Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, Illinois 60607, USA.
Genes Dev. 2011 Sep 1;25(17):1820-34. doi: 10.1101/gad.16947411. Epub 2011 Aug 19.
The E2F family of transcription factors regulates the expression of both genes associated with cell proliferation and genes that regulate cell death. The net outcome is dependent on cellular context and tissue environment. The mir-11 gene is located in the last intron of the Drosophila E2F1 homolog gene dE2f1, and its expression parallels that of dE2f1. Here, we investigated the role of miR-11 and found that miR-11 specifically modulated the proapoptotic function of its host gene, dE2f1. A mir-11 mutant was highly sensitive to dE2F1-dependent, DNA damage-induced apoptosis. Consistently, coexpression of miR-11 in transgenic animals suppressed dE2F1-induced apoptosis in multiple tissues, while exerting no effect on dE2F1-driven cell proliferation. Importantly, miR-11 repressed the expression of the proapoptotic genes reaper (rpr) and head involution defective (hid), which are directly regulated by dE2F1 upon DNA damage. In addition to rpr and hid, we identified a novel set of cell death genes that was also directly regulated by dE2F1 and miR-11. Thus, our data support a model in which the coexpression of miR-11 limits the proapoptotic function of its host gene, dE2f1, upon DNA damage by directly modulating a dE2F1-dependent apoptotic transcriptional program.
E2F 转录因子家族调节与细胞增殖相关的基因和调节细胞死亡的基因的表达。净结果取决于细胞环境和组织环境。miR-11 基因位于果蝇 E2F1 同源基因 dE2f1 的最后一个内含子中，其表达与 dE2f1 平行。在这里，我们研究了 miR-11 的作用，发现 miR-11 特异性调节其宿主基因 dE2f1 的促凋亡功能。miR-11 突变体对 dE2F1 依赖性、DNA 损伤诱导的细胞凋亡高度敏感。一致地，miR-11 在转基因动物中的共表达抑制了 dE2F1 诱导的多种组织中的细胞凋亡，而对 dE2F1 驱动的细胞增殖没有影响。重要的是，miR-11 抑制了直接受 DNA 损伤调控的促凋亡基因 reaper(rpr)和 head involution defective(hid)的表达。除了 rpr 和 hid，我们还鉴定了一组新的细胞死亡基因，它们也直接受 dE2F1 和 miR-11 调控。因此，我们的数据支持这样一种模型，即 miR-11 的共表达通过直接调节 dE2F1 依赖性凋亡转录程序，限制了其宿主基因 dE2f1 在 DNA 损伤时的促凋亡功能。
