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  • 1
    Keywords: ENDOTHELIAL GROWTH-FACTOR ; FACTOR-BETA ; BRAIN-TUMORS ; MALIGNANT GLIOMAS ; TGF-BETA ; ASTROCYTIC TUMORS ; RECEPTOR TYROSINE KINASES ; TO-MESENCHYMAL TRANSITION ; HUMAN PROTEIN ATLAS ; STEM-LIKE CELLS
    Abstract: Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFbeta2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFbeta signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFbeta2 may represent a new target for vascular normalization therapy. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Publication: Journal article published
    PubMed ID: 22786655
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  • 2
    Keywords: RECEPTOR ; CELLS ; GROWTH ; INHIBITOR ; proliferation ; INHIBITION ; SYSTEM ; GENE ; PROTEIN ; PROTEINS ; RNA ; transcription ; ACTIVATION ; COMPLEX ; DNA ; BINDING ; ASSOCIATION ; CHROMATIN ; SWEDEN ; RECRUITMENT ; C-MYC ; POLYMERASE-I ; RNA-POLYMERASE-I ; RIBOSOME BIOGENESIS ; interaction ; GENE-TRANSCRIPTION ; COFACTOR ; nucleolus ; PROTEIN-DEGRADATION ; RECRUITS ; ribosome ; RNA polymerase I
    Abstract: The c-Myc oncoprotein regulates transcription of genes that are associated with cell growth, proliferation and apoptosis(1). c-Myc levels are modulated by ubiquitin/proteasome-mediated degradation(1). Proteasome inhibition leads to c-Myc accumulation within nucleoli(2), indicating that c-Myc might have a nucleolar function. Here we show that the proteins c-Myc and Max interact in nucleoli and are associated with ribosomal DNA. This association is increased upon activation of quiescent cells and is followed by recruitment of the Myc cofactor TRRAP, enhanced histone acetylation, recruitment of RNA polymerase I (Pol I), and activation of rDNA transcription. Using small interfering RNAs (siRNAs) against c-Myc and an inhibitor of Myc - Max interactions, we demonstrate that c-Myc is required for activating rDNA transcription in response to mitogenic signals. Furthermore, using the ligand-activated MycER ( ER, oestrogen receptor) system, we show that c-Myc can activate Pol I transcription in the absence of Pol II transcription. These results suggest that c-Myc coordinates the activity of all three nuclear RNA polymerases, and thereby plays a key role in regulating ribosome biogenesis and cell growth
    Type of Publication: Journal article published
    PubMed ID: 15723053
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