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  • EXPRESSION  (6)
  • moss
  • orobol
  • 1
    Keywords: CANCER ; EXPRESSION ; LINES ; AMPLIFICATION ; CHROMATIN ; SPECIFICATION ; STEM-CELLS ; expression profiling ; RETINOIC ACID ; PATTERN ; medulloblastoma ; MIDBRAIN ; Immunoprecipitation ; CEREBELLAR DEVELOPMENT ; AURORA KINASE ; OTX2
    Abstract: The transcription factor OTX2 has been implicated as an oncogene in medulloblastoma, which is the most common malignant brain tumor in children. It is highly expressed in most medulloblastomas and amplified in a subset of them. To study the role OTX2 has in medulloblastoma we investigated the downstream pathway of OTX2. We generated D425 medulloblastoma cells in which endogenous OTX2 can be silenced by inducible shRNA. Silencing of OTX2 strongly inhibited cell proliferation and resulted in a neuronal-like differentiation. Expression profiling of time courses after silencing showed a progressive change in gene expression for many cellular processes. Downregulated genes were highly enriched for cell cycle and visual perception genes, while upregulated genes were enriched for genes involved in development and differentiation. This shift is reminiscent of expression changes described during normal cerebellum development where proliferating granule progenitor cells have high OTX2 expression, which diminishes when these cells exit the cell cycle and start to differentiate. ChIP-on-chip analyses of OTX2 in D425 cells identified cell cycle and perception genes as direct OTX2 targets, while regulation of most differentiation genes appeared to be indirect. The expression of many directly regulated genes correlated to OTX2 expression in primary tumors, suggesting the in vivo relevance of these genes and their potential as targets for therapeutic intervention. These analyses provide more insight in the molecular network of OTX2, demonstrating that OTX2 is essential in medulloblastoma and directly drives proliferation by regulation of cell cycle genes
    Type of Publication: Journal article published
    PubMed ID: 21964830
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  • 2
    Keywords: EXPRESSION ; COLORECTAL-CANCER ; microsatellite instability ; CENTRAL-NERVOUS-SYSTEM ; C-MYC ; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ; PROMOTER METHYLATION ; CHILDRENS ONCOLOGY GROUP ; Lynch syndrome ; PEDIATRIC BRAIN-TUMORS
    Abstract: Background:Tumours are responsive to temozolomide (TMZ) if they are deficient in O(6)-methylguanine-DNA methyltransferase (MGMT), and mismatch repair (MMR) proficient.Methods:The effect of TMZ on medulloblastoma (MB) cell killing was analysed with clonogenic survival assays. Expression of DNA repair genes and enzymes was investigated using microarrays, western blot, and immunohistochemistry. DNA sequencing and promoter methylation analysis were employed to investigate the cause of loss of the expression of MMR gene MLH1.Results:Temozolomide exhibited potent cytotoxic activity in D425Med (MGMT deficient, MLH1 proficient; IC(50)=1.7 muM), moderate activity against D341Med (MGMT proficient, MLH1 deficient), and DAOY MB cells (MGMT proficient, MLH1 proficient). MGMT inhibitor O(6)-benzylguanine sensitised DAOY, but not D341Med cells to TMZ. Of 12 MB cell lines, D341Med, D283Med, and 1580WU cells exhibited MMR deficiency due to MLH1 promoter hypermethylation. DNA sequencing of these cells provided no evidence for somatic genetic alterations in MLH1. Expression analyses of MMR and MGMT in MB revealed that all patient specimens (n=74; expression array, n=61; immunostaining, n=13) are most likely MMR proficient, whereas some tumours had low MGMT expression levels (according to expression array) or were totally MGMT deficient (3 out of 13 according to immunohistochemistry).Conclusion:A subset of MB may respond to TMZ as some patient specimens are MGMT deficient, and tumours appear to be MMR proficient.
    Type of Publication: Journal article published
    PubMed ID: 22976800
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  • 3
    Keywords: EXPRESSION ; GENE ; DIFFERENTIATION ; IDENTIFICATION ; EMBRYONIC STEM-CELLS ; HYPERMETHYLATION ; SUPPRESSOR ; methylome ; CANCER GENOME ; CPG ISLAND SHORES
    Abstract: Epigenetic alterations, that is, disruption of DNA methylation and chromatin architecture, are now acknowledged as a universal feature of tumorigenesis. Medulloblastoma, a clinically challenging, malignant childhood brain tumour, is no exception. Despite much progress from recent genomics studies, with recurrent changes identified in each of the four distinct tumour subgroups (WNT-pathway-activated, SHH-pathway-activated, and the less-well-characterized Group 3 and Group 4), many cases still lack an obvious genetic driver. Here we present whole-genome bisulphite-sequencing data from thirty-four human and five murine tumours plus eight human and three murine normal controls, augmented with matched whole-genome, RNA and chromatin immunoprecipitation sequencing data. This comprehensive data set allowed us to decipher several features underlying the interplay between the genome, epigenome and transcriptome, and its effects on medulloblastoma pathophysiology. Most notable were highly prevalent regions of hypomethylation correlating with increased gene expression, extending tens of kilobases downstream of transcription start sites. Focal regions of low methylation linked to transcription-factor-binding sites shed light on differential transcriptional networks between subgroups, whereas increased methylation due to re-normalization of repressed chromatin in DNA methylation valleys was positively correlated with gene expression. Large, partially methylated domains affecting up to one-third of the genome showed increased mutation rates and gene silencing in a subgroup-specific fashion. Epigenetic alterations also affected novel medulloblastoma candidate genes (for example, LIN28B), resulting in alternative promoter usage and/or differential messenger RNA/microRNA expression. Analysis of mouse medulloblastoma and precursor-cell methylation demonstrated a somatic origin for many alterations. Our data provide insights into the epigenetic regulation of transcription and genome organization in medulloblastoma pathogenesis, which are probably also of importance in a wider developmental and disease context.
    Type of Publication: Journal article published
    PubMed ID: 24847876
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  • 4
    Keywords: APOPTOSIS ; EXPRESSION ; INHIBITION ; NEUROBLASTOMA-CELLS ; CELL-CYCLE ; PHOSPHORYLATION ; TNF-ALPHA ; MYCN ; NEGATIVE BREAST-CANCER ; CDK1
    Abstract: Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks.
    Type of Publication: Journal article published
    PubMed ID: 26029996
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  • 5
    Keywords: CELLS ; EXPRESSION ; CELL ; Germany ; MODEL ; DISEASE ; GENE ; GENE-EXPRESSION ; PROTEIN ; PROTEINS ; DIFFERENTIATION ; MONOCLONAL-ANTIBODY ; MATURATION ; antibodies ; antibody ; MOUSE ; IN-SITU ; immunohistochemistry ; gene expression ; CELL-LINE ; LINE ; SURFACE ; MONOCLONAL-ANTIBODIES ; STRATEGIES ; CELIAC-DISEASE ; EXPRESSION PROFILES ; GLUTEN ; STRATEGY ; DNAJ ; J-DOMAIN
    Abstract: Background: Maturation of enterocytes along the small intestinal crypt-villus axis is associated with significant changes in gene expression profiles. fls485 coding a putative chaperone protein has been recently suggested as a gene involved in this process. The aim of the present study was to analyze fls485 expression in human small intestinal mucosa. Methods: fls485 expression in purified normal or intestinal mucosa affected with celiac disease was investigated with a molecular approach including qRT-PCR, Western blotting, and expression strategies. Molecular data were corroborated with several in situ techniques and usage of newly synthesized mouse monoclonal antibodies. Results: fls485 mRNA expression was preferentially found in enterocytes and chromaffine cells of human intestinal mucosa as well as in several cell lines including Rko, Lovo, and CaCo2 cells. Western blot analysis with our new anti-fls485 antibodies revealed at least two fls485 proteins. In a functional CaCo2 model, an increase in fls485 expression was paralleled by cellular maturation stage. Immunohistochemistry demonstrated fls485 as a cytosolic protein with a slightly increasing expression gradient along the crypt-villus axis which was impaired in celiac disease Marsh IIIa-c. Conclusions: Expression and synthesis of fls485 are found in surface lining epithelia of normal human intestinal mucosa and deriving epithelial cell lines. An interdependence of enterocyte differentiation along the crypt-villus axis and fls485 chaperone activity might be possible
    Type of Publication: Journal article published
    PubMed ID: 20205943
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  • 6
    Keywords: CELLS ; EXPRESSION ; DISEASE ; MICE ; MOUSE ; ABERRATIONS ; mutagenesis ; SOLID TUMORS ; CANCER METASTASIS ; BEAUTY TRANSPOSON SYSTEM
    Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord(1). Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and inmost children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system(2). The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour(3,4). Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies
    Type of Publication: Journal article published
    PubMed ID: 22343890
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  • 7
    ISSN: 0031-9422
    Keywords: 6''-malonyl glucosides ; 7-O-glucosides ; Bryales ; Bryum capillare ; Musci ; NMR spectra. ; isoflavones ; moss ; orobol ; pratensein
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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