Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts
Identification of novel target genes specifically activated by deregulated E2F in human normal fibroblasts
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DOI：
10.1111/gtc.12268
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发表时间：
2015-09-01
期刊：
影响因子：
2.1
通讯作者：
Ohtani, Kiyoshi
中科院分区：
文献类型：
--
作者：
Kitamura, Hodaka;Ozono, Eiko;Ohtani, Kiyoshi
转录因子E2F是肿瘤抑制因子pRB的主要靶点。E2F不仅通过激活生长相关基因在细胞增殖中起关键作用，而且通过激活促凋亡基因和生长抑制基因在肿瘤抑制中起关键作用。我们以前报道，在人类正常成纤维细胞，肿瘤抑制基因ARF，p27（Kip1）和TAp73被激活由pRB的强制失活诱导的E2F活性失调，但不是由生长刺激诱导的生理E2F活性。相反，生长相关的E2F靶点被两种E2F活性激活，强调了在功能失调的pRB背景下，失调的E2F在肿瘤抑制中的作用。在这项研究中，为了进一步了解去调控的E2F的作用，我们使用DNA微阵列探索了由去调控的E2F特异性激活的新靶点。该分析确定了9个新靶点（BIM，RASSF1，PPP1R13B，JMY，MOAP 1，RBM38，ABTB 1，RBBP4和RBBP7），其中许多涉及p53和RB肿瘤抑制途径。在这些基因中，BIM基因被证明是通过非典型的E2F响应启动子元件激活，并有助于E2F1介导的细胞凋亡。我们的研究结果强调了E2F在生长抑制中的关键作用，以抵消pRB功能的丧失。
The transcription factor E2F is the principal target of the tumor suppressor pRB. E2F plays crucial roles not only in cell proliferation by activating growth-related genes but also in tumor suppression by activating pro-apoptotic and growth-suppressive genes. We previously reported that, in human normal fibroblasts, the tumor suppressor genes ARF, p27(Kip1) and TAp73 are activated by deregulated E2F activity induced by forced inactivation of pRB, but not by physiological E2F activity induced by growth stimulation. In contrast, growth-related E2F targets are activated by both E2F activities, underscoring the roles of deregulated E2F in tumor suppression in the context of dysfunctional pRB. In this study, to further understand the roles of deregulated E2F, we explored new targets that are specifically activated by deregulated E2F using DNA microarray. The analysis identified nine novel targets (BIM, RASSF1, PPP1R13B, JMY, MOAP1, RBM38, ABTB1, RBBP4 and RBBP7), many of which are involved in the p53 and RB tumor suppressor pathways. Among these genes, the BIM gene was shown to be activated via atypical E2F-responsive promoter elements and to contribute to E2F1-mediated apoptosis. Our results underscore crucial roles of deregulated E2F in growth suppression to counteract loss of pRB function.