MicroRNA regulation of a cancer network: Consequences of the feedback loops involving miR-17-92, E2F, and Myc

Abstract

The transcription factors E2F and Myc participate in the control of cell proliferation and apoptosis, and can act as oncogenes or tumor suppressors depending on their levels of expression. Positive feedback loops in the regulation of these factors are predicted-and recently shown experimentally-to lead to bistability, which is a phenomenon characterized by the existence of low and high protein levels (''off'' and ''on'' levels, respectively), with sharp transitions between levels being inducible by, for example, changes in growth factor concentrations.

MicroRNA-based regulation of epithelial–hybrid–mesenchymal fate determination

“…The dependence of the functional form on the number of binding sites of μ on m is described in SI Appendix. We note that this system of threecoupled deterministic equations, derived by a more biologically consistent approach, differs from the previously derived models studied in the context of miRNA-TF chimeric circuits (21,(28)(29)(30)(31). Because, typically, miRs are more stable than mRNAs (32), in some cases, Eqs.…”

“…Compared with previous studies (21,(28)(29)(30)(31), the approach taken here incorporates in detail the dynamics of miR-mediated silencing (both translational repression and the active mRNA/miR degradation) and includes the effect of the number of binding sites of miR on mRNA (known for the circuits studied here). This framework was used to unravel the modular design principles of the epithelial-hybrid-mesenchymal core regulatory network.…”

microRNA-17 regulates the expression of ATG7 and modulates the autophagy process, improving the sensitivity to temozolomide and low-dose ionizing radiation treatments in human glioblastoma cells

“…To date, it is still debated how autophagy switches between these two cellular fates; probably, the degradation of cytosol and organelles beyond a certain threshold, depending on nature and duration of the induced cellular stress as well as on the involved tumor type, lead to miRWalk software, 30 miR-17, already known to be entangled in tumor development 18,20,21 and demonstrated to be overexpressed in GBM, 31 was predicted to target various ATGs (i.e., ATG2, ATG4, ATG5, ATG7, ATG10, ATG12, and ATG16 ), suggesting a multiple role in the modulation of the autophagy process. Next, in refining miR-17 and ATGs interactions, Miranda target tool predicted four putative interaction sites between the miR-17 seeding core and the 3'-UTR of ATG7 transcript, while fewer complementary sites were predicted for the other ATG genes.…”

“…This miRNA is part of the miR-17-92 cluster, already known for its role in tumor development via MYC and E2F1 signals. [18][19][20] The primary transcript of this miR was named "OncomiR-1". 21 In particular, miR-17 was already demonstrated to act specifically at the G 1 /S-phase cell cycle boundary, targeting many genes involved in the transition between these phases.…”

Characterization of the structure, function and regulation of the chicken mir-17-92 cluster

“…cluster 在 B 细胞发育、肺祖细胞增殖和分化、脂肪 细胞分化及血管发生等中发挥重要作用 Lu et al, 2007)。mir-17-92 cluster 是目前公认 的 第 一 个 非 编 码 癌 基 因 (oncomir-1), 现 已 发 现 mir-17-92 cluster 在肺癌、B 细胞淋巴瘤、淋巴瘤、 肝癌、膀胱癌、结肠癌、前列腺癌、胃癌及胰腺癌 等多种肿瘤细胞中高表达 (Lu et al, 2007;Olive et al, 2010), 而且, 在淋巴瘤、肺癌等多种癌细胞中均存 在 mir-17-92 cluster 基因扩增现象 (Ota et al, 2004 (Aguda et al, 2008;Carraro et al, 2009;Mu et al, 2009;O'Donnell et al, 2005;Olive et al, 2010;Peter, 2010;Sylvestre et al, 2007;Trompeter et al, 2011;Yu et al, 2008)。尽管 mir-17-92 cluster 的一些靶基因已 得到验证, 但是, 该 miRNA 基因簇参与的生物学过 程和通路还远未弄清楚 (de Pontual et al, 2011) cluster 有两个旁系同源体 mir-106a-363 cluster 和 mir-106b-25 cluster (Ventura et al, 2008)。人 mir106a-363 cluster 位于 X 染色体, 该基因簇的初级转 录本称为 Kis2, 包含 mir-106a、mir-18b、mir-20b、 mir-19b-2、mir-92-2 和 mir-363 等 6 个 miRNA。人 mir-106b-25 cluster 位于 7 号染色体上一个蛋白质编 码基因 MCM7 的第 13 个内含子内, 包含 mir-106b、 图 2 鸡 mir-17-92 基因簇及其旁系同源体 mir-106-20b 基因簇中各 miRNA 种子序列比较 …”