Department of Molecular Oncology, Göttingen Center of Molecular Biosciences -GZMB, Ernst Caspari Haus, University of Göttingen, Justus von Liebig Weg 11, 37077 Göttingen, Germany.
Cell Death Differ. 2010 Mar;17(3):452-8. doi: 10.1038/cdd.2009.188. Epub 2009 Dec 4.
E2F1 is a positive regulator of cell cycle progression and also a potent inducer of apoptosis, especially when activated by DNA damage. We identified E2F1-inducible microRNAs (miRNAs) by microarray hybridization and found that the levels of miRNAs 449a and 449b, as well as their host gene CDC20B, are strongly upregulated by E2F1. High miR-449 levels were found in testes, lung, and trachea, but not in testicular and other cancer cells. MiR-449a/b structurally resemble the p53-inducible miRNA 34 family. In agreement with a putative tumor-suppressive role, miR-449a as well as miR-34a reduced proliferation and strongly promoted apoptosis by at least partially p53-independent mechanisms. Both miRNAs reduced the levels of CDK6, implying miR-449 in a negative feedback mechanism for E2F1. Moreover, miR-449a and miR-34a diminished the deacetylase Sirt1 and augmented p53 acetylation. We propose that both miRNAs provide a twofold safety mechanism to avoid excessive E2F1-induced proliferation by cell cycle arrest and by apoptosis. While responding to different transactivators, miRNAs 449 and 34 each repress E2F1, but promote p53 activity, allowing efficient cross-talk between two major DNA damage-responsive gene regulators.
E2F1 是细胞周期进程的正调控因子，也是凋亡的有效诱导剂，尤其是在 DNA 损伤激活时。我们通过微阵列杂交鉴定了 E2F1 诱导的 microRNAs（miRNAs），发现 miRNAs 449a 和 449b 及其宿主基因 CDC20B 的水平受 E2F1 强烈上调。miR-449 水平在睾丸、肺和气管中较高，但在睾丸和其他癌细胞中较低。miR-449a/b 在结构上与 p53 诱导的 miRNA 34 家族相似。与推测的肿瘤抑制作用一致，miR-449a 以及 miR-34a 通过至少部分非 p53 依赖的机制减少增殖并强烈促进凋亡。这两种 miRNA 都降低了 CDK6 的水平，暗示 miR-449 处于 E2F1 的负反馈机制中。此外，miR-449a 和 miR-34a 减少了去乙酰化酶 Sirt1 并增加了 p53 的乙酰化。我们提出，这两种 miRNA 提供了一种双重安全机制，通过细胞周期停滞和凋亡来避免过度的 E2F1 诱导增殖。虽然对不同的转录激活子有反应，但 miRNAs 449 和 34 都抑制 E2F1，但促进 p53 活性，允许两个主要的 DNA 损伤反应基因调节剂之间进行有效的交叉对话。
