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  • Cell & Developmental Biology  (54)
  • GENE  (47)
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  • 1
    Keywords: brain ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; CELL ; Germany ; human ; GENE ; GENES ; HYBRIDIZATION ; TISSUE ; TUMORS ; DNA ; prognosis ; chromosome ; DELETION ; IN-SITU ; AMPLIFICATION ; COMPARATIVE GENOMIC HYBRIDIZATION ; PROMOTER ; MUTATION ; DELETIONS ; PATHOGENESIS ; TUMOR-SUPPRESSOR GENE ; MUTATIONS ; FLUORESCENCE ; IMBALANCES ; METHYLATION ; TUMOR CELLS ; CHROMOSOMES ; in situ hybridization ; CELL CARCINOMA ; CANDIDATE GENES ; WEIGHT ; MUTATIONAL ANALYSIS ; LEVEL ; analysis ; TUMOR-CELL ; ROLES ; DNA-MICROARRAY ; p53 mutation ; LOSSES ; MOLECULAR PATHOGENESIS ; CANDIDATE ; genomic ; RARE ; CHROMOSOME-9 ; molecular genetics ; LOCI ; array-based CGH ; GLIOMA PROGRESSION ; 9Q34 ; pleomorphic xanthoastrocytomas ; SCLEROSIS GENE TSC1
    Abstract: The molecular pathogenesis of pleomorphic xanthoastrocytoma (PXA), a rare astrocytic brain tumor with a relatively favorable prognosis, is still poorly understood. We characterized 50 PXAs by comparative genomic hybridization (CGH) and found the most common imbalance to be loss on chromosome 9 in 50% of tumors. Other recurrent losses affected chromosomes 17 (10%), 8, 18, 22 (4% each). Recurrent gains were identified on chromosomes X (16%), 7, 9q, 20 (8% each), 4, 5, 19 ( 4% each). Two tumors demonstrated amplifications mapping to 2p23-p25, 4p15, 12q13, 12q21, 21q21 and 21q22. Analysis of 10 PXAs with available high molecular weight DNA by high-resolution array-based CGH indicated homozygous 9p21.3 deletions involving the CDKN2A/p14(ARF)/CDKN2B loci in six tumors (60%). Interphase fluorescence in situ hybridization to tissue sections confirmed the presence of tumor cells with homozygous 9p21.3 deletions. Mutational analysis of candidate genes on 9q, PTCH and TSC1, revealed no mutations in PXAs with 9q loss and no evidence of TSC1 promoter methylation. However, PXAs consistently showed low TSC1 transcript levels. Taken together, our study identifies loss of chromosome 9 as the most common chromosomal imbalance in PXAs and suggests important roles for homozygous CDKN2A/p14ARF/CDKN2B deletion as well as low TSC1 mRNA expression in these tumors
    Type of Publication: Journal article published
    PubMed ID: 16909113
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  • 2
    Keywords: CANCER ; tumor ; carcinoma ; CLASSIFICATION ; COHORT ; DISTINCT ; GENE ; GENES ; TUMORS ; PATIENT ; prognosis ; treatment ; FREQUENCY ; SUSCEPTIBILITY ; BREAST ; DESIGN ; AGE ; BRCA1 ; OVARIAN-CANCER ; WOMEN ; MUTATION ; REPRODUCIBILITY ; p53 ; MUTATIONS ; MORPHOLOGY ; adenocarcinoma ; CARRIERS ; CANCER-RESEARCH ; SERIES ; POOR-PROGNOSIS ; FEATURES ; BRCA2 GENE ; GRADE ; MUTATION CARRIERS ; GERM-LINE MUTATIONS ; FAMILIAL BREAST-CANCER
    Abstract: Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer.Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated.Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21-2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P 〈 0.0001), had a higher percentage solid component (P 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers.Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively. aggressive and may be expected to have poor prognosis, although this may be treatment dependent
    Type of Publication: Journal article published
    PubMed ID: 15073127
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  • 3
    Keywords: CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; IN-VIVO ; INHIBITION ; VIVO ; DISEASE ; SITE ; SITES ; GENE ; transcription ; DIFFERENTIATION ; NF-KAPPA-B ; ACTIVATION ; FAMILY ; TRANSCRIPTION FACTOR ; AP-1 ; T cell ; T cells ; T-CELL ; T-CELLS ; BINDING ; RESPONSE ELEMENT ; TRANSCRIPTION FACTORS ; PROMOTER ; BETA ; immune response ; IMMUNE-RESPONSE ; LIVING CELLS ; CD28 ; C-REL ; T lymphocyte,transcription factor,cytokine
    Abstract: IL-4 plays a pivotal role in the development of the Th2 cell mediated humoral immune response and causes IgE-dependent allergic inflammatory diseases. Expression of IL-4 in differentiated Th2 cells is regulated by transcription factors such as NF-AT AP-1 and NF-IL6. Recently, increasing evidence indicates that the pro-inflammatory transcription factor NF-kappaB,13 may also participate in IL-4 expression. In this study, we show that the IL-4 promoter is synergistically activated by NF-kappaB, NF-AT and NF-IL6 at the NF-kappaB/NF-AT/NF-IL6 composite sites. In addition, we performed the chromatin immunoprecipitation technique to determine the functional relevance of NF-kappaB in the activation of the IL-4 gene in vivo. We demonstrate that NF-kappaB binds to the IL-4 promoter in vivo upon T cell activation. Inhibition of NF-kappaB nuclear translocation in living cells blocked binding of NF-kappaB to the IL-4 promoter. The data provide first evidence that NF-kappaB is directly involved in IL-4 transcription
    Type of Publication: Journal article published
    PubMed ID: 15048722
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  • 4
    Keywords: PEPTIDE ; CELLS ; EXPRESSION ; CELL ; Germany ; KINASE ; DEATH ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; NF-KAPPA-B ; FAMILY ; INDUCTION ; INTERVENTION ; PROTEIN-KINASE ; SEQUENCE ; SEQUENCES ; TARGET ; MOUSE ; IDENTIFICATION ; gene expression ; CELL-DEATH ; NUMBER ; PRODUCT ; OVEREXPRESSION ; RAT-BRAIN ; P21(WAF1/CIP1) ; CYCLIN G1 ; differential display,focal cerebral ischaemia,gene expression,middle cerebral artery occlusion,mouse ; PHOSPHORYLATES HUMAN CDC25C ; SERINE-216
    Abstract: Cerebral ischaemia induces transcriptional changes in a number of pathophysiologically important genes. Here we have systematically studied gene expression changes after 90 min and 24 h of permanent focal ischaemia in the mouse by an advanced fragment display technique (restriction-mediated differential display). We identified 56 transcriptionally altered genes, many of which provide novel hints to ischaemic pathophysiology. Particularly interesting were two pro-apoptotic genes (Grim19 and Tdag51), whose role in cerebral ischaemia and neuronal cell death has not been recognized so far. Among the unknown sequences, we identified a gene that was rapidly and transiently up-regulated. The encoded protein displayed high homology to the MARK family of serine-threonine protein kinases and has recently been described as MARKL1/MARK4. Here we demonstrate that this protein is a functional protein kinase with the ability to specifically phosphorylate a cognate peptide substrate for the AMP-kinase family. Upon overexpression in heterologous cells, the functional wild-type protein, but not its kinase-dead mutant, led to decreased cell viability. We conclude that the up-regulation of this kinase during focal ischaemia may represent an interesting new target for pharmacological intervention
    Type of Publication: Journal article published
    PubMed ID: 15009667
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  • 5
    Keywords: IN-VITRO ; Germany ; IN-VIVO ; VITRO ; VIVO ; IMAGES ; GENE ; TIME ; PATIENT ; MR ; MRI ; SEQUENCE ; SIGNAL ; MAGNETIC-RESONANCE ; MUTATION ; inactivation ; MUTATIONS ; MUSCLE ; ALPHA-SUBUNIT ; HUMAN SKELETAL-MUSCLE ; IMPLEMENTATION ; INCREASE ; technique ; correlation ; in vivo ; MR-IMAGES ; H1 ; NA+ ; HYPERKALEMIC PERIODIC PARALYSIS ; III-IV LINKER ; MYOTONIA-FLUCTUANS ; PARAMYOTONIA-CONGENITA ; POTASSIUM ; SODIUM-CHANNEL MUTATIONS
    Abstract: Background: Muscle channelopathies such as paramyotonia, hyperkalemic periodic paralysis, and potassium-aggravated myotonia are caused by gain-of-function Na+ channel mutations. Methods: Implementation of a three-dimensional radial Na-23 magnetic resonance (MR) sequence with ultra-short echo times allowed the authors to quantify changes in the total muscular Na-23 signal intensity. By this technique and T2-weighted H-1 MRI, the authors studied whether the affected muscles take up Na+ and water during episodes of myotonic stiffness or of cold- or exercise-induced weakness. Results: A 22% increase in the Na-23 signal intensity and edema-like changes on T2-weighted H-1 MR images were associated with cold-induced weakness in all 10 paramyotonia patients; signal increase and weakness disappeared within 1 day. A 10% increase in Na-23, but no increase in the T2-weighted H-1 signal, occurred during cold- or exercise-induced weakness in seven hyperkalemic periodic paralysis patients, and no MR changes were observed in controls or exercise-induced stiffness in six potassium-aggravated myotonia patients. Measurements on native muscle fibers revealed provocation-induced, intracellular Na+ accumulation and membrane depolarization by -41 mV for paramyotonia, by -30 mV for hyperkalemic periodic paralysis, and by -20 mV for potassium-aggravated myotonia. The combined in vivo and in vitro approach showed a close correlation between the increase in Na-23 MR signal intensity and the membrane depolarization (r = 0.92). Conclusions: The increase in the total Na-23 signal intensity reflects intracellular changes, the cold-induced Na+ shifts are greatest and osmotically relevant in paramyotonia patients, and even osmotically irrelevant Na+ shifts can be detected by the implemented Na-23 MR technique
    Type of Publication: Journal article published
    PubMed ID: 16931510
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; INHIBITION ; GENE ; GENE-EXPRESSION ; GENES ; PROTEIN ; RNA ; cell line ; MOLECULES ; LINES ; ACTIVATION ; DNA ; MECHANISM ; prognosis ; mechanisms ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CELL-LINES ; CYCLE ; DOWN-REGULATION ; FREQUENCY ; FREQUENCIES ; MOLECULE ; TARGET ; IDENTIFICATION ; PATTERNS ; gene expression ; CELL-LINE ; LINE ; DNA methylation ; DEGRADATION ; TARGETS ; cell lines ; METHYLATION ; CHRONIC LYMPHOCYTIC-LEUKEMIA ; HUMAN CANCER ; TUMORIGENESIS ; CPG ISLANDS ; analysis ; HUMAN CANCER-CELLS ; USA ; function ; HUMAN CANCERS ; CPG-ISLAND METHYLATION ; CANDIDATE ; CANCERS ; CpG island ; DNA-METHYLATION ; MICRORNA ; epimutation
    Abstract: MicroRNAs ( miRNAs) are small RNA molecules that control gene expression by inhibition of protein translation or by degradation of cognate target mRNAs. Even though strict developmental and tissue-specific regulation appears to be critical for miRNA function, very little is known about the mechanisms governing miRNA gene expression. Several recent studies have shown that miRNA genes can be regulated by DNA methylation and other epigenetic mechanisms. The observation of altered miRNA gene methylation patterns in human cancers also suggested that miRNA gene methylation is functionally relevant for tumorigenesis. We have now performed a comprehensive analysis of miRNA genes and found that about half of these genes are associated with CpG islands and thus represent candidate targets of the DNA methylation machinery. An expanded analysis of several miRNA-associated CpG islands in five cell lines indicated that miRNA gene methylation is detectable at high frequencies, both in normal and malignant cells. Possible explanations for this phenomenon include the specific structure of miRNA genes and/or their requirement for strict expression regulation
    Type of Publication: Journal article published
    PubMed ID: 17457051
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  • 7
    Keywords: CELLS ; GROWTH ; BLOOD ; GENE ; MATURATION ; DISRUPTION ; EXPRESSION ANALYSIS ; TUMOR ANGIOGENESIS ; MORPHOGENESIS ; neuropilin-1
    Abstract: OBJECTIVE: To characterize the role of a vascular-expressed class 3 semaphorin (semaphorin 3G [Sema3G]). METHODS AND RESULTS: Semaphorins have been identified as axon guidance molecules. Yet, they have more recently also been characterized as attractive and repulsive regulators of angiogenesis. Through a transcriptomic screen, we identified Sema3G as a molecule of angiogenic endothelial cells. Sema3G-deficient mice are viable and exhibit no overt vascular phenotype. Yet, LacZ expression in the Sema3G locus revealed intense arterial vascular staining in the angiogenic vasculature, starting at E9.5, which was detectable throughout adolescence and downregulated in adult vasculature. Sema3G is expressed as a full-length 100-kDa secreted molecule that is processed by furin proteases to yield 95- and a 65-kDa Sema domain-containing subunits. Full-length Sema3G binds to NP2, whereas processed Sema3G binds to NP1 and NP2. Expression profiling and cellular experiments identified autocrine effects of Sema3G on endothelial cells and paracrine effects on smooth muscle cells. CONCLUSIONS: Although the mouse knockout phenotype suggests compensatory mechanisms, the experiments identify Sema3G as a primarily endothelial cell-expressed class 3 semaphorin that controls endothelial and smooth muscle cell functions in autocrine and paracrine manners, respectively.
    Type of Publication: Journal article published
    PubMed ID: 20947821
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  • 8
    Keywords: APOPTOSIS ; DISEASE ; POPULATION ; GENE ; LINES ; BIOLOGY ; chemotherapy ; p53 ; CANCER-CELLS ; MUTATIONS ; STEM-CELLS ; MDM2 ; chemoresistance ; MUTANT P53 ; WILD-TYPE P53 ; P53/MDM2/P14(ARF) PATHWAY ; ANTAGONIST NUTLIN-3 ; CHEMORESISTANT NEUROBLASTOMA ; nutlin-3 ; RHABDOMYOSARCOMA CELLS
    Abstract: Six p53 wild-type cancer cell lines from infrequently p53-mutated entities (neuroblastoma, rhabdomyosarcoma, and melanoma) were continuously exposed to increasing concentrations of the murine double minute 2 inhibitor nutlin-3, resulting in the emergence of nutlin-3-resistant, p53-mutated sublines displaying a multi-drug resistance phenotype. Only 2 out of 28 sublines adapted to various cytotoxic drugs harboured p53 mutations. Nutlin-3-adapted UKF-NB-3 cells (UKF-NB-3(r)Nutlin(10 muM), harbouring a G245C mutation) were also radiation resistant. Analysis of UKF-NB-3 and UKF-NB-3(r)Nutlin(10 muM) cells by RNA interference experiments and lentiviral transduction of wild-type p53 into p53-mutated UKF-NB-3(r)Nutlin(10 muM) cells revealed that the loss of p53 function contributes to the multi-drug resistance of UKF-NB-3(r)Nutlin(10 muM) cells. Bioinformatics PANTHER pathway analysis based on microarray measurements of mRNA abundance indicated a substantial overlap in the signalling pathways differentially regulated between UKF-NB-3(r)Nutlin(10 muM) and UKF-NB-3 and between UKF-NB-3 and its cisplatin-, doxorubicin-, or vincristine-resistant sublines. Repeated nutlin-3 adaptation of neuroblastoma cells resulted in sublines harbouring various p53 mutations with high frequency. A p53 wild-type single cell-derived UKF-NB-3 clone was adapted to nutlin-3 in independent experiments. Eight out of ten resulting sublines were p53-mutated harbouring six different p53 mutations. This indicates that nutlin-3 induces de novo p53 mutations not initially present in the original cell population. Therefore, nutlin-3-treated cancer patients should be carefully monitored for the emergence of p53-mutated, multi-drug-resistant cells.
    Type of Publication: Journal article published
    PubMed ID: 22170099
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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; EXPRESSION ; IN-VITRO ; TUMOR-CELLS ; carcinoma ; Germany ; PATHWAY ; THERAPY ; DEATH ; GENE ; GENE-EXPRESSION ; TUMORS ; LINES ; NF-KAPPA-B ; LIGAND ; breast cancer ; BREAST-CANCER ; TARGET ; p53 ; MEDIATED APOPTOSIS ; ENDOPLASMIC-RETICULUM STRESS ; T-cell leukemia
    Abstract: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anticancer agent that kills various tumor cells without damaging normal tissues. However, many cancers remain resistant to TRAIL. To overcome TRAIL resistance, combination therapies using sensitizers of the TRAIL pathway would be an efficacious approach. To investigate potential sensitizers of TRAIL-induced apoptosis, we used TRAIL-resistant human T cell leukemia virus type 1 (HTLV-1)-associated adult T cell leukemia/lymphoma (ATL) cells as a model system. So far, HTLV-1-associated ATL is incurable by presently known therapies. Here, we show that wogonin and the structurally related natural flavones apigenin and chrysin break TRAIL resistance in HTLV-1-associated ATL by transcriptional down-regulation of c-FLIP, a key inhibitor of death receptor signaling, and by up-regulation of TRAIL receptor 2 (TRAIL-R2). This effect is mediated through transcriptional inhibition of the p53 antagonist murine double minute 2 (Mdm2), leading to an increase in p53 levels and, consequently, to up-regulation of the p53 target gene TRAIL-R2. We also show that these flavones can sensitize to TNFalpha- and CD95-mediated cell death. Furthermore, we show that wogonin, apigenin, and chrysin also enhance TRAIL-mediated apoptosis in other human cancer cell lines including breast cancer cell line MDA-MB-231, colon cancer cell line HT-29, hepatocellular carcinoma cell line HepG2, melanoma cell line SK-MEL-37, and pancreatic carcinoma cell line Capan-1 by the same mechanism. Thus, our study suggests the potential use of these flavones as an adjuvant for TRAIL-mediated anticancer therapy.
    Type of Publication: Journal article published
    PubMed ID: 22086925
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  • 10
    Keywords: CANCER ; GENE ; GENOME ; MUTATIONS ; STEM-CELLS ; ZINC-FINGER PROTEIN ; T-CELL LYMPHOMAGENESIS ; MYC ; SUPER-ENHANCERS ; SUBGROUP
    Abstract: Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
    Type of Publication: Journal article published
    PubMed ID: 25043047
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