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  • 1
    Abstract: The gene tailless is a member of the superfamily of genes that encode transcription factors of the ligand-activated nuclear receptor type, and is expressed in the invertebrate and vertebrate brain. In mice, its transcripts are restricted to the periventricular zone of the forebrain, the site of origin of neurons and glia. Here we use homologous recombination to generate mice that lack a functional tailless protein. Homozygous mutant mice are viable at birth, indicating that tailless is not required for prenatal survival; however, adult mutant mice show a reduction in the size of rhinencephalic and limbic structures, including the olfactory, infrarhinal and entorhinal cortex, amygdala and dentate gyrus. Both male and female mice are more aggressive than usual and females lack normal maternal instincts. These animals therefore enable a molecular approach to be taken towards understanding the genetic architecture and morphogenesis of the forebrain.
    Type of Publication: Journal article published
    PubMed ID: 9394001
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; proliferation ; tumor ; CELL ; COMBINATION ; Germany ; KINASE ; POPULATION ; GENE ; GENES ; GENOME ; microarray ; ACTIVATION ; FAMILY ; REDUCTION ; CONTRAST ; BIOLOGY ; cell cycle ; CELL-CYCLE ; CYCLE ; PHOSPHORYLATION ; BREAST ; breast cancer ; BREAST-CANCER ; TARGET ; PROGRESSION ; ASSAY ; resistance ; TUMOR PROGRESSION ; METASTASIS ; genetics ; LINE ; REGION ; CANCER-CELLS ; REGIONS ; ONCOGENE ; sensitivity ; TARGETS ; OVEREXPRESSION ; LUCIFERASE ; ONCOLOGY ; TUMOR-SUPPRESSOR ; cell proliferation ; PHASE ; CELL-CYCLE ARREST ; MicroRNAs ; miRNA ; MICRORNA ; MESENCHYMAL TRANSITION ; CELL BIOLOGY ; tumor suppressor ; FAMILY-MEMBERS ; Genetic ; hypothesis ; REPORTER ; CONTRIBUTES ; miR-200 family ; PLC gamma 1
    Abstract: The genes encoding microRNAs of the human miR-200 family map to fragile chromosomal regions and are frequently downregulated upon tumor progression. Although having been reported to regulate epithelial-to-mesenchymal transition and transforming growth factor-beta- driven cell invasion, the role of the miR-200 family in EGF-driven breast cancer cell invasion, viability, apoptosis and cell cycle progression is still unknown. In particular, there is no study comparing the roles of the two clusters of this miRNA family. In this study, we show for the first time that miR-200 family members differentially regulate EGF-driven invasion, viability, apoptosis and cell cycle progression of breast cancer cells. We showed that, all miR-200 family members regulate EGF-driven invasion, with the miR-200bc/429 cluster showing stronger effects than the miR-200a/141 cluster. Furthermore, expression of the miR-200a/141 cluster results in G1 arrest supported by increased p27/Kip1 and decreased cyclin dependent kinase 6 expression. In contrast, expression of the 200bc/429 cluster decreases G1 population and increases G2/M phase, in line with the observed reduction of p27/Kip1 and upregulation of the inhibitory phosphorylation of Cdc25C, respectively. To test the hypothesis that phenotypical differences observed between the two clusters are caused by differential targeting spectrums, we performed genome-wide microarray profiling in combination with gain-of-function studies. This identified phospholipase C gamma 1 (PLCG1), which was downregulated only by the miR-200bc/429 cluster, as a potential candidate contributing to these phenotypical differences. Luciferase reporter assays validated PLCG1 as a direct functional target of miR-200bc/429 cluster, but not of miR-200a/141 cluster. Finally, loss of PLCG1 in part mimicked the effect of miR-200bc/429 overexpression in viability, apoptosis and EGF-driven cell invasion of breast cancer cells. Our results suggest that the miR-200 family has a tumor-suppressor function by negatively regulating EGF-driven cell invasion, viability and cell cycle progression in breast cancer. Oncogene (2010) 29, 4297-4306; doi: 10.1038/onc.2010.201; published online 31 May 2010
    Type of Publication: Journal article published
    PubMed ID: 20514023
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