E2F1 regulates autophagy and the transcription of autophagy genes
E2F1 regulates autophagy and the transcription of autophagy genes
复制标题
DOI：
10.1038/onc.2008.117
复制
发表时间：
2008-08-14
期刊：
影响因子：
8
通讯作者：
Ginsberg, D.
中科院分区：
文献类型：
--
作者：
Polager, S.;Ofir, M.;Ginsberg, D.
视网膜母细胞瘤通路在人类肿瘤中经常失活，导致E2F活性失调，从而诱导增殖和细胞死亡。虽然E2F在细胞凋亡中的作用已经被很好地描述了，但关于它在其他细胞死亡途径中的可能参与却知之甚少。我们发现，激活E2F1可上调自噬基因微管相关蛋白-1轻链-3 （LC3）、自噬相关基因-1 （ATG1）、ATG5和损伤调节自噬调节剂（DRAM）的表达。E2F1介导的LC3， ATG1和DRAM的诱导是直接的，事实上，内源性E2F1可以被发现结合到包含这些基因启动子的区域。E2F1对ATG5的调控是间接的。重要的是，我们证明了E2F1激活增强自噬，相反，降低内源性E2F1表达抑制DNA损伤诱导的自噬。这些研究确定了E2F1是自噬的转录调节因子，并首次确定了E2F1在DNA损伤诱导的自噬中的作用。
The retinoblastoma pathway is often inactivated in human tumors resulting in deregulated E2F activity that can induce both proliferation and cell death. Although the role of E2F in apoptosis is well characterized, little is known regarding its putative participation in other cell death pathways. We show here that activation of E2F1 upregulates the expression off our autophagy genes microtubule-associated protein-1 light chain-3 (LC3), autophagy-related gene-1 (ATG1), ATG5 and damage-regulated autophagy modulator (DRAM). E2F1-mediated induction of LC3, ATG1 and DRAM is direct and indeed, endogenous E2F1 can be found bound to regions encompassing the promoters of these genes. Regulation of ATG5 by E2F1 is indirect. Importantly, we demonstrate that E2F1 activation enhances autophagy and conversely, reducing endogenous E2F1 expression inhibits DNA damage-induced autophagy. These studies identify E2F1 as a transcriptional regulator of autophagy, and for the first time establish a role for E2F1 in DNA damage-induced autophagy.