The Mina and Everard Goodman Faculty of Life Science, Bar Ilan University, Ramat Gan, Israel.
Mol Cancer Res. 2010 Mar;8(3):363-72. doi: 10.1158/1541-7786.MCR-09-0137. Epub 2010 Mar 2.
The E2F1 transcription factor is a critical downstream target of the tumor suppressor RB. When activated, E2F1 can induce cell proliferation and/or apoptosis. In addition, E2F1 overexpression sensitizes cancer cells to chemotherapeutic drugs. In a screen for genes that are regulated synergistically by E2F1 and chemotherapy in cancer cells, we identified the proapoptotic tumor suppressor gene maspin (mammary serine protease inhibitor) as a novel E2F1-regulated gene. In line with being an E2F-regulated gene, maspin expression is inhibited by short hairpin RNA directed against E2F1 and increases upon activation of endogenous E2F. Furthermore, maspin mRNA and protein levels are elevated upon activation of exogenous E2F1. Importantly, we show that E2F1-mediated upregulation of maspin is enhanced by chemotherapeutic drugs, and inhibition of maspin expression significantly impairs the ability of E2F1 to promote chemotherapy-induced apoptosis. Summarily, our data indicate that maspin is an important effector of E2F1-induced chemosensitization.
E2F1 转录因子是肿瘤抑制因子 RB 的关键下游靶标。当被激活时，E2F1 可以诱导细胞增殖和/或细胞凋亡。此外，E2F1 的过表达使癌细胞对化疗药物敏感。在一项针对 E2F1 和化疗在癌细胞中协同调控的基因筛选中，我们鉴定了促凋亡肿瘤抑制基因 maspin（乳腺丝氨酸蛋白酶抑制剂）作为一种新的 E2F1 调控基因。与作为 E2F 调控基因一致，短发夹 RNA 靶向 E2F1 可抑制 maspin 的表达，而内源性 E2F 的激活则增加其表达。此外，外源性 E2F1 的激活可使 maspin mRNA 和蛋白水平升高。重要的是，我们发现化疗药物增强了 E2F1 介导的 maspin 上调，而抑制 maspin 的表达显著削弱了 E2F1 促进化疗诱导细胞凋亡的能力。总之，我们的数据表明 maspin 是 E2F1 诱导化疗增敏的重要效应因子。
