Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2010 Feb 26;285(9):6348-63. doi: 10.1074/jbc.M109.072074. Epub 2009 Dec 29.
Regulation of the E2F family of transcription factors is important in control of cellular proliferation; dysregulation of the E2Fs is a hallmark of many cancers. One member of the E2F family, E2F1, also has the paradoxical ability to induce apoptosis; however, the mechanisms underlying this selectivity are not fully understood. We now identify a nucleolar protein, RRP1B, as an E2F1-specific transcriptional target. We characterize the RRP1B promoter and demonstrate its selective response to E2F1. Consistent with the activation of E2F1 activity upon DNA damage, RRP1B is induced by several DNA-damaging agents. Importantly, RRP1B is required for the expression of certain E2F1 proapoptotic target genes and the induction of apoptosis by DNA-damaging agents. This activity is mediated in part by complex formation between RRP1B and E2F1 on selective E2F1 target gene promoters. Interaction between RRP1B and E2F1 can be found inside the nucleolus and diffuse nucleoplasmic punctates. Thus, E2F1 makes use of its transcriptional target RRP1B to activate other genes directly involved in apoptosis. Our data also suggest an underappreciated role for nucleolar proteins in transcriptional regulation.
E2F 转录因子家族的调节对于控制细胞增殖非常重要；E2Fs 的失调是许多癌症的标志。E2F 家族的一个成员 E2F1 也具有诱导细胞凋亡的矛盾能力；然而，这种选择性的机制尚不完全清楚。我们现在确定了核仁蛋白 RRP1B 是 E2F1 特异性转录靶标。我们对 RRP1B 启动子进行了表征，并证明了其对 E2F1 的选择性反应。与 DNA 损伤时 E2F1 活性的激活一致，RRP1B 被几种 DNA 损伤剂诱导。重要的是，RRP1B 是某些 E2F1 促凋亡靶基因表达和 DNA 损伤剂诱导凋亡所必需的。这种活性部分是通过 RRP1B 和 E2F1 在选择性 E2F1 靶基因启动子上形成复合物来介导的。RRP1B 和 E2F1 之间的相互作用可以在核仁内和弥散的核质点状结构中找到。因此，E2F1 利用其转录靶标 RRP1B 直接激活其他直接参与细胞凋亡的基因。我们的数据还表明核仁蛋白在转录调节中具有被低估的作用。
