID: 16539710
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  • 105
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    Cancer Journal 13 (1), 17-22 
    Keywords: CANCER ; INHIBITOR ; tumor ; CLINICAL-TRIAL ; Germany ; human ; INHIBITION ; THERAPY ; GENE ; GENES ; DRUG ; TUMORS ; PATIENT ; RESPONSES ; DNA ; MARKER ; treatment ; MOLECULE ; TRIAL ; TRIALS ; PATTERNS ; DESIGN ; MUTATION ; CLINICAL-TRIALS ; leukemia ; DNA methylation ; MARKERS ; MUTATIONS ; METHYLTRANSFERASE ACTIVITY ; ESTABLISHMENT ; cell lines ; METHYLATION ; CANCER-THERAPY ; DNA methyltransferase ; HYPERMETHYLATION ; MYELODYSPLASTIC SYNDROME ; INHIBITORS ; PERFORMANCE LIQUID-CHROMATOGRAPHY ; molecular ; ONCOLOGY ; PATTERN ; TUMOR-SUPPRESSOR ; SUPPRESSOR GENE ; HUMAN CANCER ; THERAPIES ; monitoring ; 5-AZA-2'-DEOXYCYTIDINE DECITABINE ; cancer therapy ; DEMETHYLATION ; METHYLTRANSFERASE ; SILENCED GENES ; development ; SUPPRESSOR ; USA ; HUMAN CANCERS ; CANDIDATE ; CANCERS ; TUMOR-SUPPRESSOR GENES ; DNA-METHYLATION ; HISTONE DEACETYLASE INHIBITION ; azacytidine ; CANDIDATES ; clinical trial ; DRUG-INDUCED LUPUS ; EPIGENETIC CHANGES
    Abstract: Aberrant DNA methylation patterns, including hypermethylation of tumor suppressor genes, have been described in many human cancers. These epigenetic mutations can be reversed by DNA methyltransferase inhibitors, which provide novel opportunities for cancer therapy. Clinical concepts for epigenetic therapies are currently being developed by using azanucleosides for the treatment of leukemias and other tumors. These trials will greatly benefit from the inclusion of molecular markers for monitoring epigenetic changes in patients and for maximizing biologic responses. In addition, novel inhibitors need to be developed that result in a direct and specific inhibition of DNA methyltransferase activity. Several recent developments indicate that rational design of small molecule DNA methyltransferase inhibitors is feasible and that this approach can result in the establishment of novel drug candidates. The use of novel DNA methyltransferase inhibitors in clinical trials that allow monitoring of drug-induced DNA methylation changes should provide the foundation for improved epigenetic cancer therapies
    Type of Publication: Journal article published
    PubMed ID: 17464242
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  • 106
    Keywords: CANCER ; EXPRESSION ; carcinoma ; CELL ; CELL LUNG-CANCER ; Germany ; POPULATION ; RISK ; GENE ; GENES ; CARCINOGENESIS ; ASSOCIATION ; polymorphism ; POLYMORPHISMS ; HEALTH ; PROMOTER ; case-control studies ; squamous cell carcinoma ; GASTRIC-CANCER ; EUROPE ; inflammation ; molecular epidemiology ; CYTOKINE ; CELL CARCINOMA ; ONCOLOGY ; case-control study ; RE ; INTERLEUKIN-1 ; PROMOTER POLYMORPHISM ; CYCLOOXYGENASE-2 ; case control studies ; methods ; INTERLEUKIN-8 ; oral cancer ; CANCERS ; ESOPHAGEAL CANCER ; SQUAMOUS-CELL ; INTERLEUKIN-8 PROMOTER ; larynx cancer ; pharynx cancer ; upper aerodigestive tract cancers
    Abstract: Objectives The purpose of this study was to investigate the role of polymorphisms of genes involved in inflammation in the risk of cancers of the upper aerodigestive tract (UADT). Methods We have evaluated the role of polymorphisms in key genes related to inflammation, namely IL1B (rs1143627), COX2/PTGS2 (rs5275), and IL8 (rs4073) in a large case-control study comprising 811 UADT cancer cases and 1,083 controls. Results An association was observed for squamous cell carcinoma of the pharynx for a polymorphism in the promoter of the IL1B gene, with an OR of 2.39 (95% CI = 1.19-4.81) for the homozygotes for the minor allele A promoter polymorphism of IL8 was associated with decreased risk of laryngeal cancer, with an OR of 0.70 (95% CI = 0.50-0.98) for carriers of the minor allele. Conclusions To our knowledge, this is the first report on the role of these polymorphisms with respect to UADT carcinogenesis. Our results suggest that inflammation-related polymorphisms play a role, albeit minor, in the risk of developing cancers of the upper aerodigestive tract
    Type of Publication: Journal article published
    PubMed ID: 17356794
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  • 107
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; IN-VITRO ; tumor ; CELL ; IN-VIVO ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VITRO ; VIVO ; SYSTEM ; SYSTEMS ; DEATH ; GENE ; GENES ; microarray ; PROTEIN ; transcription ; EPITHELIA ; TUMORS ; validation ; MICE ; TRANSCRIPTION FACTOR ; KERATINOCYTES ; SKIN ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; TARGET ; ISOFORM ; ENCODES ; PROMOTER ; PROMOTERS ; REQUIRES ; DNA-DAMAGE ; BAX ; HUMAN KERATINOCYTES ; SQUAMOUS-CELL CARCINOMA ; TARGETS ; RECEPTORS ; MICROARRAY ANALYSIS ; epidermis ; TRAIL ; DEATH RECEPTORS ; tetramer ; CD95 ; chemoresistance ; review ; TUMOR-SUPPRESSOR ; keratinocyte ; LIGHT ; TUMORIGENESIS ; development ; STRATIFIED EPITHELIA ; TARGET GENES ; analysis ; P63 ; death receptor ; EPITHELIUM ; EPITHELIAL TUMORS ; KINASE C-ABL ; P53-DEPENDENT APOPTOSIS ; REGULATES P73 ; USA ; function ; in vivo ; E ; PROTECTS ; MAINTENANCE ; inactive ; cornification ; FAMILY-MEMBER GENES ; GENE ENCODES ; IKK alpha ; ISOFORM EXPRESSION ; P53 HOMOLOG P63
    Abstract: The epidermis is a multilayered stratified epithelium, continuously regenerated by differentiating keratinocytes, that requires the transcription factor p63 for its development and maintenance. The TP63 gene encodes two major protein isoforms, TAp63 and Delta Np63, which have both transactivating and transcriptional repressing activities and regulate a wide range of target genes. TAp63 shows clear pro-apoptotic activity, mediated both by death receptors (CD95, TNF, TRAIL) and mitochondrial (bax, puma) pathways. Conversely, DNp63 protects from apoptosis by directly competing for TAp63 target promoters or sequestering it, forming inactive tetramers. Accordingly, p63 is expressed in epithelial tumors, contributing to both tumorigenesis and chemoresistance. However, the predominant physiological role of p63 is in epithelial development, as demonstrated by the lack of epidermis and other epithelia in p63-deficient mice. The specific role of TAp63 and DNp63 isoforms in epithelial development remains mostly unclear. Nevertheless, recent work utilizing in vivo genetic complementation of TAp63 and/or DNp63 into a p63 null background has shed new light into the specific functions of the two isoforms and allowed the in vivo validation of several p63 transcriptional targets, originally identified by microarray analysis in in vitro systems. However, despite concerted efforts to address the role of p63 isoforms, several questions remain unanswered. The main aim of this review is to critically discuss the data available in the literature and thoroughly analyze the models proposed
    Type of Publication: Journal article published
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  • 108
    Keywords: CELLS ; EXPRESSION ; IN-VITRO ; BLOOD ; CELL ; human ; IN-VIVO ; THERAPY ; VITRO ; VIVO ; COMMON ; SYSTEM ; SITE ; SITES ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; PROTEIN ; gene therapy ; FREQUENCY ; FREQUENCIES ; MALIGNANCIES ; gene expression ; VECTORS ; VECTOR ; NUMBER ; HUMAN GENOME ; REGION ; REGIONS ; STEM-CELLS ; SAFETY ; SELECTION ; RECURRENT ; HEMATOPOIETIC-CELLS ; GENE-THERAPY ; HIGH-FREQUENCY ; DNA INTEGRATION ; INTEGRATION ; MALIGNANCY ; PROGRAM ; THERAPIES ; development ; IMMUNE-SYSTEM ; SEVERE COMBINED IMMUNODEFICIENCY ; EVENTS ; USA ; in vivo ; RETROVIRAL INTEGRATION ; VECTOR INTEGRATION ; HIV-1 INTEGRASE ; INSERTION ; PREINTEGRATION COMPLEXES
    Abstract: Insertional oncogenesis is a possible consequence of the integration of gamma-retroviral (RV) or lentiviral (LV) vectors into the human genome. RV common insertion sites (CISs) have been identified in hematopoietic malignancies and in the nonmalignant progeny of transduced hematopoietic stem/progenitor cells (HSCs), possibly as a consequence of clonal selection in vivo. We have mapped a large number of RV and LV integrations in human CD34(+) HSCs, transduced in vitro and analyzed without selection. Recurrent insertion sites (hot spots) account for more than 21% of the RV integration events, while they are significantly less frequent in the case of LV vectors. RV but not LV hot spots are highly enriched in proto-oncogenes, cancer-associated CISs, and growth-controlling genes, indicating that at least part of the biases observed in the HSC progeny in vivo are characteristics of RV integration, already present in nontransplanted cells. Genes involved in hematopoietic and immune system development are targeted at high frequency and enriched in hot spots, suggesting that the CD34(+) gene expression program is instrumental in directing RV integration. The lower propensity of LV vectors for integrating in potentially dangerous regions of the human genome may be a factor determining a better safety profile for gene therapy applications
    Type of Publication: Journal article published
    PubMed ID: 17507662
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  • 109
    Keywords: CANCER ; EXPRESSION ; GROWTH ; proliferation ; CELL ; Germany ; INHIBITION ; PATHWAY ; PATHWAYS ; NETWORK ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; ACTIVATION ; cell cycle ; CELL-CYCLE ; CYCLE ; ASSOCIATION ; chromosome ; LESIONS ; PROGRESSION ; gene expression ; DIFFERENCE ; CELL-DEATH ; MUTATION ; genetics ; COMPONENT ; MUTATIONS ; MALIGNANT-MELANOMA ; OVEREXPRESSION ; heredity ; B-RAF ; TRANSCRIPTS ; ONCOLOGY ; RE ; N-RAS MUTATIONS ; analysis ; cell death ; senescence ; ERK ; USA ; CELL-CYCLE ARREST ; SET ; apoptotic
    Abstract: We studied gene expression in 18 melanocytic nevi with and four nevi without the V600E mutation in the BRAF gene using HG-U133A 2.0 microarray with 22,277 transcripts. Data analysis revealed 92 genes up-regulated and 105 genes down-regulated in nevi with the mutation compared to nevi without mutation. Pathway analysis showed that differentially regulated genes mapped to 10 genetic networks. The major network included genes involved in cell death, cell cycle, and cellular growth and proliferation. Up-regulated genes in nevi with the mutation included CDKN2A, CDKN1C, and MITF; whereas down-regulated genes included those involved in apoptotic and other pathways. Principal component analysis identified 22 probe sets (20 genes) that caused separate segregation of nevi with and without mutations. In conclusion, our data showed differences in gene expression between nevi with and without the V600E BRAF mutation. Moreover, nevi with mutations showed overexpression of genes involved in melanocytic senescence and cell cycle inhibition. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. (C) 2007 Wiley-Liss, Inc
    Type of Publication: Journal article published
    PubMed ID: 17696195
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  • 110
    Keywords: EXPRESSION ; CT ; SITE ; GENE ; GENES ; PROTEIN ; transcription ; COMPONENTS ; ACTIVATION ; DNA ; MECHANISM ; REDUCTION ; DOMAIN ; BINDING ; CYCLE ; PHOSPHORYLATION ; TRANSACTIVATOR ; virus ; ASSAY ; COMPONENT ; PHENOTYPE ; REPLICATION ; AMINO-ACIDS ; AFFINITY ; INITIATION ; ORIGIN ; BINDING-PROTEIN ; BZLF1 ; PRODUCTIVE CYCLE ; ROLES ; function ; ORIGIN RECOGNITION COMPLEX ; DEFECT ; PROMOTES ; PREVENTS ; ATP-BINDING ; CYCLE GENES
    Abstract: The Epstein-Barr virus ZEBRA protein controls the viral lytic cycle. ZEBRA activates the transcription of viral genes required for replication. ZEBRA also binds to oriLyt and interacts with components of the viral replication machinery. The mechanism that differentiates the roles of ZEBRA in regulation of transcription and initiation of lytic replication is unknown. Here we show that S173, a residue in the regulatory domain, is obligatory for ZEBRA to function as an origin binding protein but is dispensable for its role as a transcriptional activator of early genes. Serine-to-alanine substitution of this residue, which prevents phosphorylation of S173, resulted in a threefold reduction in the DNA binding affinity of ZEBRA for oriLyt, as assessed by chromatin immunoprecipitation. An independent assay based on ZEBRA solubility demonstrated a marked defect in DNA binding by the Z(S173A) mutant. The phenotype of a phosphomimetic mutant, the Z(S173D) mutant, was similar to that of wild-type ZEBRA. Our findings suggest that phosphorylation of S173 promotes viral replication by enhancing ZEBRA's affinity for DNA. The results imply that stronger DNA binding is required for ZEBRA to activate replication than that required to activate transcription
    Type of Publication: Journal article published
    PubMed ID: 17215287
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  • 111
    Keywords: CANCER ; EXPRESSION ; tumor ; Germany ; human ; THERAPY ; INFORMATION ; TOOL ; DISEASE ; RISK ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; GENOME ; microarray ; SAMPLE ; SAMPLES ; PATIENT ; DNA ; MECHANISM ; prognosis ; mechanisms ; BIOLOGY ; BREAST ; breast cancer ; BREAST-CANCER ; DELETION ; IDENTIFICATION ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; PATTERNS ; gene expression ; CHROMOSOMAL-ABERRATIONS ; TUMOR PROGRESSION ; statistics ; ABERRATIONS ; DELETIONS ; DNA methylation ; REGION ; REGIONS ; bioinformatics ; PARAMETERS ; ONCOGENE ; CLASS-I ; DNA AMPLIFICATION ; IMBALANCES ; METHYLATION ; CHROMOSOMAL IMBALANCES ; P53 STATUS ; SINGLE ; RE ; PATTERN ; THERAPIES ; PATIENT SURVIVAL ; LEVEL ; analysis ; methods ; computational biology ; RISK STRATIFICATION ; genomic ; microbiology ; transcriptome ; CONTACT ; ARRAY-CGH ; MYC ; aberration ; HUMAN-BREAST ; DNA-METHYLATION ; biotechnology ; chromosomal aberration
    Abstract: Motivation: In cancer, chromosomal imbalances like amplifications and deletions, or changes in epigenetic mechanisms like DNA methylation influence the transcriptional activity. These alterations are often not limited to a single gene but affect several genes of the genomic region and may be relevant for the disease status. For example, the ERBB2 amplicon (17q21) in breast cancer is associated with poor patient prognosis. We present a general, unsupervised method for genome-wide gene expression data to systematically detect tumor patients with chromosomal regions of distinct transcriptional activity. The method aims to find expression patterns of adjacent genes with a consistently decreased or increased level of gene expression in tumor samples. Such patterns have been found to be associated with chromosomal aberrations and clinical parameters like tumor grading and thus can be useful for risk stratification or therapy. Results: Our approach was applied to 12 independent human breast cancer microarray studies comprising 1422 tumor samples. We prioritized chromosomal regions and genes predominantly found across all studies. The result highlighted not only regions which are well known to be amplified like 17q21 and 11q13, but also others like 8q24 (distal to MYC) and 17q24-q25 which may harbor novel putative oncogenes. Since our approach can be applied to any microarray study it may become a valuable tool for the exploration of transcriptional changes in diverse disease types. Availability: The R source codes which implement the method and an exemplary analysis are available at http://www.dkfz.de/mga2/people/buness/CTP/. Contact: a.buness@gmx.de Supplementary information: Supplementary data are available at Bioinformatics online
    Type of Publication: Journal article published
    PubMed ID: 17599933
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  • 112
    Keywords: CELLS ; EXPRESSION ; GROWTH ; POPULATION ; GENE ; GENES ; PROTEIN ; TISSUE ; PATIENT ; ACTIVATION ; microarrays ; ONCOLOGY ; HEMOGLOBIN
    Abstract: In this study, we provide a molecular signature of highly enriched CD34+ cells from bone marrow of untreated patients with chronic myelogenous leukemia (CML) in chronic phase in comparison with normal CD34+ cells using microarrays covering 8746 genes. Expression data reflected several BCR-ABL-induced effects in primary CML progenitors, such as transcriptional activation of the classical mitogen-activated protein kinase pathway and the phosphoinositide-3 kinase/AKT pathway as well as downregulation of the proapoptotic gene IRF8. Moreover, novel transcriptional changes in comparison with normal CD34+ cells were identified. These include upregulation of genes involved in the transforming growth factorbeta pathway, fetal hemoglobin genes, leptin receptor, sorcin, tissue inhibitor of metalloproteinase 1, the neuroepithelial cell transforming gene 1 and downregulation of selenoprotein P. Additionally, genes associated with early hematopoietic stem cells (HSC) and leukemogenesis such as HoxA9 and MEIS1 were transcriptionally activated. Differential expression of differentiation-associated genes suggested an altered composition of the CD34+ cell population in CML. This was confirmed by subset analyses of chronic phase CML CD34+ cells showing an increase of the proportion of megakaryocyte-erythroid progenitors, whereas the proportion of HSC and granulocyte-macrophage progenitors was decreased in CML. In conclusion, our results give novel insights into the biology of CML and could provide the basis for identification of new therapeutic targets.Leukemia (2007) 21, 494-504. doi:10.1038/sj.leu.2404549; published online 25 January 2007
    Type of Publication: Journal article published
    PubMed ID: 17252012
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  • 113
    Keywords: CANCER ; CELL ; human ; LUNG ; MODEL ; PATHWAY ; PATHWAYS ; lung cancer ; LUNG-CANCER ; SUPPORT ; SYSTEM ; SYSTEMS ; RISK ; RISKS ; SITE ; ENZYMES ; GENE ; GENES ; GENOME ; PATIENT ; DNA ; MARKER ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; SEQUENCE ; ASSOCIATION ; POLYMORPHISMS ; SUSCEPTIBILITY ; VARIANTS ; HEALTH ; DNA-REPAIR ; REPAIR ; COMPONENT ; MARKERS ; DAMAGE ; HUMAN GENOME ; REGION ; REGIONS ; DNA-DAMAGE ; CANCER-PATIENTS ; CANCER PATIENTS ; CYCLE CONTROL ; MULTICENTER ; DNA repair ; O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE ; ONCOLOGY ; RE ; VARIANT ; CHECKPOINT ; biomarker ; INTERVAL ; ENZYME ; analysis ; DNA damage ; HAPLOTYPE ; USA ; odds ratio ; cancer research ; cell cycle checkpoints ; modeling ; cell cycle control ; block ; nonsmokers ; INTEGRITY
    Abstract: The DNA repair systems maintain the integrity of the human genome and cell cycle checkpoints are a critical component of the cellular response to DNA damage. We hypothesized that genetic variants in DNA repair and cell cycle control pathways will influence the predisposition to lung cancer, and studied 27 variants in 17 DNA repair enzymes and 10 variants in eight cell cycle control genes in 1,604 lung cancer patients and 2,053 controls. To improve the estimation of risks for specific variants, we applied a Bayesian approach in which we allowed the prior knowledge regarding the evolutionary biology and physicochemical properties of the variant to be incorporated into the hierarchical model. Based on the estimation from the hierarchical modeling, MGMT 143V or 178R, and CHEK2 157I had an odds ratio of lung cancer equal to 1.45 [95% confidence interval (95% CI), 1.05-2.00], 1.18 (95% CI, 1.01-1.40), and 1.58 (95% CI, 1.14-2.17). The association of CHEK2 1571 seems to be overestimated in the conventional analysis. Nevertheless, this association seems to be robust in the hierarchical modeling. None of the pathways seem to have a prominent effect. In general, our study supports the notion that sequence variation may explain at least some of the variation of inherited susceptibility. In particular, further investigation of OGG1, MGMT, and CHEK2 focusing on the genetic regions where the present markers are located or the haplotype blocks tightly linked with these markers might be warranted
    Type of Publication: Journal article published
    PubMed ID: 18086781
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  • 114
    Keywords: RECEPTOR ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INHIBITOR ; CELL ; COMBINATION ; Germany ; INHIBITION ; KINASE ; VITRO ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; transcription ; METABOLISM ; ACCUMULATION ; ACTIVATION ; LIGAND ; TRANSCRIPTION FACTOR ; IMPACT ; REDUCTION ; DOWN-REGULATION ; PHOSPHORYLATION ; SIGNAL ; ALPHA ; BREAST ; breast cancer ; BREAST-CANCER ; ELEMENT ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; hormone ; gene expression ; ASSAY ; DECREASE ; CANCER-CELLS ; BETA ; transactivation ; DEGRADATION ; RECEPTORS ; PROTEASOME ; ESTRADIOL ; ESTROGEN-RECEPTOR ; CANCER CELL-LINES ; ENDOCRINE ; RE ; SYNTHASE ; PROTEIN-SYNTHESIS ; regulation ; REPORTER GENE ; SUBSTRATE ; ESTROGEN ; LEVEL ; analysis ; ASSAYS ; NUCLEAR ; estrogen receptor ; MCF-7 CELLS ; USA ; function ; HORMONES ; ANTAGONISTS ; PROTECTS ; progesterone receptor ; in combination ; E2 ; TURNOVER ; MESSENGER-RIBONUCLEIC-ACID
    Abstract: Glycogen synthase kinase- 3 ( GSK- 3) plays a key role in the regulation of transcription factors including steroid receptors. Having identified estrogen receptor-alpha ( ER alpha) as substrate for GSK- 3, the impact of GSK- 3 on ER alpha function and activity upon 17 beta- estradiol ( E2)- dependent activation remains to be clarified. Here we show by using small interfering technology in combination with immunoblot, gene expression analysis, and luciferase reporter assays that silencing of GSK- 3 alpha or GSK- 3 beta results in the reduction of ER alpha levels and transcriptional activity in ER alpha- positive breast cancer cells. Using MCF- 7 cells we demonstrate that reduction of ER alpha levels upon GSK- 3 silencing was due to increased proteasomal degradation of ER alpha rather than inhibition of ER alpha protein synthesis. Indeed, under this condition, ER alpha protein was rescued using the proteasome inhibitor MG132 in presence of the protein synthesis inhibitor cycloheximide. In addition, strong accumulation of ubiquitinated ER alpha was obtained after GSK- 3 silencing in the presence of MG132. We conclude that GSK- 3 protects ER alpha from proteasomal degradation and plays a crucial role in ER alpha protein stabilization and turnover. Furthermore, in vitro kinase assay depicted that GSK- 3 beta phosphorylates ER alpha at Ser- 118. GSK- 3 silencing resulted in decrease of E2- induced nuclear ER alpha phosphorylation at Ser- 118 and E2- induced estrogen response element- dependent luciferase reporter gene expression. Neither Ser- 118 phosphorylation nor luciferase activity was restored by use of MG132. Moreover, the expression of estrogenresponsive genes ( pS2 and progesterone receptor) was decreased upon GSK- 3 silencing. These findings demonstrated that GSK- 3 is required for E2- induced ER alpha phosphorylation at Ser118 and full transcriptional activity of the receptor upon E2 stimulation
    Type of Publication: Journal article published
    PubMed ID: 17609434
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  • 115
    Keywords: CELLS ; CELL ; Germany ; DISTINCT ; ENZYMES ; GENE ; GENES ; PROTEINS ; RNA ; transcription ; ACTIVATION ; COMPLEX ; COMPLEXES ; DNA ; MECHANISM ; mechanisms ; BIOLOGY ; MOLECULAR-BIOLOGY ; CHROMATIN ; genetics ; INTERACTS ; CHROMATIN STRUCTURE ; METHYLATION ; heredity ; LAYER ; molecular biology ; molecular ; MOLECULAR-MECHANISM ; review ; RE ; LIFE ; POLYMERASE-I TRANSCRIPTION ; MOLECULAR-MECHANISMS ; ENZYME ; METHYLTRANSFERASES ; NoRC ; NUCLEOLAR DOMINANCE ; GROWTH-CONTROL
    Abstract: Eukaryotic cells contain several hundred ribosomal RNA (rRNA) genes (rDNA), a fraction of them being silenced by epigenetic mechanisms. The presence of two epigenetically distinct states of rRNA genes provides a unique opportunity to decipher the molecular mechanisms that establish the euchromatic, i.e. transcriptionally active, and the heterochromatic, i.e. transcriptionally silent, state of rDNA. This article summarizes our knowledge of the epigenetic mechanisms that control rDNA transcription and emphasizes how DNA methyltransferases and histone-modifying enzymes work in concert with chromatin-remodeling complexes and RNA-guided mechanisms to establish a specific chromatin structure that defines the transcriptional state of rRNA genes. These studies exemplify the mutual dependence and complex crosstalk among different epigenetic players in the alteration of the chromatin structure during the process of gene activation or silencing
    Type of Publication: Journal article published
    PubMed ID: 17613545
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  • 116
    Keywords: APOPTOSIS ; CANCER ; EXPRESSION ; GROWTH ; proliferation ; carcinoma ; CELL ; CELL-PROLIFERATION ; Germany ; LUNG ; DIAGNOSIS ; lung cancer ; LUNG-CANCER ; DEATH ; GENE ; GENES ; microarray ; PROTEIN ; cell line ; meningioma ; TISSUE ; LINES ; primary ; DOMAIN ; tumour ; SKIN ; BIOLOGY ; CELL-LINES ; MEMBER ; MOLECULAR-BIOLOGY ; SIGNAL ; PROGRESSION ; ASSAY ; INDUCED APOPTOSIS ; genetics ; COUNTRIES ; skin cancer ; CELL-LINE ; LINE ; ONCOGENE ; SUPERFAMILY ; EPITHELIAL-CELLS ; Jun ; PHENOTYPE ; STRATEGIES ; OVEREXPRESSION ; cell lines ; heredity ; LUNG-CARCINOMA ; SKIN-CANCER ; tumour suppressor gene ; ORIGIN ; molecular biology ; molecular ; ONCOLOGY ; non-small cell lung carcinoma ; SUPPRESSOR GENE ; cell proliferation ; SUPPRESSOR ; tumour suppressor ; NSCLC ; SET ; BREAST-CANCER CELLS ; DAL-1 ; ferm containing 3 ; GROWTH SUPPRESSION ; protein 4.1 ; PROTEIN 4.1B
    Abstract: Lung cancer including non-small cell lung carcinoma (NSCLC) represents a leading cause of cancer death in Western countries. Yet, understanding its pathobiology to improve early diagnosis and therapeutic strategies is still a major challenge of today's biomedical research. We analyzed a set of differentially regulated genes that were identifi. ed in skin cancer by a comprehensive microarray study, for their expression in NSCLC. We found that ferm domain containing protein 3 (FRMD3), a member of the protein 4.1 superfamily, is expressed in normal lung tissue but silenced in 54 out of 58 independent primary NSCLC tumours compared to patient-matched normal lung tissue. FRMD3 overexpression in different epithelial cell lines resulted in a decreased clonogenicity as measured by colony formation assay. Although cell attachment capabilities and cell proliferation rate remained unchanged, this phenotype was most likely owing to induced apoptosis. Our data identify FRMD3 as a novel putative tumour suppressor gene suggesting an important role in the origin and progression of lung cancer
    Type of Publication: Journal article published
    PubMed ID: 17260017
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  • 117
    Keywords: RECEPTOR ; ANGIOGENESIS ; APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; proliferation ; ANGIOSTATIN ; BLOOD ; CELL ; CELL-PROLIFERATION ; Germany ; human ; IN-VIVO ; PERFUSION ; VIVO ; imaging ; VOLUME ; HEPATOCELLULAR-CARCINOMA ; NEW-YORK ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; METABOLISM ; cell line ; gene therapy ; LINES ; NUCLEAR-MEDICINE ; TRANSDUCTION ; RAT ; RATS ; tumour ; CELL-LINES ; signal transduction ; SIGNAL ; gene expression ; ARRAYS ; STRESS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; chemotherapy ; LINE ; HEPATOMA ; EXCHANGE ; positron emission tomography ; POSITRON-EMISSION-TOMOGRAPHY ; tomography ; SQUAMOUS-CELL CARCINOMA ; RT-PCR ; GLUCOSE ; PET ; cell lines ; nuclear medicine ; TNF-ALPHA ; INCREASED EXPRESSION ; INHIBITORS ; HUMAN BREAST-CANCER ; radiology ; MATRIX ; TUMOR-GROWTH ; ARRAY ; TRANSPORTER ; cell proliferation ; methods ; HIGH-THROUGHPUT ; NUCLEAR ; USA ; uptake ; vascular endothelial growth factor ; FDG-PET ; in vivo ; ENDOTHELIAL-CELL ; FDG ; EMISSION-TOMOGRAPHY ; gene profiling ; gene array ; MEDICINE ; EMISSION ; emission tomography ; positron ; ENDOTHELIAL GROWTH ; HSV THYMIDINE KINASE ; MORRIS HEPATOMA
    Abstract: Purpose Human troponin I (TROP), the soluble receptor for vascular endothelial growth factor (sFLT) and angiostatin (ASTAT) are potent inhibitors of endothelial cell proliferation, angiogenesis and tumour growth in vivo. Transfer of these genes into tumours may induce changes not only in perfusion, but also more general ones such as changes in metabolism. The aim of this study was to assess these reactions using FDG-PET and high-throughput methods such as gene profiling. Methods We established Morris hepatoma (MH3924A) cell lines expressing TROP, sFLT or ASTAT and quantified F-18-fluorodeoxyglucose ((18)FDG) uptake by dynamic positron emission tomography (PET) after tumour inoculation in ACI rats. Furthermore, expression of glucose transporter-1 and -3 (GLUT-1 and GLUT-3) as well as hexokinase-1 and -2 were investigated by RT-PCR and immunohistomorphometry. In addition, gene array analyses were performed. Results (18)FDG uptake, vascular fraction and distribution volume were significantly higher in all genetically modified tumours. Immunohistomorphometry showed an increased percentage of hexokinase-1 and -2 as well as GLUT-1 and -3 immunoreactive (ir) cells. Using gene arrays and comparing all three groups of genetically modified tumours, we found upregulated expression of 36 genes related to apoptosis, signal transduction, stress or metabolism. Conclusion TROP-, sFLT- or ASTAT-expressing MH3924A tumours show enhanced influx of (18)FDG, which seems to be caused by several factors: enhanced exchange of nutrients between blood and tumour, increased amounts of glucose transporters and hexokinases, and increased expression of genes related to apoptosis, matrix and stress, which induce an increased demand for glucose
    Type of Publication: Journal article published
    PubMed ID: 17701172
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  • 118
    Keywords: EXPRESSION ; CELL ; Germany ; KINASE ; GENE ; GENES ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; transcription ; DRUG ; TUMORS ; PATIENT ; treatment ; ALPHA ; culture ; AMPLIFICATION ; COPY NUMBER ; NUMBER ; REGION ; FUTURE ; gene amplification ; OVEREXPRESSION ; ASTROCYTOMAS ; GLIOMAS ; targeting ; ONCOLOGY ; SUBSET ; GLIOMA ; GRADE ; TRANSLATION ; FACTOR VEGF ; LEVEL ; SIZE ; KINASES ; oligodendroglioma ; glioblastoma multiforme ; GLIOBLASTOMA-MULTIFORME ; KIT ; USA ; DRUGS ; GENE AMPLIFICATIONS ; GLIOBLASTOMA ; GROWTH-FACTOR-RECEPTOR ; SET ; KDR ; AUTOCRINE LOOP ; HUMAN-MALIGNANT GLIOMAS ; PDGFRA
    Abstract: A subset of glioblastomas (GBMs) carry gene amplifications on chromosomal segment 4q12. To characterize this amplicon in detail, we analyzed a set of 100 samples consisting of 65 GBMs, 10 WHO grade III astrocytomas, 12 oligodendrogliomas, and 13 glioma cell cultures. We applied multiplex ligation-dependent probe amplification to determine the gene dosage of PDGFRA, KIT, and KDR and the flanking genes USP46, RASL11B, LNX1, CHIC2, SEC3L1, and IGFBP7. The amplicon was highly variable in size and copy number and extended over a region of up to 5 Mb. Amplifications on 4q12 were observed in 15% of GBMs and 23% of GBM cell cultures but not in 22 other gliomas. We analyzed transcription and translation of some genes within this amplicon. Gene amplification generally correlated with high transcript levels but did not necessarily result in increased protein levels. However, we detected frequent expression of proteins encoded by PDGFRA, KIT, and KDR in GBMs and GBM cell cultures independent of the amplification status. Future treatment of GBM patients may include drugs targeting multiple kinases that are encoded by genes on chromosomal segment 4q12
    Type of Publication: Journal article published
    PubMed ID: 17504929
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  • 119
    Keywords: EXPRESSION ; GENE ; GENES ; SACCHAROMYCES-CEREVISIAE ; METABOLISM ; IDENTIFICATION ; Saccharomyces cerevisiae ; MUTATION ; MUTATIONS ; MITOCHONDRIA ; KINASE CASCADE ; LEVEL ; analysis ; ROLES ; INCREASES ; D-lactate dehydrogenase ; DLD3 ; GLYOXALASE I ; GRE2 ; isoamyl alcohol-induced filamentation ; isovaleraldehyde reductase ; METHYLGLYOXAL ; PSEUDOHYPHAE
    Abstract: A transcriptome analysis was performed of Saccharomyces cerevisiae undergoing isoamyl alcohol-induced filament formation. In the crucial first 5 h of this process, only four mRNA species displayed strong and statistically significant increases in their levels of more than 10-fold. Two of these (YEL071w/DLD3 and YOL151w/GRE2) appear to play important roles in filamentation. The biochemical activities ascribed to these two genes (D-lactate dehydrogenase and methylglyoxal reductase, respectively) displayed similarly timed increases to those of their respective mRNAs. Mutants carrying dld3 mutations displayed reduced filamentation in 0.5% isoamyl alcohol and needed a higher concentration of isoamyl alcohol to effect more complete filament formation. Hence, DLD3 seems to be required for a full response to isoamyl alcohol, but is not absolutely essential for it. Mutants carrying gre2 mutations were derepressed for filament formation and formed large, invasive filaments even in the absence of isoamyl alcohol. These results indicate a previously unsuspected and novel role for the GRE2 gene product as a suppressor of filamentation by virtue of encoding isovaleraldehyde reductase activity
    Type of Publication: Journal article published
    PubMed ID: 16999827
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  • 120
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; CELL ; Germany ; GENE ; GENES ; PROTEIN ; SAMPLES ; cell cycle ; CELL-CYCLE ; DOWN-REGULATION ; TARGET ; DELETION ; LYMPHOMA ; MUTATION ; COMPONENT ; inactivation ; PATHOGENESIS ; MUTATIONS ; B-CELLS ; DEGRADATION ; POLYMERASE-CHAIN-REACTION ; point mutation ; REGULATOR ; TRANSCRIPTS ; ONCOLOGY ; TUMOR-SUPPRESSOR ; CLL ; ATM MUTATIONS ; POINT MUTATIONS ; LEVEL ; TARGET GENES ; analysis ; leukaemia ; ATM ; PP2A ; PHOSPHATASE ; CONFORMATION ; B-CELL ; apoptosis regulation ; B-cell chronic lymphocytic ; 11q22-q23 ; CUL5 ; NPAT ; PHOSPHATASE 2A ; PPP2R1B
    Abstract: Deletion of 11q22-q23 is associated with an aggressive course of B-cell chronic lymphocytic leukaemia (B-CLL). Since only in a subset of these cases biallelic inactivation of ATM was observed, we sought to identify other disease-associated genes within 11q22-q23 by analysing NFAT (cell-cycle regulation), CUL5 (ubiquitin-dependent apoptosis regulation) and PPP2R1B (component of the cell-cycle and apoptosis regulating PP2A) for point mutations and their expression in B-CLL by single-strand conformation polymorphism/sequence analysis of the transcripts and real-time polymerase chain reaction. Though none of the genes were affected by deleterious mutations, we observed a significant down-regulation of NPAT in B-CLL versus CD19+ B cells and of CUL5 in 11q deletion versus non-deletion B-CLL samples and measured reduced PPP2R1B transcript levels in a subset of B-CLL cases. Alternative splicing of PPP2R1B transcripts (skipping of exons 2/3, 3, 9) was associated with a reduced activity of protein phosphatase 2A. Together, these results implicate deregulation of the cell-cycle and apoptosis regulators NPAT, CUL5 and PPP2R1B and a role for these genes in the pathogenesis of B-CLL. (C) 2007 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17449237
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  • 121
    Keywords: brain ; EXPRESSION ; tumor ; Germany ; human ; DISTINCT ; GENE ; GENES ; microarray ; TUMORS ; DNA ; primary ; IDENTIFICATION ; DIFFERENCE ; MUTATION ; LINE ; ABERRATIONS ; pathology ; expression profiling ; METHYLATION ; ASTROCYTOMAS ; GLIOMAS ; LOH ; HYPERMETHYLATION ; CDNA MICROARRAY ; neuroblastoma ; molecular ; aberrant expression ; TUMOR-SUPPRESSOR ; SUPPRESSOR GENE ; GLIOMA ; HUMAN GLIOMAS ; analysis ; SUPPRESSOR ; MOLECULAR-GENETICS ; PROFILES ; LOSSES ; OLIGODENDROGLIAL TUMORS ; CANDIDATE ; UNIT ; GLIOBLASTOMA ; MULTIPLE GENES ; aberration ; SECONDARY GLIOBLASTOMAS ; CDNA-MICROARRAY ; PHASE-III TRIAL ; 19Q LOSS ; CANDIDATE TUMOR-SUPPRESSOR
    Abstract: Allelic losses on 19q are found in the majority of oligodendroglial tumors and approximately one-third of diffuse astrocytomas. However, the tumor suppressor genes (TSG) on 19q are still elusive. Using cDNA microarray expression profiling, EMP3 at 19q13.3 was among those genes showing the most pronounced expression differences. In line with this, other authors reported EMP3 as being epigenetically silenced in neuroblastomas and astrocytomas. To further investigate EMP3 as a TSG candidate on 19q13.3, we performed molecular analysis of this gene in 162 human gliomas. Mutation analysis did not reveal EMP3 alteration in 132 gliomas. In oligodendroglial tumors, we found that aberrant methylation in the 5'-region of EMP3 was significantly associated with reduced mRNA expression and LOH 19q. In astrocytomas, EMP3 hypermethylation was also paralleled by reduced expression but was independent of the 19q status. EMP3 hypermethylation was detected in more than 80% of diffuse, anaplastic astrocytomas and secondary glioblastomas. Primary glioblastomas, however, mostly lacked EMP3 hypermethylation and frequently overexpressed EMP3. Our data corroborate that oligodendroglial and astrocytic gliomas often show EMP3 hypermethylation and aberrant expression. Furthermore, our findings suggest that primary and secondary glioblastomas are not only characterized by distinct genetic profiles but also differ in their epigenetic aberrations
    Type of Publication: Journal article published
    PubMed ID: 17610521
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  • 122
    Keywords: brain ; tumor ; CELL ; evaluation ; human ; COMMON ; GENE ; GENES ; HYBRIDIZATION ; microarray ; primary ; BIOLOGY ; MOLECULAR-BIOLOGY ; FORM ; IDENTIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; genetics ; PROSTATE-CANCER ; mass spectrometry ; DNA methylation ; inactivation ; PCR ; TUMOR-SUPPRESSOR GENE ; REGION ; MASS-SPECTROMETRY ; REGIONS ; bioinformatics ; ONCOGENE ; RT-PCR ; SELECTION ; CHAIN-REACTION ; METHYLATION ; heredity ; HYPERMETHYLATION ; EPIGENETIC INACTIVATION ; MASSES ; molecular biology ; molecular ; CHAIN ; ONCOLOGY ; brain tumor ; TUMOR-SUPPRESSOR ; SUPPRESSOR GENE ; TUMORIGENESIS ; GLIOMA ; MALIGNANT GLIOMA ; human brain ; SUPPRESSOR ; MASS ; PROMOTER HYPERMETHYLATION ; USA ; LOSSES ; CPG ISLAND HYPERMETHYLATION ; oligonucleotide microarray ; CANDIDATE ; ENGLAND ; GLIOBLASTOMA ; LOCI ; MULTIPLE GENES ; SHORT-TERM ; TUMOR-SUPPRESSOR GENES ; gene profiling ; CANDIDATE TUMOR-SUPPRESSOR ; 5-aza-dC ; ASTROCYTIC GLIOMAS ; RETINOBLASTOMA GENE
    Abstract: Glioblastoma, the most aggressive and least treatable form of malignant glioma, is the most common human brain tumor. Although many regions of allelic loss occur in glioblastomas, relatively few tumor suppressor genes have been found mutated at such loci. To address the possibility that epigenetic alterations are an alternative means of glioblastoma gene inactivation, we coupled pharmacological manipulation of methylation with gene profiling to identify potential methylation-regulated, tumor-related genes. Duplicates of three short-term cultured glioblastomas were exposed to 5 mu m 5-aza-dC for 96h followed by cRNA hybridization to an oligonucleotide microarray (Affymetrix U133A). We based candidate gene selection on bioinformatics, reverse transcription-polymerase chain reaction (RT-PCR), bisulfite sequencing, methylation-specific PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Two genes identified in this manner, RUNX3 and Testin (TES), were subsequently shown to harbor frequent tumor-specific epigenetic alterations in primary glioblastomas. This overall approach therefore provides a powerful means to identify candidate tumor-suppressor genes for subsequent evaluation and may lead to the identification of genes whose epigenetic dysregulation is integral to glioblastoma tumorigenesis
    Type of Publication: Journal article published
    PubMed ID: 16909125
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  • 123
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; INVASION ; SURVIVAL ; tumor ; CELL ; Germany ; INHIBITION ; SITE ; GENE ; GENE-EXPRESSION ; GENES ; cell line ; TISSUE ; TUMORS ; LINES ; PATIENT ; MECHANISM ; AP-1 ; REDUCTION ; TISSUES ; mechanisms ; BINDING ; BIOLOGY ; CELL-LINES ; MOLECULAR-BIOLOGY ; DELETION ; gene expression ; ASSAY ; PROMOTER ; METASTASIS ; genetics ; colorectal cancer ; COLORECTAL-CANCER ; CELL-LINE ; LINE ; REGION ; ONCOGENE ; UROKINASE RECEPTOR ; CANCER-PATIENTS ; CANCER PATIENTS ; cell lines ; PROGRAMMED CELL-DEATH ; heredity ; REGULATOR ; molecular biology ; molecular ; ONCOLOGY ; BINDING-PROTEIN ; RE ; TUMOR-SUPPRESSOR ; INCREASE ; PROGNOSTIC IMPACT ; SOLID TUMORS ; regulation ; ACTIVATOR ; Sp1 ; SUPPRESSOR ; correlation ; UNIT ; Mol Oncol ; PLASMINOGEN-ACTIVATOR RECEPTOR ; u-PAR ; INHIBIT ; colorectal ; PROMOTES ; PROTEIN-2-ALPHA-RELATED FACTOR ; AP-1 TRANSACTIVATION ; INITIATION-FACTOR 4A ; intravasation ; INVASIVE COLON-CANCER ; Pdcd4 ; Sp3 ; TOPOISOMERASE INHIBITORS ; TRANSFORMATION SUPPRESSOR
    Abstract: Tumor suppressor Pdcd4 has recently been shown to inhibit invasion by activating activator protein-1 (AP-1); however, little is known of the functionally significant Pdcd4-target genes. The urokinase receptor (u-PAR) promotes invasion/metastasis, and is associated with poor cancer-patient survival. The present study was conducted (1) to investigate a role for Pdcd4 in intravasation, invasion and u-PAR regulation, and (2) to describe mechanisms by which this is achieved. Fourteen cell lines showed reciprocal expression of u-PAR/Pdcd4. Resected tumor/normal tissues of 29 colorectal cancer patients demonstrated a significant inverse correlation between Pdcd4/u-PAR. siRNA-Pdcd4-transfected GEO cells significantly increased endogenous u-PAR mRNA/protein. A u-PAR-promoter-chloramphenicol acetyl transferase (CAT)-reporter was reduced in activity with increasing Pdcd4 expression in RKO. Deletion of a putative Sp-1-binding site (-402/-350) inhibited u-PAR promoter regulation by Pdcd4, this being paralleled by a reduction of Sp1 binding to this region in pdcd4-transfected cells. Pdcd4-transfected cells showed an increase in Sp3 binding to u-PAR promoter region -152/-135, the deletion of which reduces the ability of Pdcd4 to suppress u- PAR promoter activity. Surprisingly, the u-PAR-AP-1 site was not targeted by Pdcd4. Finally, RKO cells overexpressing Pdcd4 showed an inhibition of invasion/intravasation (chicken embryo metastasis assay). These data suggest Pdcd4 as a new negative regulator of intravasation, and qas the invasion-related gene u-PAR. It is the first study to implicate Pdcd4 regulation of gene expression via Sp1/Sp3
    Type of Publication: Journal article published
    PubMed ID: 17297470
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  • 124
    Keywords: EXPRESSION ; proliferation ; CELL ; CELL-PROLIFERATION ; Germany ; DISEASE ; GENE ; GENE-EXPRESSION ; GENES ; kidney ; MECHANISM ; RAT ; RATS ; mechanisms ; BIOLOGY ; TRANSPORT ; PROGRESSION ; gene expression ; DIFFERENCE ; NUMBER ; STRESS ; genetics ; RATES ; US ; OXIDATIVE STRESS ; SUPEROXIDE ; heredity ; RENAL-FAILURE ; molecular ; MOLECULAR-MECHANISM ; RE ; genomics ; cell proliferation ; MOLECULAR-MECHANISMS ; LEVEL ; HORMONES ; female ; Male ; NCBI ; genomic ; microbiology ; biotechnology ; GENDER-DIFFERENCES
    Abstract: Background: Post-puberty deterioration of kidneys is more rapid in males than in females. To reveal the underlying molecular mechanisms for this difference, we analyzed gender-dependent gene expression in kidneys of three groups of 36 day-old rats. Results: The number of genes exhibiting gender-dependent expression was highly influenced by the genetic background of the rat group examined. 373, 288 and 79 genes showed differential gene expression between males and females (p = 0.001) in US, Mhm and Mhm* BN rats, respectively. Of all gender dependently expressed genes, only 39 genes were differentially expressed in all tested groups and the direction of expression change was the same for those genes for all groups. The gene expression profile suggests higher metabolic and transport activities, enhanced cell proliferation, elevated oxidative stress, and altered vascular biology in males. Furthermore, elevated levels of superoxide anion (two-to three-fold) in males compared to females were detected at early puberty, but neither at pre-puberty nor at late puberty/early adulthood. Conclusion: Our data suggest that early puberty, with gender-related elevation in oxidative stress in males, is a key compromising factor on kidneys in males
    Type of Publication: Journal article published
    PubMed ID: 17620128
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