Browsing by Subject "Gene control"

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Open Access
MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer
(John Wiley and Sons Ltd, 2014) Ward, A.; Shukla, K.; Balwierz, A.; Soons, Z.; König, R.; Sahin, O.; Wiemann, S.
Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.
Open Access
Regulation of Homer and group I metabotropic glutamate receptors by nicotine
(Wiley-Blackwell Publishing Ltd., 2005) Kane, J. K.; Hwang, Y.; Konu, O.; Loughlin, S. E.; Leslie, F. M.; Li, M. D.
The present study focuses on the nicotine-induced modulation of mRNA and protein expression of a number of genes involved in glutamatergic synaptic transmission in rat brain over different time periods of exposure. A subchronic (3 days) but not the chronic (7 or 14 days) administration of nicotine resulted in the up-regulation of Homer2a/b mRNA in the amygdala while in the ventral tegmental area (VTA) no change in expression of either Homer2a/b or Homer1b/c was observed. Although the increase in Homer2a/b mRNA was not translated into the protein level in the amygdala, a slight but significant up-regulation of Homer1b/c protein was observed in the same region at day 3. Both Homer forms were up-regulated at the protein level in the VTA at day 3. In the nucleus accumbens, 14 days of nicotine treatment up-regulated mRNA of Homer2b/c by 68.2% (P < 0.05), while the short form Homer1a gene was down-regulated by 65.0% at day 3 (P < 0.05). In regard to other components of the glutamatergic signalling, we identified an acute and intermittent increase in the mRNA and protein levels of mGluR1 and mGluR5 in the amygdala. In the VTA, however, the effects of nicotine on mGluR mRNA expression were long-lasting but rather specific to mGluR1. Nevertheless, mGluR1 protein levels in the VTA area were up-regulated only at day 3, as in the amygdala. These data provide further evidence for the involvement of nicotine in the glutamatergic neuronal synaptic activity in vivo, suggesting a role for the newly identified Homer proteins in this paradigm.
Open Access
The systems biology graphical notation
(Nature Publishing Group, 2009-08) Le Novère, N.; Hucka, M.; Mi, H.; Moodie, S.; Schreiber, F.; Sorokin, A.; Demir, Emek; Wegner, K.; Aladjem, M. I.; Wimalaratne, S. M.; Bergman, F. T.; Gauges, R.; Ghazal, P.; Kawaji, H.; Li, L.; Matsuoka, Y.; Villéger, A.; Boyd, S. E.; Calzone, L.; Courtot, M.; Doğrusöz, Uğur; Freeman, T. C.; Funahashi, A.; Ghosh, S.; Jouraku, A.; Kim, S.; Kolpakov, F.; Luna, A.; Sahle, S.; Schmidt, E.; Watterson, S.; Wu, G.; Goryanin, I.; Kell, D. B.; Sander, C.; Sauro, H.; Snoep, J. L.; Kohn, K.; Kitano, H.
Circuit diagrams and Unified Modeling Language diagrams are just two examples of standard visual languages that help accelerate work by promoting regularity, removing ambiguity and enabling software tool support for communication of complex information. Ironically, despite having one of the highest ratios of graphical to textual information, biology still lacks standard graphical notations. The recent deluge of biological knowledge makes addressing this deficit a pressing concern. Toward this goal, we present the Systems Biology Graphical Notation (SBGN), a visual language developed by a community of biochemists, modelers and computer scientists. SBGN consists of three complementary languages: process diagram, entity relationship diagram and activity flow diagram. Together they enable scientists to represent networks of biochemical interactions in a standard, unambiguous way. We believe that SBGN will foster efficient and accurate representation, visualization, storage, exchange and reuse of information on all kinds of biological knowledge, from gene regulation, to metabolism, to cellular signaling. © 2009 Nature America, Inc.